[House Hearing, 105 Congress] [From the U.S. Government Publishing Office]DEPARTMENTS OF LABOR, HEALTH AND HUMAN SERVICES, EDUCATION, AND RELATED AGENCIES APPROPRIATIONS FOR 1998 ======================================================================== HEARINGS BEFORE A SUBCOMMITTEE OF THE COMMITTEE ON APPROPRIATIONS HOUSE OF REPRESENTATIVES ONE HUNDRED FIFTH CONGRESS FIRST SESSION ________ SUBCOMMITTEE ON THE DEPARTMENTS OF LABOR, HEALTH AND HUMAN SERVICES, EDUCATION, AND RELATED AGENCIES JOHN EDWARD PORTER, Illinois, Chairman C. W. BILL YOUNG, Florida DAVID R. OBEY, Wisconsin HENRY BONILLA, Texas LOUIS STOKES, Ohio ERNEST J. ISTOOK, Jr., Oklahoma STENY H. HOYER, Maryland DAN MILLER, Florida NANCY PELOSI, California JAY DICKEY, Arkansas NITA M. LOWEY, New York ROGER F. WICKER, Mississippi ROSA L. DeLAURO, Connecticut ANNE M. NORTHUP, Kentucky NOTE: Under Committee Rules, Mr. Livingston, as Chairman of the Full Committee, and Mr. Obey, as Ranking Minority Member of the Full Committee, are authorized to sit as Members of all Subcommittees. S. Anthony McCann, Robert L. Knisely, Susan E. Quantius, Michael K. Myers, and Francine Mack, Subcommittee Staff ________ PART 4A (Pages 1-1307) NATIONAL INSTITUTES OF HEALTH ________ U.S. GOVERNMENT PRINTING OFFICE 40-478 O WASHINGTON : 1997 ------------------------------------------------------------------------ For sale by the U.S. Government Printing Office Superintendent of Documents, Congressional Sales Office, Washington, DC 20402 COMMITTEE ON APPROPRIATIONS BOB LIVINGSTON, Louisiana, Chairman JOSEPH M. McDADE, Pennsylvania DAVID R. OBEY, Wisconsin C. W. BILL YOUNG, Florida SIDNEY R. YATES, Illinois RALPH REGULA, Ohio LOUIS STOKES, Ohio JERRY LEWIS, California JOHN P. MURTHA, Pennsylvania JOHN EDWARD PORTER, Illinois NORMAN D. DICKS, Washington HAROLD ROGERS, Kentucky MARTIN OLAV SABO, Minnesota JOE SKEEN, New Mexico JULIAN C. DIXON, California FRANK R. WOLF, Virginia VIC FAZIO, California TOM DeLAY, Texas W. G. (BILL) HEFNER, North Carolina JIM KOLBE, Arizona STENY H. HOYER, Maryland RON PACKARD, California ALAN B. MOLLOHAN, West Virginia SONNY CALLAHAN, Alabama MARCY KAPTUR, Ohio JAMES T. WALSH, New York DAVID E. SKAGGS, Colorado CHARLES H. TAYLOR, North Carolina NANCY PELOSI, California DAVID L. HOBSON, Ohio PETER J. VISCLOSKY, Indiana ERNEST J. ISTOOK, Jr., Oklahoma THOMAS M. FOGLIETTA, Pennsylvania HENRY BONILLA, Texas ESTEBAN EDWARD TORRES, California JOE KNOLLENBERG, Michigan NITA M. LOWEY, New York DAN MILLER, Florida JOSE E. SERRANO, New York JAY DICKEY, Arkansas ROSA L. DeLAURO, Connecticut JACK KINGSTON, Georgia JAMES P. MORAN, Virginia MIKE PARKER, Mississippi JOHN W. OLVER, Massachusetts RODNEY P. FRELINGHUYSEN, New Jersey ED PASTOR, Arizona ROGER F. WICKER, Mississippi CARRIE P. MEEK, Florida MICHAEL P. FORBES, New York DAVID E. PRICE, North Carolina GEORGE R. NETHERCUTT, Jr., Washington CHET EDWARDS, Texas MARK W. NEUMANN, Wisconsin RANDY ``DUKE'' CUNNINGHAM, California TODD TIAHRT, Kansas ZACH WAMP, Tennessee TOM LATHAM, Iowa ANNE M. NORTHUP, Kentucky ROBERT B. ADERHOLT, Alabama James W. Dyer, Clerk and Staff Director C O N T E N T S __________ NATIONAL INSTITUTES OF HEALTH VOLUME 4 Page National Institutes of Health Overview........................... 1 National Cancer Institute........................................ 199 National Eye Institute........................................... 419 National Center for Human Genome Research........................ 495 National Institute of Allergy and Infectious Diseases............ 583 National Institute of Environmental Health Sciences.............. 711 National Institute on Deafness and Other Communication Disorders. 805 National Heart, Lung, and Blood Institute........................ 865 National Institute on Drug Abuse................................. 983 National Institute on Alcohol Abuse and Alcoholism............... 1091 National Institute of Diabetes, Digestive and Kidney Diseases.... 1177 National Library of Medicine..................................... 1309 National Institute of Nursing Research........................... 1377 Fogarty International Center..................................... 1443 National Institute of Arthritis and Musculoskeletal and Skin Diseases....................................................... 1491 National Center for Research Resources........................... 1573 National Institute of Child Health and Human Development......... 1635 National Institute of Dental Research............................ 1737 National Institute of Mental Health.............................. 1809 National Institute on Aging...................................... 1915 National Institute of Neurological Disorders and Strokes......... 2001 National Institute of General Medical Sciences................... 2095 Office of AIDS Research.......................................... 2155 Office of the Director and National Institutes of Health Buildings and Facilities....................................... 2249 DEPARTMENTS OF LABOR, HEALTH AND HUMAN SERVICES, EDUCATION, AND RELATED AGENCIES APPROPRIATIONS FOR 1998 ---------- Wednesday, February 26, 1997. NATIONAL INSTITUTES OF HEALTH WITNESSES HAROLD VARMUS M.D., DIRECTOR, NATIONAL INSTITUTES OF HEALTH RUTH KIRSCHSTEIN M.D., DEPUTY DIRECTOR WENDY BALDWIN Ph.D., DEPUTY DIRECTOR FOR EXTRAMURAL RESEARCH MICHAEL GOTTESMAN M.D., DEPUTY DIRECTOR FOR INTRAMURAL RESEARCH ANTHONY ITTEILAG, DEPUTY DIRECTOR FOR MANAGEMENT FRANCINE LITTLE, DIRECTOR, OFFICE OF FINANCIAL MANAGEMENT DENNIS WILLIAMS, DEPUTY ASSISTANT SECRETARY, BUDGET, DEPARTMENT OF HEALTH AND HUMAN SERVICES Mr. Porter. The subcommittee will come to order. We're very pleased to welcome Dr. Harold Varmus and Dr. Kirschstein and the representatives of the National Institutes of Health this morning for another round of hearings on the NIH. We relish these opportunities to learn about the remarkable scientific advances that your fine institution makes possible. I have high hopes for NIH this year, because I see increasing recognition in many quarters of the importance of biomedical research, from the designation of the AIDS researcher, Dr. David Ho, as Time's man of the year, to news that the Washington Post will be sponsoring a public television series on biomedical research, to the repeated mention of research in the President's speeches. I'm also encouraged that the support of NIH seems to be broadening in the Congress, particularly in the Senate. I have to say, Dr. Varmus, I'm very disappointed, however, that the President's NIH budget does not match the rhetoric of his speeches. I've already expressed my dismay to Secretary Shalala about what I consider to be an inadequate NIH budget request, which is below the rate of biomedical inflation and therefore amounts to a cut in your budget. I sincerely hope that we can do much better. I would caution everyone in this room, however, that it will not be easy to craft a bill with the kinds of increases NIH deserves and that NIH has had for the last two years, given the competing demands of education and other priorities. We must have a 602(b) allocation with enough room to address all of these priorities so that we can produce a bill that can be passed by the House of Representatives and signed into law by the President. Mr. Obey, the ranking minority member on the panel, is at another hearing. I will call on him for opening remarks when he arrives here. And Dr. Varmus, we'd be pleased to hear from you. Introduction of Witnesses Dr. Varmus. Thank you, Mr. Porter. Before I begin, let me introduce the colleagues who are here at the table with me. Dr. Wendy Baldwin, the Deputy Director for Extramural Research; Mr. Tony Itteilag is the Deputy Director for Administration; Dr. Ruth Kirschstein, well known to you, is my Deputy Director; and Francine Little, who's the Director of the Office of Financial Management; and the indefatigable Mr. Dennis Williams represents the Department on these occasions. Mr. Porter, this is the fourth time I've had the pleasure and the honor to represent the NIH at appropriations hearings. I had not anticipated the press would be so interested in this anniversary. [Laughter.] Opening Statement Dr. Varmus. As you know, I very much enjoy on these occasions relating our recent accomplishments and telling you about promising paths our research may take in the immediate future. But before we get into these annualized accounts of our progress and descriptions of promise, we need to remind ourselves of a few stern realities: that the conquest of disease is a formidable challenge; that progress is best measured over many years or decades; that advances against disease require long-term investments in research and training and facilities; and that the benefit of most research is in fact unpredictable, demanding that we institute a broad range of research activities. culminations of research Now, over the course of the next ten days, you'll hear from the Institute directors who are arrayed behind me about two kinds of recent accomplishments, kinds that I will refer to as ``culminations'' and ``inspirations.'' Culminations are practical health benefits built upon many years of research in which NIH has had a very significant role. Let me mention just a few examples of such culminations. The further validation of an effective treatment for stroke with tissue plasminogen activator and of cryotherapy for the retinopathy of premature infants; the evidence that we can reduce disability among the elderly; the first measured real declines in cancer mortality for cancers of the lung, colon, gynecological cancers, prostate cancer and breast cancer; the efficacy of vaccines in nearly eliminating hemophilus influenza meningitis among our children, and more recently, an effective vaccine against rotavirus, which causes diarrhea worldwide; the application of the Visible Human project that you've heard about in previous years to the teaching of medicine and the practice of surgery; the use of antibiotic combinations to treat the common cause of gastric ulcers, H. pylori; and the increasing use of recombinant DNA products, growth factors, for the treatment of marrow suppression that occurs during cancer chemotherapy. inspirations of research Inspirations are more common. They are the important discoveries in basic science that may, we hope, be the foundations for future culminations. They are abundant. Let me give you just a few examples from three areas of recent research. In genetics, the area that has attracted a great deal of press attention, we've all read about the complete sequencing of the genomes, the entire collection of genes, from a number of organisms, yeast and several bacteria. Other genomes have been fully mapped, and some partially mapped, including the human, and all this information has been made miraculously accessible to all investigators and to the public through the GeneBank at the National Library of Medicine. Many other disease genes have been isolated--disease genes for glaucoma, polycystic kidney disease, for retinitis pigmentosa, for a number of forms of diabetes that are inherited, for basal cell carcinoma in hereditary form, for hemochromatosis. Other disease genes have been identified but not yet isolated in pure form. Those include, most importantly in the past year, the gene for a familial form of Parkinson's disease and one for a familial form of prostate cancer. Advances in neuroscience continue at a remarkable pace. Imaging technologies are showing us the physiological basis of many important neurological phenomenon, including aspects of behavior, pain, emotion and drug abuse. Animal models have been increasingly useful in the study of neurological disorders, clarifying the causes of disease, for example, Alzheimer's disease, Huntington's disease and spinal cerebellar atrophy. And the animal models are also stimulating new kinds of treatment, for example, the use of growth factors in treatment of spinal cord injury. Finally, in the area of cell biology, the understanding of blood vessel growth is signalling new strategies for improving blood supply to the heart and the brain; and our understanding of how blood clotting occurs is even giving rise to the new strategies for treatment of cancers. New information about how cells talk to each other is informing research in a wide variety of categories, too numerous to mention. culminations in hiv research I'd like to give you some sense of how these inspirations and culminations actually work in the pace of research, by telling you about a couple of events that have occurred in the past year in the area of our research on HIV and AIDS. First, a culmination. We've referred already to the public attention that's been given to recent progress in the treatment of HIV through your mention of the man of the year award by Time Magazine. The demonstrated efficacy of protease inhibitors has been seen as a bombshell by the public, but from our perspective, this is a culmination that depends upon many years of fundamental work. Our work on retroviruses extends back to the early days of this century. Work on the enzymes that are programmed by retroviruses extends back to the 1970s. Identification of one of those enzymes, the protease; and the determination of how it works biochemically; its three dimensional structure; studies of other proteases made by cells; and the development of inhibitors that are used in the treatment of hypertension. All this was followed by drug development, largely by the pharmaceutical industry, whose strengths also depend upon NIH-sponsored training and research. inspiration in hiv research Inspiration in HIV research has come from the long-awaited discovery of a class of cell proteins that is required to allow HIV to enter cells, proteins known as the co-receptors. These co-receptors, which are essential for establishing HIV infection, turn out to be proteins we already knew, proteins that recognize molecules called chemokines, proteins that are important in inflammation. We already know, even in the span of a few months, that chemokines can block infection with HIV, and that some people lack, medically lack, the co-receptors and can't be infected, even though they're otherwise healthy. What this means is that there is inspiration here for new strategies to prevent infection through vaccines and to control infection when it occurs. oversight and administrative activities Well, so much for science. Let me say a few words about oversight and administrative activities. Last year in our hearings, we focused on problems that beset clinical research and the need to build a new clinical research center at the NIH and to reorganize the existing clinical center. I'm happy to report that due to the generosity of this committee and your Senate counterparts, funding for the clinical research center has begun. The design is underway. We have carried out many of the improvements we talked about last year in the functioning of the clinical center. A board of governors has been established. We've been devising new ways to recruit clinical investigators. We've expanded our training in clinical research. We've just instituted a new program that brings medical students to the NIH campus for training in clinical research--a specific response to a recommendation made by my panel on clinical research that's staffed by mostly extramural investigators. We have responded to a variety of other administrative directives and concerns that we discussed last year. We have held our research management and support dollars steady, and we have initiated a more extensive study of all our administrative activities as a result of consultations with you and your colleagues in recent months. We have made increased use of our competitive service centers at NIH to allow institutes to carry out administrative tasks conjointly and to thereby effect some reductions in our FTEs. We have developed a search for a chief information officer and mounted a number of other strategies to improve our information systems, which could represent large cost savings over the next several years. I have instituted a number of new reviews in conformity with earlier patterns of behavior--reviews of institute directors, of several intramural programs, and of a variety of research areas, including AIDS, clinical research, and gene therapy. the president's budget proposal Finally, a few comments about the budget. As you know, the President is requesting $13.078 billion for the NIH. This is $337 million more than was in the 1997 budget, a 2.6 percent increase. That request includes $90 million for the Mark O. Hatfield Clinical Research Center. That $90 million is not, however, part of the increase, because it equals the amount that was in the 1997 appropriation. And we should also say that we expect to ask for $90 million in 1999, and another $40 million in the year 2000 to finish the construction project. Most of the increased monies will be devoted to research project grants, our traditional strength and pride. There is a 3.9 percent increase in that category. We recognize the constraints upon the Federal budget that restrict our ability to pursue every inspiration. So we believe that the increase requested by the President--built on the very strong appropriations we've received due to the generosity of the Congress and the Administration the last two years--will allow us to maintain our momentum and achieve the largest number of grants in the history of NIH, nearly 27,000 grants total. We can do this because the rates of inflation in biomedical research have been lower in the last couple of years, because we are concentrating the increased dollars on our research project grant pool, and because we plan to limit increases in awards to 2 percent per year. In summary, the Institute and center directors and I are proud of what has been done with the generous appropriations we've received in the past. We are optimistic about our future prospects to use science for the advances in human health and relief of human suffering. They and I look forward to answering any questions you may have over the next ten days. [The prepared statement follows:] [Pages 6 - 10--The official Committee record contains additional material here.] budget estimates Mr. Porter. Dr. Varmus, thank you for your opening statement. Let me spend just a minute looking into the budget figures. Because NIH two years ago was increased by 5.7 percent, last year by 6.9 percent. At the Democratic convention, the President had Christopher Reeve talk to the American people about the importance of biomedical research and has mentioned it very prominently, both in his acceptance speech and in his State of the Union speech this year. And yet, the budgetary increase that the President suggests is 2.6 percent. I believe that is below the rate of biomedical inflation. I would first like to ask you, because there are really three filters here, one is your own in preparing your budget with your Institute directors, the second is the Department's and Secretary Shalala's, and the third of OMB and the White House. I would like to ask you first what request you made of Secretary Shalala in the beginning of this process. What was the budget that you developed within NIH? Dr. Varmus. Mr. Porter, we had a professional judgment budget that was in the range of $13.88 billion. And what we were allowed by the Department was $12.865 billion. The OMB returned to---- Mr. Porter. A billion dollars less than what you asked for or would suggest in your professional judgment budget? Dr. Varmus. We didn't submit a direct request at that stage. The numbers returned to us by OMB were $12.667 billion. Mr. Porter. So OMB initially suggested a cut from last year's appropriation? Dr. Varmus. That's correct. Mr. Porter. A cut in nominal terms as well as real terms? Dr. Varmus. Correct. Mr. Porter. And what happened then? Dr. Varmus. There was a series of discussions involving OMB and the White House and the Department and NIH. And the final agreement was the budget request that you've heard, $13.078 billion. [Clerk's Note.--The following was submitted by Dr. Varmus to clarify his remarks:] The NIH budget request to the Department for 1998 was for $12.865 billion, a 3.9 percent increase over the 1997 President's budget of $12.377 billion. Prior to final 1997 Congressional appropriations action, the Department submitted a 1998 budget request to OMB for NIH of $12.667 billion, representing a 2.3 percent increase over the 1997 President's budget. The Congress then appropriated $12.741 billion for NIH for 1997, which established a new base for discussions of the 1998 proposals. Finally, the 1998 President's budget request for NIH of $13.078 billion was developed, a 2.6 percent increase over the 1997 appropriations level. professional judgment budget Mr. Porter. I realize that you and NIH have to be good soldiers and all this, but our job is to determine priorities for the country and where the money can best be spent. And if your professional judgment budget is $13.88 billion, that means you believe that you can wisely spend that amount of money in the next fiscal year. And I would like for you to give us some idea of what has to be foregone between the $13.88 billion that you've suggested in your professional judgment budget, and the $13.1 that is suggested by OMB and the President. Dr. Varmus. Let me first point out, Mr. Porter, that we make that professional judgment in an intellectual framework in which we don't worry about the other demands on the budget process. Mr. Porter. Yes. Dr. Varmus. We recognize that's a number that represents a starting point in a dialogue that will lead to some kind of compromise with the realities of balancing the budget and meeting other important demands upon the economy and upon the budget. Mr. Porter. Absolutely. Dr. Varmus. It's very difficult to say that there is one thing we cannot do. Because obviously we're going to continue to work on all fronts with the budget that's below our professional judgment. But what will happen is that some projects will not get funded. And many things that could go quickly will go less quickly. In some areas, it's possible to say that certain fairly predictable milestones will be met less quickly. For example, in a process like the sequencing of the human genome, where we can say that given a certain amount of money and equipment and personnel, we can do the sequencing so much more quickly, we can actually make some very clear predictions about how many fewer nucleotide sequences will be determined. In other areas of less predictable, discovery type science, we simply have to say that we will fund fewer grants. establishing priorities During the process of putting together the 1998 budget, I met individually with every institute director and asked them to tell me about areas of priority that they would like to receive allocations for in the context of the NIH areas of emphasis. These are, as you recall, broad areas of research promise that we put together in a way that emphasizes the interactions among the institutes, the broad themes of biological research that we think are useful in the advancement of health. And I received, during the course of the several weeks in which we deliberated, long lists of research projects, research areas that institute directors felt were particularly promising, and warranted my assigning to them amounts of money that might range from an additional $1 million to an additional $10 million. I put together a series of budget possibilities based on various levels of increment in our budget that might be anticipated. And as I reviewed that list, I can see that the institute directors and I worked out a list of priorities that now reflects the conviction we have that progress could be made with varying limits on our budget. So I could give you some sense in detail, if you like, but I think it's better to say that some of these initiatives that we would like to undertake will not be undertaken, or will be undertaken with fewer dollars, instead of putting $2 million into a project to work on asthma in the Heart Institute, maybe we'll put in $1 million. success rates Mr. Porter. Let me raise this in a different way. Isn't it true that in most institutes, if not all, the percentage of competing grants, that is science that has been peer reviewed and thought to be very promising, that we can fund, even with the increases we've had recently, is going down rather than up? Dr. Varmus. The success rate actually varies among the institutes. But of course, in the last two years, because we've had good appropriations from the Congress, our success rate is currently, we estimate, about 28 percent for 1997. And we expect it will be fairly similar in 1998. Mr. Porter. So we're funding three out of every ten? Dr. Varmus. A little less than that. It's important to point out, Mr. Porter, that that number is an aggregate number and it is slightly misleading in the sense that there are, first of all, lower rates for new grants as opposed to renewal grants, lower rates for new investigators. We find it's very important to bring new investigators who are just out of training into the process early, otherwise they become discouraged and leave science. It may be lower in some of the most competitive areas, in areas where the demand upon NIH monies is particularly tight. So it's an aggregate number, it's somewhat misleading about the---- Mr. Porter. Well, we're very concerned that we maintain the momentum that NIH has had and that we don't lose a young, promising scientist because they can't get their promising projects funded and become discouraged. And our job, as you know, is to choose priorities. We may end up seeing it a little differently than the President. I sincerely hope that we do, because I believe that this is among the best money that we ever spend, that it pays for itself many times over, that there is so much promising science there that to delay and put NIH on hold is unwise policy. And I believe that this Congress can do that, to put NIH at a high priority within the context of bringing the budget into balance. That, after all, is our job. cloning Let me now raise another question that has come up in the news over the weekend, that I think shocked many in the scientific community, because they said it couldn't be done. But we've read of experiments in Great Britain by Dr. Wilmot where they have used adult DNA to clone a sheep. And I would like to ask you if you will tell us whether this is valid science, whether it would lead to cloning of adult human beings, what the implications are, both positive and negative, for science itself, and what the ethical implications are for all of society. Dr. Varmus. How much time do I have, Mr. Porter? [Laughter.] Mr. Porter. As much as you'd like. Dr. Varmus. Let me begin by telling you something about these experiments and perhaps describing them slightly more precisely and give you some idea of the intellectual context in which they arise. These experiments have strong antecedents in research that dates back quite a long time, to work by Gurdon and his colleagues in England who showed some years ago that it was possible to take the nucleus of a frog skin cell that had been grown in culture and to transfer that into the egg of a frog that had been relieved of its own nucleus. By appropriate stimulation, it was possible to allow that egg, now supplied with the nucleus from the skin cell, to grow to the tadpole stage. Never to the full adult, but nevertheless, this was the first indication that one could do something that has a deep scientific meaning that I will come back to, and that is, you can take a cell which has undergone the process of differentiation--the process by which certain genes are turned off and others are turned on--to make a cell with a defined function and demonstrate that the nucleus of that cell--the nucleus being the compartment of the cell surrounded by a membrane, containing all the genes of the organism--could undergo some kind of still not fully understood process that would allow the cell to be able to generate all the components of a tadpole. an earlier cloning experiment The report you refer to is not the first report that's been published from the Roslyn Institute in Edinburgh. About a year ago, the same group of investigators, headed by Ian Wilmot, published a paper in Nature in which they had done the following kind of experiment with sheep. That experiment had followed the clue from frogs, starting with an oocyte that had been relieved of its own nucleus and adding to that enucleated egg the genetic material from a very, very young sheep embryo, this actually was an embryo at the 8 to 16 cell stage. And the DNA, or the genes of the organism, were introduced by fusing an entire cell, including the nucleus after growth of the embryo cells in culture into the enucleated egg. At this very early stage in embryogenesis, the cells are still believed to have all the potential for making all of the tissues of the organism. So it wasn't as electrifying as the current experiment when it turned out that by fusing cultured cells to the enucleated egg and returning the reconstituted egg with its nucleus from a cultured cell to a potential surrogate mother, that sheep were born. As I said, this work was published about a year ago. The investigators in Edinburgh then took the next step of using other sources of genetic material--namely whole cells at other stages of development--and fusing them to the enucleated egg. Those additional sources of cells included older embryos, embryos that had been allowed to proceed to a much more complicated multi-cell stage; cells from a fetus representing a partly-developed sheep; and most dramatically, a cell that had been taken from the udder, from the mammary gland, of a six year old female sheep. In each case, the cells were manipulated in an interesting way. After they had been grown in culture, the cells were returned to a resting state by slowly reducing the nutrients supplied to the cells. Normally when cells are grown in a petri dish in culture, they are grown in serum obtained from animal sources. By reducing the level of serum, it was possible to make the cells quiescent, so they weren't undergoing growth. That appears to be quite important in the success of these experiments. In any event, with all three new sources of genetic material--that is, older embryos, fetal cells, or, in one case, mammary cells--a reconstituted egg, now carrying the nucleus from each of those three cell types, was returned to a prepared uterus and the investigators waited for a sheep to develop. In all three cases, they did. Only one succeeded out of 277 reconstituted eggs, in the case of the cells derived from the adult female sheep. It was inefficient, nevertheless, it was successful. Now, as you know, public attention has been focused initially on the most sensational aspects of this. And that's only natural. Because it is quite clear that this experiment opens the possibility of being able to do the same experiment with virtually any other mammal. And naturally, given the imaginations and novelistic inclinations of all of us, the idea of generating human clones of mature individuals has been much discussed. scientific significance of cloning In my view, this makes interesting movies, but poor science and poor ethics. Let me speak a little bit to the scientific importance of the experiments that were described, and then come back to some of the ethical issues. The first level of significance of the experiments that are described is very much in the tradition of agricultural husbandry. Both in the area of agriculture and in animal husbandry, there is a strong tradition of trying to recapitulate strains that are particularly productive for food production. So whether it's the selfing of corn, or the generation of in-bred strains of animals, or the twinning of cattle, there is tremendous interest in trying to enlarge a population that appears to be very productive. And in that sense, there are practical applications of what we've read about, with respect to agriculture. medical uses of cloning The second application has to do with the medical research uses of animals. There are a number of possible experimental routes that are opened by the experiments we've read about. In one case, the interest would be in the production of medically useful products. Proteins that are produced in animals, for example, in milk, could be made in large amounts in a more convenient way that is currently possible through recombinant DNA technology. Another product that might be possible is to make organs for transplantation that have been made more like human organs because they are programmed to make antigenic proteins on their surface that would lead to less problem with rejection in transplantation procedures. Equally important is the possibility of using animal models other than the mouse or the rat for certain disease states. I'm sure you're aware that in recent years scientists have made increasing use of our ability to manipulate the genetic constitution of mice. We can add genes to the mouse, we can change the genes that exist, and we can make use of our increasing knowledge of disease genes of humans to attempt to generate models for disease that can be used for developing novel therapies that may be applicable to man. In not all cases, however, have those disease models reproduced faithfully and instructively the kinds of pathology that are seen in human beings. One good example of that is in the case of cystic fibrosis, where we know the human gene and the mutations that exist in the gene have been identified. We can make the same mutations in the mouse, but the disease is different. Using an animal like the sheep might open the way to make better disease models that could be instruments for developing and testing more useful therapies for some of these disorders. how genes turn on and off The third area of importance is one that has been neglected for the most part in discussions today, but to my mind is the most important. And that is that these experiments open the door to a much deeper understanding of how genes are turned off and turned on. I remind you that we as human beings have roughly 80,000 genes, that all of those genes are useful in some of our many different kinds of cells. We have perhaps 200 different types of cells in our bodies. Each expresses a different subset of those 80,000 genes. During the course of our development to produce an organism that has a liver and skin and brain and many other organs, our bodies are programmed to turn such genes on and off. And it's generally been considered difficult, if not impossible, to redirect a cell of one type to behave like a cell of another type. In the sheep experiments we've been discussing, a cell derived from an adult mammary gland has been reprogrammed to become a fully potent cell to make every component of a sheep. That's a remarkable achievement. We know very little about what that process entails, save for the fact that it seems to be fostered by moving a growing cell into a quiescent state, as I mentioned before, by reducing the serum in the medium used for growth of the cell. There are many applications that could be imagined for greater knowledge of how genes are turned off and on. Let me begin with the simplest. We already use such a strategy for the treatment of sickle cell disease. In sickle cell disease, one of the globin genes is impaired. We know that we can overcome that impairment by expressing another form of globin gene that's normally expressed only in the fetus. Hydroxyusea is a drug therapy that's currently in use and shown to be quite effective; it turns on the fetal globin gene in the adult and reduces the morbidity of sickle cell disease by about 50 percent. We still have an imperfect notion of how to turn that gene back on. So anything further to help in our ability to control that process would be very useful. use in bone marrow transplants Let me give you some other examples. We know that when persons undergo chemotherapy for cancer that their bone marrows are frequently severely affected, and it's been increasingly common to treat such individuals with bone marrow transplants. Those transplants are difficult because of rejection of the donated marrow, because of protein incompatibility between the donor and the recipient. So one long-term goal has been to use, in such transplantation experiments, marrow that's compatible with the recipient. Sometimes that's done by using the marrow from the individual who's undergoing treatment. But that's obviously less than ideal, because those cells may include cancer cells. The prospect of being able to take the nucleus from a skin cell and put it into some other, cell, to produce bone marrow cells in culture, and return those to cancer patients is made real by the experiments with the sheep--far off, but nevertheless possible. One could imagine, and if you'd like an inversion of that experiment, where you consider somebody who's been incapacitated by massive burns and needs skin transplantations, one can imagine taking the nucleus from a liver cell, for example, putting it into another enucleated cell as a recipient, and making skin cells that could then be used for a non-rejectable transplant to the burned individual. One could imagine similar kinds of experiments in neuro- degenerative diseases. There are instruments for remodeling cells to behave as mature nerve cells with the antigenic properties, of the recipient. So there are some remarkable possibilities here that definitely require exploration and will be fired by the sheep experiments. ethical implications Let me say a few words about some of the ethical issues. We have been aware of the possibility of doing such experiments for some time. In 1994, I convened a panel headed by Dr. Steven Muller to look at the ethical issues that surround many forms of human embryo research, including this form. And in that year, that panel brought back to me recommendations about which kinds of experiments involving the human embryo would be suitable for Federal funding, unsuitable for Federal funding, or fall in between. And with respect to carrying out experiments of the sort described for the sheep in the human being, that is, human cloning, the committee designated such experiments as not suitable for Federal support, for reasons that I think perhaps are worth reading very briefly. The panel said, ``the notion of cloning an existing human being or of making carbon copies of an existing embryo, appears repugnant to members of the public. Many members of the panel share this view, and see no justification for Federal funding of research involving nuclei transplantation for this purpose.'' I agree with that point of view. Frankly, as an experimental strategy, it doesn't offer anything. We have a much better experiment carried out in nature. We have identical twins who are sometimes reared together, sometimes reared apart. That to my mind, if one wants to look at the effects of environment on human development, using genetically identical subjects, that experiment has already been done. It occurs done very commonly in human populations. Secondly, our sense of ourselves as human beings is very closely linked to our diversity. And the notion of carrying out cloning of the human population, to my mind, is not consistent with the traditional ideas of human individuality and diversity. This does not mean that cloning strategies should not be used in other animals for purposes of agriculture or for purposes of medical research. But in the case of human beings, the NIH panel rejected it, as it happens, these experiments would also be forbidden by the amendment that's attached to our appropriation bill, the so-called Dickey-Wicker amendment. That's a long speech, Mr. Porter. I'd be happy to answer any more questions. Mr. Porter. Thank you, Dr. Varmus. I might say to my colleagues that I'm not going to charge myself with that question or answer, because all of us wanted to ask the question. And I also would say, Dr. Varmus, that's probably the longest answer ever not interrupted by a member of Congress. [Laughter.] Dr. Varmus. I appreciate your indulgence. Mr. Porter. Mrs. Lowey. legislating cloning Mrs. Lowey. Thank you very much, Mr. Chairman. And again, Dr. Varmus, it truly is an honor to have you here before us. We feel honored to be on this committee to somehow have some role in this great Nation's investment in biomedical research. So I want to thank you personally for your leadership. Just briefly, and I guess this will be counted against my time, or maybe not, I just wanted to have a few comments about your response. Because thus far, the sheep cloning has raised a great deal of justifiable anxiety across the Nation. In my own State of New York, a bill has already been introduced in the State senate to ban scientists from cloning humans. And we are clearly at the dawn of a new era in the history of mankind. Fifty-two years ago, the world changed forever at Alamagordo, New Mexico, when we exploded the first atomic bomb. This past week, as we know, and I appreciate your asking this question, the world has changed again. Cloning raises the most profound questions about man's humanity, about God, about religion, about life and death. These are sensitive issues, and they must be dealt with seriously and thoughtfully. And I want to say, I applaud the President's decision this week to appoint a high level panel to examine the issue. And I look forward to reading their report. As you stated, we have to ensure that science does not outrace our values. But we must also recognize that once the genie is out of the bottle, it cannot easily be put back in. And history demonstrates that if the technology exists, it will be applied. So the question before us then is whether or not we will be able to harness this scientific advance, this miracle, in fact, to work for us and improve the human condition. Will advances in cloning be able to cure diseases like breast cancer and Alzheimer's? You referred to the great possibilities of medical research. Can we utilize this technology to provide hope to tens of millions of people with genetic disorders across the Nation and around the world? Perhaps so. And I certainly hope so. And while I know that cloning technology is fraught with peril, it also contains real opportunity and promise. The future of cloning can look like our worst nightmare, like all this Huxley's Brave New World or the Island of Dr. Moreau, a world where freakish experiments know no bounds. Or cloning technology can cure diseases and improve our lives. And it's really up to all of us to decide. And as members of the Congressional panel that funds biomedical research, we have a special responsibility to engage this issue in all its complexity. And I certainly look forward to the discussion. There is clearly a need for regulation. But regulation, I hope, that is consistent both with our human values and our support of biomedical advances. I was going to ask you to discuss it, but I think perhaps we've taken a good deal of time, and I hope that in a rational, reasonable way, we can engage in this discussion if you have additional comments. Dr. Varmus. I'd like to make one comment, Mrs. Lowey, because your point reminds me of something that I was hoping to say at some point, which is that I'm concerned about the rush to legislation in this arena. We have a new finding. It needs to be absorbed and discussed. I, too, applaud the President's referral of this matter to his National Bioethics Advisory Commission, which as you know was established about a year ago to consider questions of just this kind. The Commission is very well suited, in the light of the personnel who have been appointed to that commission, to discuss these issues and to make some recommendations. I am worried, as my comments reflected, about the possibility that in rejecting the one aspect of these experiments that all of us find repugnant--that is, the idea of cloning adult human beings--that we end up with legislation, be it state or Federal, that restricts the experimental possibilities that will be beneficial to all. Mrs. Lowey. I thank you. I assume I can go on. I'm not sure if I was charged for that comment. But I have a little time left. Mr. Porter. Yes, you were charged. [Laughter.] iom recommendation on clinical research Mrs. Lowey. Then I'll ask one of my questions. Thank you. Dr. Varmus, this subcommittee supports the construction, as you know, of a new clinical research center on the NIH campus which you are undertaking. And I'm pleased that the new center will surely strengthen the clinical research conducted on the NIH campus. However, we continue to hear from clinical researchers at academic medical centers across the country that they face major obstacles in obtaining Federal funding and retaining talented researchers. Last year, this committee did urge NIH to respond to the recommendations of the 1994 Institute of Medicine report on clinical research as well as to accelerate the work of the NIH panel formed to deal with the problems faced by clinical researchers. As you know, last Congress I introduced legislation with three colleagues on this subcommittee to implement the IOM recommendation. This legislation was included in the Senate NIH authorization bill. However, NIH has the authority to implement most of the recommendations without legislation. And I need your help in responding to the frustrations, frankly, of the extramural clinical research community. Can you provide to this subcommittee, by perhaps the end of March, what specific extramural initiatives NIH will undertake in the next six months to reinvigorate clinical research in this country? We'd be most appreciative. [The information follows:] The National Cancer Institute (NCI) and the Department of Defense (DoD) signed an agreement to allow DoD medical beneficiaries to participate in various NCI sponsored clinical trials of new cancer treatments. Participants may receive treatment either through the medical treatment facilities that have been approved to conduct NCI trials or through medical care arrangements reimbursed through TRICARE/CHAMPUS, the DoD's health program. This partnership allows DoD beneficiaries throughout the country to receive state-of-the-art care through NCI sponsored clinical activities by participating in emerging new approaches that have significant promise for the successful treatment of cancers. NCI will continue to provide a user-friendly, active information system through an expansion of the Physician Data Query. This allows physicians quick access to information about open available protocols at the nearest or most appropriate institution or to physician participating in the suitable protocols. In the training area, the NCI has developed a new program, the Career Transition Award, to provide support to outstanding newly trained basic or clinical investigators to develop their independent research skills through a two phase program; an initial period involving an intramural appointment at the NIH and a final period of support at an extramural institution. The award is intended to facilitate the establishment of a record of independent research by the clinical investigator in order to sustain or promote a successful research career. It is anticipated that this new program will be announced in the NIH GUIDE in the next few months. In addition, the NCI has recently implemented an Accelerated Executive Review (AER) that targets new competing research grant applications that are within 4 percentile points of the payline for basic research or 10 percentile points for ``patient oriented research''. This AER is designed to encourage clinical projects by allowing a broader range of eligible applications, 10 percentile beyond the payline for funding. In FY 96, the NCI Executive Committee reviewed 51 applications under the AER (31 basic research and 20 patient oriented research). The committee recommended 26 of these for awards, for a total cost of $6.7 million. Nine of these were for ``patient oriented research''. The National Heart, Lung and Blood Institute, in collaboration with the Health Care Financing Administration, is sponsoring a randomized trial, Lung Volume Reduction Clinical Trial, to determine the benefits and risks of this operation to patients with end-stage emphysema. Currently, hundreds of patients are being subjected to this operation despite the fact that its effectiveness had never been established. Furthermore, there are no data on long-term outcome, and no evidence is available to indicate which patients might benefit from the operation. This trial will provide patients with the information they need to make informed, intelligent decisions about their health care. Within the next six months, the National Institute of Allergy and Infectious Diseases (NIAID) will fund ten new clinical research initiatives in FY 1997 and announce an intent to fund 12 additional ones that will be funded in FY 98. These initiatives span the range of clinical research activities from small pilot studies to large clinical studies and phase II and III clinical trials. New career development activities for clinical investigators are included in the goals of the initiatives on emerging and re-emerging diseases. The clinical research needs and opportunities addressed by these 22 new clinical research initiatives include AIDS, vaccine development and testing, chronic fatigue syndrome, immunological effects of aging, women's health issues, sexually transmitted diseases in adolescents, transplantation, and emerging and re-emerging infectious diseases, including malaria. A list of the titles of these initiatives is attached. The NIAID is also conducting a review of its infectious diseases research training programs to ensure that these programs are producing investigators with the capacity to carry out independent research in clinical investigation. Beyond its specific initiatives and activities, the NIAID is also applying newly developed, streamlined grants management procedures to expedite the evaluation and funding of clinical research grant applications. These streamlined procedures consist of selective payment of applications that are identified as having important clinical research goals; electronic peer review and early Council review to expedite the award of grants to clinical investigators. In FY 97, The National Center for Research Resources (NCRR) will support the network of GCRC and other related activities with a total of $157 million. The NCRR funded one new GCRC in FY 96 and depending on available funds, may consider funding an additional new center in FY 97. The FY 96 award was made to Howard University which is particularly significant in that it related to research on diseases that affect African Americans and for Historically Black Colleges and Universities. In addition, NCRR funded a new satellite site at Children's Hospital, Seattle, WA. The NIH loan repayment program is currently limited to scientists in the intramural program and is being implemented. The NIH may seek a legislative change to broaden the eligibility for the loan repayment program to include clinical researchers at academic health centers throughout the country, a situation under legislative restrictions now. Mrs. Lowey. I know that NIH is currently working with certain health plans such as the military's CHAMPUS plans, to arrange for their subscribers to participate in NIH research protocols. This is an important development. I know you share that opinion. Could you explain to us the prospects for similar arrangements with private insurers and more broadly speaking, can NIH help to encourage managed care companies to support academic research? Dr. Varmus. Mrs. Lowey, you've given me a large task. I'd be happy to provide more written details. We're going to be out of time if I don't do that. Mrs. Lowey. Right. [The information follows:] Subscribers Participation in NIH Protocols I and my staff recognize the importance of new partnerships to enhance clinical research in the coming century. These partnerships must include the NIH, academic health centers (AHCs), foundations, the pharmaceutical industry, managed care organizations (MCOs) and private insurers. I believe NIH can help to encourage MCOs to support academic research in the context of such partnerships. Heartened by NCI's successes in working with the Department of Defense/CHAMPUS and the Veteran's Administration to obtain coverage for the routine clinical care component of clinical trials, NIH's Institutes and Centers, including the Clinical Center, will work with MCOs to ensure the nation's clinical research endeavors. In November 1996, some Institute Directors and I met with representatives of managed care organizations, including Aetna/ US Healthcare, Group Health Cooperative of Puget Sound, Harvard Pilgrim Health Plan, HealthPartners, Kaiser Permanente, Prudential and the United Healthcare Corporation. Many of these organizations already maintain extensive research portfolios and receive NIH funding for some of their research projects. We agreed to work together to address our mutual interests in clinical research and identified significant research areas where NIH and others can cooperate. This dialogue will be enhanced by a recently-developed NIH Fellowship in Managed Care. We have identified a senior MCO manager of research to serve as liaison to enhance communication among NIH, AHCs and MCOs. NIH's goals are to develop proposals to advance clinical research through greater involvement of health plans and their patients in peer-reviewed research studies; to determine what is known about participation of MCO beneficiaries in NIH-approved protocols; to assess health plan policies regarding enrollment in NIH studies; and to explore models of health plan collaboration with AHCs. Other NIH initiatives include the convening of an NIH-wide Managed Care Workgroup made up of representatives from each Institute and Center to serve as a central source for discussing and coordinating approaches for collaborating with the managed care community. The Workgroup will share strategies advanced by individual Institutes and Centers, develop proposals for grass-roots experiments, design innovative approaches for linking AHCs with managed care partnerships, enhance NIH research information dissemination, and communicate widely about what has been learned in the process. The effects of changes in the financing and delivery of health care on the research infrastructure, the nation's capacity to sustain medical progress and the quality of health care are issues of particular concern to NIH. I remain committed to our traditional venues of support for clinical research, but at the same time I am ready to explore new opportunities for collaborative research partnerships. As managed care organizations become responsible for the health care of greater numbers of Americans, their support of patient- oriented studies will be increasingly critical to the NIH as it seeks to develop new mechanisms to enhance and stimulate clinical research. progress in support for clinical research Dr. Varmus. But as you know, first of all, we're working very closely with the clinical research panel that I established about a year and a half ago. Many of their recommendations are already being implemented. And I think you'll find that clinical researchers around the country are appreciative of the changes we've made. In some cases, we're limited by authorization, for example, we're attempting to develop a loan repayment program for clinical investigators, but we simply don't have the authorization to institute it. But we do have such a program on the NIH campus. We have had very productive conversations with representatives of the managed care industry to explore our common interest in research, for example, in clinical trials and epidemiology, in health services research, we are dealing with some of the most enlightened members of what is obviously a very heterogeneous group of organizations, but they represent many millions of patients. We are finding common ground, and I am hopeful we'll be able to work very productively with them. But I think in view of the time constraints, I'd rather give you a more detailed account of the very considerable progress I think we've made in the last year in the clinical research arena for your perusal. Mrs. Lowey. Given the time, I will close. And I just want to thank you again. We're aware of the progress, but I'm sure you're aware of the frustrations as well. So I look forward to that response and I thank you again. Mr. Porter. Thank you, Mrs. Lowey. Mr. Wicker. impact of 7.5 percent increase Mr. Wicker. Thank you, Mr. Chairman. Dr. Varmus, we're always glad to have you before our subcommittee. Let me ask you about money. I understand you've commented about the funding level briefly in your opening statement. But particularly, we have here that Senator Specter has suggested a 7.5 percent increase in your budget, as opposed to a rather modest 2.6 percent Administration request. I wonder if you could comment on the difference in programs that impact the health of Americans between those two levels of funding. And also, in the out years, are you making plans at NIH for the very modest level of growth proposed by the Administration? Dr. Varmus. Mr. Wicker, as the numbers you've given me to work with in answering this question indicate, we would have over $500 million more under the proposal made by Senator Specter compared to the President's request. And obviously, with that money, we could support a large number of additional grants that otherwise might not be funded because of the constraints of the budget that's being proposed. Mr. Wicker. What would be your priorities there? Dr. Varmus. Well, as I mentioned earlier, we've established, during a reiterative process during the past year, a long list of new efforts we'd like to undertake. And I have tried to look at those initiatives in the context of an inflationary increase, an increase of perhaps 5 percent, 7 percent, and 9 percent. And there are some initiatives we wouldn't undertake and there are some we would undertake with less money if we were to receive a smaller budget. So it's not as though we would not do genetics research with one budget but would with another. But in general, things would go more slowly. And fewer investigators would be working on the problem, or certain areas, certain narrowly defined initiatives might not be undertaken with the smaller budget appropriation. So it's difficult to say that there is one thing that we will not be working on, because we will continue to work, albeit less rapidly than we might be able to with a larger budget, on a broad range of research activities. As far as the out-years are concerned, I have developed a mind set over the last few years of concentrating on the year at hand. So right now, I'm concentrating on 1998. The President and OMB, in making the out-year projections for NIH, have proposed very modest increases. But those modest increases are indications that we are a Presidential priority, and we take that as a sign that when the budget is formulated for 1999, that there will be a solid budget for the NIH. We are planning around 1998 and not making specific plans based on the budget projections for 1999 and 2000. consensus development panels Mr. Wicker. Let me ask you, Dr. Varmus, what is a consensus development panel? Dr. Varmus. We have a tradition dating back over 20 years of bringing together, and we have done so over 100 times, groups of speakers who are informed about a certain medical topic, for example, a new treatment for a disease, to present their findings to a panel of informed but impartial individuals who then, after listening to the speakers, puts together a statement that hopefully represents consensus in the scientific community about the state of the art in a certain area. Let me give you one particularly useful example. About two years ago, we had a conference on ulcers and an organism known as Helicobactor pylori. For many years, it was thought that stress and gastric acidity were the major causes of gastric and duodenal ulcer. It wasn't appreciated until more recently that there was a bacterial cause. And the consensus conference allowed a number of investigators to present the findings and to have a public airing of this new view about the cause and treatment of gastric and duodenal ulcer. The effect of the consensus was to diffuse through the medical community these new ideas, to establish their credibility, and make anti- bacterials more widely used. Mr. Wicker. The witnesses are people outside. Dr. Varmus. They are outside, they are experts brought to the NIH to present their findings to a panel, which is also from the outside. But the panelists have no declared views on this topic. They have not published opinions about that area of research. They listen to the experts then come up with a statement. Mr. Wicker. Let me just ask you, because we are short on time, I understand there was recently such a consensus development panel focused in part on needle exchange programs. Dr. Varmus. That's correct. panel on potential research on marijuana Mr. Wicker. Perhaps another one on legalization of marijuana. Dr. Varmus. No, let me correct you on that. The marijuana discussion was not a consensus development conference. Mr. Wicker. It was a different type of panel? Dr. Varmus. Yes. We can discuss that if you like. It had a very different intention in mind. If you like, I can expand on that. Mr. Wicker. Please, yes. Dr. Varmus. As you know, due to the passage of referendums in Arizona and California, the use of marijuana for medical purposes has become an important public health issue. There is very limited evidence available on the issue of whether there's any appropriate use for marijuana in the treatment of a number of conditions, including the anorexia and wasting syndromes that occur in AIDS, nausea in cancer chemotherapy, glaucoma, multiple sclerosis and so forth. And we felt that it was incumbent on us to ask whether there was enough evidence to suggest that there should be more clinical trials in this area. And equally importantly, whether methodology existed for doing a credible clinical trial on a smoked product. So we brought experts in clinical trial design, in the pharmacology of marijuana, and in the treatment of the various conditions for which marijuana has been recommended in the past, to come together and discuss these issues. The outcome of the meeting, for which a formal report has not yet been written, is that there is very limited evidence on the efficacy of smoked marijuana in these conditions. There are some indications that it may be useful in certain limited contexts and that it would be possible to design credible clinical trials. And the NIH has been open to applications for clinical trials in this area. We've funded very few because we've had very few applications that passed peer review. But we are prepared to do such studies if they are properly designed and pass peer review. needle exchange Mr. Wicker. Let me back up then to the needle exchange programs. As you are aware, section 505 of our appropriation bill specifically states that no such funds should be used for needle exchanges. In light of that, why is it appropriate for a consensus development panel to be focusing in on this issue, and to conclude, among other things, that significant policy and legal barriers must be removed in order for this powerful weapon to be effective? Dr. Varmus. Two points, Mr. Wicker. First of all, the consensus conference was not about needle exchange solely. It was about behavioral modalities that might be used to restrict the spread of HIV, which as you know is the cause of a lethal disease. Second, section 505 does not simply prevent the use of Federal money for needle exchange. It prevents such use unless the Secretary can certify that needle exchange programs would reduce the spread of infection without increasing the use of intravenous drugs. We are continually asking whether those conditions can be met, because we are seeking, in the light of the threat posed by HIV, any means that can be used to reduce the spread of infection. Now, we all acknowledge that, first of all, drug abuse is a major avenue for the spread of infection. We believe that at present, perhaps half of the new infections that occur in the U.S. each year, half of between 40,000 and 80,000 new infections that occur each year, can be directly attributable to drug use or to sexual encounters with drug users, or to being the offspring of somebody who uses drugs. Those are troubling numbers. There have been many studies of the use of needle exchange programs in a variety of communities in this country and elsewhere. And there is increasing evidence in favor of the idea that needle exchange programs can reduce the spread of blood-borne infections with hepatitis viruses and with HIV. There is also evidence--less compelling because of the nature of the evidence, but nevertheless evidence--that the use of needle exchange programs does not increase the use of intravenous drugs. Therefore, it seemed to those who listened to the consensus conference that good could be achieved by needle exchange programs--namely, a reduction in transmission of these lethal infections--without apparent harm, that is, increase in drug use. Mr. Wicker. A quick follow-up. Do you believe, based on the evidence that you now have, that the Secretary should make a finding that the use of needle exchanges is appropriate? Dr. Varmus. It is a difficult issue. Because the nature of the evidence for the absence of increased use of drugs is less compelling than the direct evidence of measuring virus in the blood for demonstration of efficacy. Nevertheless, my own personal view is that the evidence is supportive of that conclusion. Mr. Porter. Thank you, Mr. Wicker. Our ranking member, who was required to be at his hearing on Armed Services, is here and I would like to call Mr. Obey for any opening statement that he might wish to make, and then he can proceed with his questions. mammography policy Mr. Obey. Mr. Chairman, thank you. I don't have any opening statement. It's just that I've recently had hernia surgery, so I ask you to please don't say anything that makes me laugh or sneeze. I just want to raise one question. I note that while I was at home, the Senate gave its advice and directed its wisdom on the subject of mammograms to NIH. And I guess I would simply say that I would like to question what appears to be conventional wisdom in the Senate that either House or Senate ought to start telling NIH exactly what it ought to be recommending in these areas. That is not a totally accurate characterization of what the Senate did. But I can recall in the 1970s, when we used to have a lot of pressure to see to it that women were told to have mammograms at earlier ages than had been the case in the past. And very frankly, at that time, it seemed to me, and certainly to a lot of people who knew a lot more about it than I did, that given the state of imaging technology it was an open question as to whether or not mammographies at an early age caused more harm than good. We've now had an improvement in the technology. But it seems to me that there are still legitimate questions about exactly how much emphasis should be given to advising women in their 40s that they ought to have mammographies. And so I guess I would just say that I would urge you, despite the Senate's resolution, to call them as you see them. Because it would seem to me that in the end, we would do the most good by seeing to it that we have a lot of emphasis on having women above 50 certainly obtain mammographies, because there is no question that you can save a lot of lives if they do. It seems to me that the greatest emphasis ought to be there. And that science, rather than conventional wisdom in the political field, ought to drive what happens with respect to other age groups. I don't know if you have a comment or not. Dr. Varmus. Well, I appreciate your comment, Mr. Obey. Yesterday, I attended the National Cancer Advisory Board meeting at which this topic was discussed. And I'm sure it will be further aired this afternoon, when Richard Klausner from the NCI testifies. In the course of the deliberations of the NCAB, the points that you were just making right now were emphasized in a very useful way, trying to place into context the much greater importance of getting women in the age range of 50 to 70 in for mammography. Currently less than half take advantage of what is clearly an effective means of detecting early cancer in that age group. And also, it is important to get those who are positive into treatment. Also emphasized during the course of the discussion was the importance of educating caretakers and patients who are in their 40s of the benefits and risks of mammography in the 40s, and to teach people that there's nothing magical about turning 40 or turning 50, that throughout the 40s, the benefits increase as one ages. And given one's attitude toward screening, given one's apprehension about a false positive diagnosis, which is fairly common in the 40s, given one's genetic family history and given the changing nature of the technology, people may make different decisions at different times in their 40s to begin mammographic screening. I believe this is a much more sensible approach than mandating one or the other. I think much of this is driven by concerns about reimbursement and perhaps that might be where some of the emphasis is placed in the discussion of this issue. cloning of humans Mr. Obey. Thank you. With respect to the marijuana question, again, I would hope that NIH would proceed to try to, as much as possible, provide the scientific answers. It seems to me that what is most important is not the opinion of Arizona or California activists, or for that matter, the President's drug czar. What's important is what the facts are. And it seems to me that we would in the end benefit from having NIH proceed to provide as much information as they can by way of whatever trials they can put together. I understand that you made some comments about the recent events in Scotland with respect to animal cloning. I guess I just have one question on that score. I am concerned about the long-term implications of that in terms of research on human beings. But I have a dark Irish soul which has taught me a long time ago that if anything bad can happen, it eventually will. Where are we in terms of the possibilities with respect to human cloning? What is the state of the science on that? And how in fact can we discourage going down that road, given the fact that as long as possibilities are there, I'm convinced that people are going to try to go down that road. Dr. Varmus. Well, to answer your question of where we are with respect to human cloning experiments, at the moment, the evidence that such experiments can be done depends entirely on what you've read about the sheep. There are similar efforts being made with other organisms, mice, for example, and experiments are being done with embryo cells from a variety of organisms. But nothing is being done with humans for a number of reasons. First, there is a prohibition, as you know, on human embryo research. As I mentioned earlier, the panel I commissioned in 1994 to look at the prospects for Federal funding of experiments that involve the human embryo had expressly indicated that experiments that would involve nuclear transplant for human cloning would not be recommended for Federal funding for a variety of reasons that I elaborated on earlier. Mr. Obey. I understand that. I know there's a prohibition on Federal funding. But not everything that happens in the world happens with Federal funds. Dr. Varmus. If you're asking whether I know that such experiments are being done in the private sector, I essentially can't comment. Mr. Obey. No, I mean, how likely do you think it is that over the next 30 or 40 years the scientific community is going to be totally dissuaded from trying to go down that road as far as the knowledge? Dr. Varmus. Well, the scientific community, I think, will not find that experiment something worth doing. It doesn't have any particular scientific objectives, and it is repugnant to the scientific community in general for a variety of reasons having to do with our belief in human diversity and individuality. That is not to say there isn't a renegade who would want to do such experiments. As the papers have repeatedly pointed out, the experimental design for the work that was done on the sheep is surprisingly simple, and doesn't require a cyclotron. It requires fairly limited scientific instrumentation. And it would be very difficult for anyone to say that there is not anybody who is trying to do such an experiment. So it's hard for me to answer you in a very direct fashion, except to say that such work done in animals has a variety of uses. The extrapolations of such work to an understanding of how genes are turned off and on, and how we can make different kinds of cell types--not whole human beings, but different kinds of human tissues--for transplantation and treatment of disease. I think it offers tremendous prospects, which is why I'm very concerned about a rush to put into place some restriction on this whole area of research, which I think could severely limit our ability to capitalize on the most interesting, important, and medically useful aspects of the work. Mr. Obey. Thank you. Mr. Porter. Thank you, Mr. Obey. Ms. Pelosi. national bioethics advisory commission Ms. Pelosi. Thank you, Mr. Chairman. Thank you for your leadership on this NIH issue. And welcome, Dr. Varmus. I was very thrilled, really, to hear your explanation of what we are calling an ``experiment,'' in Scotland. Mr. Obey, when I had to run out of the room to testify in Transportation, I used up my time re-explaining it to them. [Laughter.] I didn't have as much time as you had, Dr. Varmus. I didn't do it justice. [Laughter.] I don't know whether I succeeded in my mission of getting more money for rapid transit for San Francisco. [Laughter.] But I think that the members of the committee are scratching their heads, wondering what a sheep in Scotland has to do with the price of rapid transit in California. But in any event, it was very interesting, and it takes me to the question that Mr. Obey was pursuing, are you satisfied that in our educational institutions the curriculum is inclusive enough of the ethics courses that we need, or the leadership in this arena to match the science as it marches ahead? Dr. Varmus. Are you referring to graduate training in science? Ms. Pelosi. Yes, graduate training in science, and then also just, for example, I'm very pleased, too, that the President has this National Bioethics Advisory Commission. I'm not completely familiar with it. If you want to say more about it. Dr. Varmus. Yes, I'd be happy to. Ms. Pelosi. What kind of people are they? Mostly scientists? Are they philosophers? Dr. Varmus. Perhaps I should address that first. The National Bioethics Advisory Commission did exist, initially I think in 1978. It was in place for a couple of years, and then was simply not constituted for many years. The President reconvened it under the leadership of Dr. Harold Shapiro, who's an economist and the president of Princeton University, about a year and a half ago. There are 18 members of the Commission. Some are scientists who work in the areas of genetics, embryology, and development. Others are ethicists. Some are lawyers. They represent a diversity of occupations. A very well balanced committee with very well-known people who have made significant contributions in the areas of the relevant science. And their charge is not simply to look at issues that surround human development or embryo research. Their mission is much broader. Indeed, some of the things they have talked about focusing on include a number of issues relating to human genetics, including issues of privacy and genetic testing. They've also been interested in informed consent and the conduct of clinical trials. So there are many issues to which they might be assigned. The President was very wise in referring this issue to them and giving them three months to begin deliberations and to make some proposals about things that might be done. As I said earlier, I am a little concerned that in the frenzy of the excitement about the novelistic possibilities here that something more limiting of the research possibilities generated by these new findings would be done precipitously. Nothing is going to happen immediately in the scientific arena. It's worth exploring some of the deeper aspects of these experiments with respect to gene regulation before we throw the baby out with the bath water. ethics training With respect to ethics training, we have made it a part of NIH graduate training programs for the last several years that there be a component devoted to the conduct of science. That encompasses a large number of topics ranging from issues of how you work with your colleagues to scientific misconduct, to how you apply for grants, and what to consider as career possibilities after training in these fields. But it would also include ethical issues of the sort that we're describing today. We don't prescribe a program narrowly, but we do require that all of our training programs have such a component. Ms. Pelosi. And do you think that in the educational institutions, the institutions of higher learning in our country, that there is sufficient attention paid to the ethical challenges that we will be facing? Dr. Varmus. Well, Ms. Pelosi, I actually think that these issues grab such attention that they should be used as vehicles for interesting people in science. All too few folks are able to appreciate the deeper significance of the purported experiments, because they know too little about genes and nuclei and eggs and how fertilization normally occurs, and how a human being or any other animal develops from a single fertilized egg. What I'd like to see is institutions at all levels, from the grade school level on up, take this news account and use it as a lasso to bring people into thinking about biology. We have tremendous opportunities generated by the genome project or by use of recombinant DNA products in generating food to attract the attention of young folks who frequently see science as tedious, because their textbooks are full of terms they have to memorize instead of being brought into the scientific arena through public issues such as the one we're discussing today, that could be the vehicles for driving people to a greater appreciation of science and how its principles underlie many public issues that we have to worry about. hiv vaccine Ms. Pelosi. Thank you. I was pleased with what you had to say earlier about your work being to promote human health and reduce human suffering. If this research is in furtherance of that, the research that you said, that you don't want to cut off because of the possibility of developing the tissue for transplantation, etc. You talked also about culminations and inspiration. And I was pleased that the new AIDS therapies were part of the culmination. I guess they're part of the inspiration as well. I wanted to ask you about, I don't know if Dr. Fauci would call it a breakthrough---- Dr. Varmus. He never calls anything a breakthrough. He's very conservative. [Laughter.] Ms. Pelosi. But I wanted to ask you about the possibility of an HIV vaccine that the President referenced in his State of the Union speech. Under your leadership, NIH has made a commitment to give a higher priority to developing a vaccine. As we all know, a vaccine is needed to end the global threat and domestic threat of HIV/AIDS. What is the status of that research? Dr. Varmus. Ms. Pelosi, as you know, about a year ago, a very broad review of all our AIDS research programs was carried out under the leadership of Arnold Levine from Princeton University, joined by 100 colleagues. One of the major recommendations of that review was that we devote greater attention to the possibility of developing a vaccine against HIV. HIV has been a difficult combatant in the development of vaccines for a variety of reasons I won't go into here. But it's been increasingly appreciated that we have not understood our failures, nor have we exploited all the potential for developing a vaccine. We are excited about protease inhibitors as treatment devices, but we know they're terribly expensive. They don't work for everybody in this country. And they're really not accessible to the parts of the world where HIV infection has its most devastating and widespread effects, because of the cost of the drugs and because of the difficulty in administering them and monitoring the response to the drugs. So we need something more decisive to control the epidemic that's occurring worldwide. A vaccine is that answer. In response to the recommendations of the Levine Committee, we have increased the amount of money that's available in our AIDS program for vaccines. We have put together an AIDS advisory group headed by David Baltimore of MIT, one of the world's leading immunologists and virologists, who with the advice of a number of people who have already met, are putting together an important program to move our vaccine program forward on a variety of fronts. Ms. Pelosi. I appreciate that. Thank you. I have some other questions about brain research and child abuse, etc., but my time is up, and I'll submit those for the record if we don't have another round. Mr. Porter. Thank you, Ms. Pelosi. Mr. Hoyer. Mr. Hoyer. I'll pass. Mr. Porter. Mr. Bonilla. commitment to diabetes research Mr. Bonilla. Thank you, Chairman. Good morning, Dr. Varmus. It's always good to see you, and I apologize for not being here for the beginning of your testimony. We were in the midst of a hearing questioning the Secretary of Defense this morning on the Defense Appropriations Subcommittee and it ran a little long. But again, welcome. I appreciate any time you call me or visit with me, because I hope you always remember that I've got that open door policy, that if you ever want to talk about anything, just pick up the phone, like you always have. I'd like to start, Dr. Varmus, by talking about why you concur with others on this committee who believe strongly that science and not politics are the direct medical research funds in this country, and you've done a great job at the NIH since day one. Example, last December, scientists at the University of Chicago were conducting research unrelated to diabetes, and made a new discovery of two genes linked to causing the disease. And prior to this surprise discovery, neither gene had been a suspect in diabetes. But this now opens the door for more research and understanding of the disease. It was a big breakthrough. Obviously, in this case, a broad approach to research served diabetes well. But with significant momentum, it concerns me that NIH has assigned a low 2.23 percent increase at NIDDK, a percentage which does not keep pace with biomedical inflation which is expected to be at 3 percent for the next two years. As you know, diabetes is extremely prevalent in Texas, and a major concern to me and other members of this committee. I especially have worked closely with Mr. Stokes on this issue. One in every 15 Texans has been diagnosed with this disease. In light of the fact that 27 percent of the entire Medicare budget is spent on caring for persons with diabetes, my concern is that if it's not given a high priority, we will lose the momentum needed to prevent and cure this disease. So if you would, Dr. Varmus, explain the NIDDK's low priority at NIH, especially when it is truly on the brink of pivotal breakthroughs in this area. Dr. Varmus. Mr. Bonilla, I agree entirely with your assessment of the discovery of the two genes that are involved in maturity onset diabetes of the young. But I would take issue with you about our lack of commitment to diabetes research. I don't believe that the NIDDK is unfairly penalized. Secondly, it's not the only venue in which diabetes research is conducted. Thirdly, that institute of course conducts research on a wide variety of topics. Let's look at the example you provided. Much of the work, that you described, of course, emerges from a study of gene regulation and from the genome project, as well as from initiatives in diabetes. What we're dealing with here is a problem in the coding of disease and the numbers which we look at, which tend to differ by fairly small percentage points, are the result of a frankly imperfect attempt to assign dollars to various categories. They are very inaccurate assignments. What really counts here is the way in which we exploit discoveries of the sort that you mentioned. And I will guarantee you that those discoveries will be very vigorously pursued, because they represent very important avenues of new discovery. Having new genes that clearly are involved in the pathogenesis of diabetes offers that most miraculous of things, a scientific opportunity that people are going to leap to. People who didn't work on diabetes before are going to be jumping on these topics, and we will be pursuing them as vigorously as possible. diagnois and detection of diabetes Mr. Bonilla. I'm sensing a lot more attention being paid to the prevention and education among those who have not yet been affected by diabetes but are in a high risk category. Are you feeling that as well? When I'm visiting with researchers and even the Speaker talks about it all the time now. He thinks it would be a great way to combat the higher projected Medicare costs in the future. Are you sensing that as well, that we really need to get on the horse here? Dr. Varmus. Yes. I think we have a responsibility in three areas. One, the area we just discussed, doing more research to advance our ability to diagnose and treat diabetes, secondly, better methods of detection. Very importantly, as was demonstrated by a long-term study of the treatment of diabetes by the NIDDK, we have a major responsibility to take those findings which show that careful control of metabolism in patients affected with diabetes has an important outcome on the complications of diabetes, reducing heart disease, renal disease, and neurological disease. And the careful control has to be instituted. The Eye Institute, which has a major role in diabetes research, has shown conclusively that early detection of the retinopathy of diabetes is incredibly important, because we can treat the retinopathy and prevent blindness. And yet, all too many individuals with diabetes fail to see an ophthalmologist regularly. So we have initiatives for discovery, initiatives to identify those who are at risk, and very importantly, initiatives to develop a sense in the physician community and among patients of the need for careful surveillance of their disorder. Because the complications in very large measure can be prevented. Mr. Bonilla. So just to sum up this area of questioning, even though I mentioned this 2.23 percent, you're not concerned that we're neglecting diabetes research at this time? Dr. Varmus. I do not believe we're neglecting diabetes research. imaging research Mr. Bonilla. I want to turn now to the subject of imaging, which we've discussed before. I'm interested in knowing how much of a priority imaging research is at the NIH. And as you know, some people would like to see an imaging institute created at the NIH. They suggest that current funding which is dispersed throughout NIH for imaging should be combined to create this institute. Tell us specifically how you intend to address imaging research, Dr. Varmus. Dr. Varmus. Well, as I mentioned in my introductory remarks, imaging is playing an increasingly important role in the study of neurological disorders and in the study of many other disorders as well, for example, in cardiology and in the study of the vascular system. Imaging is fundamental to both research and to clinical practice. Virtually every institute has some involvement in imaging technology and the use of new imaging devices, be it advanced x-ray procedures or magnetic resonance imaging or PET scanning to further their understanding of the body and the diseases that afflict it. I know there is an interest in an imaging institute. My personal attitude is, this will not occur on my watch. That's true for many reasons. Administrative expenses will be increased if we do that, it will remove from the place where imaging should be practiced, namely the institutes looking at various diseases, the incentive to advance instrumentation in the areas of special interest to that institute. And right now, we coordinate our activities in imaging extremely well. We've had a recent review of our imaging activities in the intramural program. And we are developing new programs that are well coordinated among the institutes. We have the existing mechanisms for coordinating our efforts in imaging. We don't need another administrative structure. Mr. Bonilla. Thank you, Dr. Varmus. Mr. Porter. Thank you, Mr. Bonilla. Ms. DeLauro. Ms. DeLauro. Thank you for being here, Dr. Varmus. I'm sorry I won't be in New Haven to listen to your lecture. I would be delighted to do it, but I know the city will treat you well while you're there. I think the questions of this morning have shown that the experiment in Edinburgh really was truly the ``baa'' that was heard around the world. [Laughter.] Ms. DeLauro. So I think we have covered the topic, so I'm not going to ask a question in this area, and, at the risk of my colleagues throwing something at me, I feel a little sheepish about doing one. [Laughter.] ovarian cancer Ms. DeLauro. But I did want to ask a couple questions. First, in 1997, the NIH spent $41 million out of the $12.7 billion budget on ovarian cancer research. And over the past few years, increases in ovarian cancer research funding have been extremely incremental. We know through the studies that if it's properly diagnosed, treated early, that the survival rate for women is 92 percent. But to date, we have no simple diagnostic test to detect ovarian cancer. My questions are, how much does the NIH plan to spend this year on ovarian cancer research? What types of initiatives does this include? And will the research be done primarily through the extramural or the intramural programs? Dr. Varmus. While my valued colleagues are digging up the exact number for 1998--it will be in the range of $40 million-- let me say a few things about what's going on. First of all, there is activity in ovarian cancer research, both intramurally and extramurally. We have clinical activities and basic science activities within the intramural program and of course, many activities outside. I agree with you that we have yet to achieve the ideal diagnostic procedure in the case of ovarian cancer. And that actually is true for many internal cancers, unfortunately. The number for 1998, I'm told, is going to be $41 million. But there are at least a couple of things that are being explored in a large scale study attempting to evaluate both trans-vaginal ultrasound and an existing immunological marker, CA-125, that I'm sure you're familiar with, that attempts to evaluate their usefulness. One major source of activity in ovarian cancer research in the last year that's given us a lot of optimism is the large number of clinical trials, approximately 60. Importantly, almost half of those are phase one trials that involve new drugs. We're also extremely encouraged by the efficacy of certain combination therapies, particularly those that use taxol and cis-platin, often in combination with a third agent. And as you know, that has had a dramatic effect on our ability to control mortality from this disease. advances in ovarian cancer research I'm also pleased to say that one of the initiatives that I'm sure Dr. Klausner will discuss this afternoon, involving our efforts to understand the genetic anatomy of cancers, includes ovarian cancer as one of the five target sites for initial investigation. As you know, one of the major discoveries of the last few years, the isolation of the BRCA-1 and BRCA-2 genes, which was initially an initiative mainly seen in the context of breast cancer, has had dividends in the area of ovarian cancer. Because individuals who are born with mutations in either of these two genes are at higher risk for ovarian cancer. It's also possible to predict from the nature of the mutation the likelihood the individual will have ovarian cancer. So there have been advances. They're not as far along as I would like. When you were here three years ago, we discussed the role of telomerase in the treatment of ovarian cancer. That has not yielded the benefits that some anticipated at the time. But you can be assured that we recognize the great significance of ovarian cancer and are pursuing it as actively as possible. Ms. DeLauro. I would call on you, and I will say the same thing to Dr. Klausner this afternoon, that 27,000 women will be diagnosed with ovarian cancer, 15,000 will die. When we can find this in the early stages, and when it's treated, it's 92 percent survival. Dr. Varmus. This year, two of those diagnosed individuals are friends of mine. So I'm with you on this one. child development and the brain Ms. DeLauro. Thank you. Can you please discuss the NIH's research in the area of child development and the work that's being done on the brain, how children learn? How has the NIH coordinated or are you coordinating with the Department of Education programs like Head Start and others that ensure that the results that you are uncovering in a brilliant way, this research, is applicable to public policy and the classroom? Dr. Varmus. Well, there is a great deal of activity in this arena. And I'm sure you'll be hearing a great deal more about it, both from Duane Alexander, when he speaks to you about the activities of the NICHD, and from Steve Hyman, when he talks about NIMH. And of course, a lot of this is yet further inspired by the President's interest in studying early brain development to ensure that all Americans can read by the third grade. One important development has been our deeper understanding of the mental processes that go on during the efforts to learn how to read, the ability to recognize phonemes, the components of words that represent a special kind of thinking that we are beginning to understand, using imaging devices and tools of behavioral research. Investigators supported by NICHD have developed methods for diagnosing difficulties in appreciating phonemes, and have developed interventions that are useful in being able to correct the reading abilities of individuals, if they are detected early. We are working closely with the Department of Education, trying to put some of these principles into effect. The evidence to date shows that the interventions are effective, and we hope that through the White House initiatives in early development and the emphasis being placed on education in the current Administration that some of the principles that we're uncovering by these studies in fundamental neurobiology will have outcomes of the most practical kind, namely a public that consists only of those who can read. impact of third party payments Ms. DeLauro. The point, and the wonder of this committee is, that the work that you do is under our purview, at the same time the work that's done with Head Start is, too. Now we're uncovering information that says, we have a successful model in Head Start, and we will continue to work to make it better. We now understand that if you can have an impact with children in the zero to three years, which also is part of the work of this committee, that we need to really work those together among departments in order for us to get the best of both worlds. In your budget, Dr. Varmus, there's a request for $15 million in savings through third party payments for the cost of patient care at the NIH clinical center. Can you explain the proposal, and what it would mean for those who are receiving the care at the clinical center, and would these payments affect NIH's ability to attract patients for clinical trials? Dr. Varmus. Well, I thank you for the question. We obviously are concerned about the possibility that requesting third party payment might impede referral of patients to the clinical center or the ability of, or the willingness of, our patients to come there. So we've been working with potential third party payors to gauge what the impact would be. We recognize our fiscal responsibility to collect for medical care delivered in the course of research, in view of the stringencies in our budget. And yet we are also sensitive to the possibility that we would impede access to the kind of research that we do. So, at the moment, we have no third party payment procedures in place. We have never collected, and we are obviously being urged by many to do so. We're moving toward that in a cautious manner. And we hope to have some payment processes that don't impede patient access. Ms. DeLauro. That would defeat our purposes. So I really do ask you to proceed cautiously. Dr. Varmus. We are doing so. Ms. DeLauro. Finally, I'd like to associate myself with the comments of my colleague Mrs. Lowey on clinical research. We're always in awe of the discoveries, and what happens with regard to patients in doctors' offices. So I look forward to seeing your response. Thank you. And thank you, Mr. Chairman. Mr. Porter. Thank you, Ms. DeLauro. Mr. Istook. comparison of medicare costs and disease research costs Mr. Istook. Thank you, Mr. Chairman. Dr. Varmus, good morning. We spoke yesterday and also some last year, of course, about allocation of research dollars within NIH. And you're well aware of my concerns of whether we are putting the resources where they can be most significantly used. I don't know if you've had a chance to look at the graph. [See figures 1 and 2.] [Pages 37 - 38--The official Committee record contains additional material here.] Dr. Varmus. Just out of the corner of my eye. Mr. Istook. Of course. Let me tell you, the document provided to you and committee members, we've spoken before about the ratio of funding of different diseases compared to the frequency of their occurrence in a population and the national cost of it. We obtained from HCFA the report of how much it is costing taxpayers through Medicare to treat patients with certain diseases. Now we were told they were not able to give us a breakdown on Medicaid. But this chart is to represent the ratio at which the taxpayers are paying for treatment of different diseases. And because it's Medicare it includes not only an aged population but also those that are disabled by their disease. Certainly there are a number of debilitating diseases, AIDS, we've talked about, is certainly one of them. So you will have people, regardless of their age, that are reflected in this chart if they're disabled. The point that I'd like to focus on is the difference in the amounts that Medicare is paying and the proportion of Medicare payments compared to the proportion of disease- specific funding by NIH. For example, if you look at cancer, you see that 9 percent of the taxpayers' money that's going for Medicare treatment is going to care for cancer patients. But only 5 percent of the NIH research is going to cancer patients. That's of the disease-specific research. [Clerk's note.--Later corrected to ``49.7%''.] Mr. Istook. If you also look through, you'll find, for example, chronic obstructive pulmonary disease, again, Medicare, 2.6 percent of its payments are to take care of patients with that difficulty. Whereas 1 percent of the disease-specific research is going to it. [Clerk's note.--Later specified at ``1.2%''.] Mr. Istook. Diabetes, if you look there, type 1 and type 2 diabetes, 2.6 percent of Medicare outlays compared to 6 percent of disease-specific NIH. However, if you drop down to the bottom of the chart and you look at the complications of diabetes, the complications are more than one-fourth of the total Medicare payments for those treatments. And again, this compares to a research allocation of about 6 percent. [Clerk's note.--Later specified at ``5.8%''.] Mr. Istook. Again, just finishing up on a couple of other examples, pneumonia and influenza is 4.3 percent of the cost to taxpayers through Medicare, whereas it's 1 percent of the disease-specific NIH research. AIDS is two-tenths of 1 percent of the outlay for Medicare. But it's 27 percent of the NIH research dollars. So that AIDS has 100 percent greater proportion of research dollars than what it's costing taxpayers through Medicare. [Clerk's note.--Later specified at ``1.2%''.] [Clerk's note.--Later specified at ``27.5%''.] Mr. Istook. I might mention also that the figure of the number of AIDS patients of some 46,000 that are being, having their expenses paid through Medicare, compares to the CDC report of just over 80,000 AIDS patients in 1994. It's a very significant proportion of the AIDS patients. In fact, the Government outlays, unique on AIDS, $1.5 billion for research, $270 million for treatment. No other disease has anywhere near that ratio, where the research outstrips the cost of care. [Clerk's note.--``New AIDS patients'' later added.] allocation of research dollars Mr. Istook. Now, this is part of the concern that I've expressed to you before about the priorities, are we putting our research dollar where it benefits a greater amount of the population, where it benefits the taxpayers and links up with the extraordinary expense to the taxpayers of providing health care. I would appreciate your comments on that, especially if there is any formal consultation process in allocating the funding for NIH disease research, any formal consultation process with HCFA, which administers the Government Medicare and Medicaid outlays, Centers for Disease Control, private insurance companies and hospital administrators, and anyone else that may be in the private sector as well. Is there any formal process for them to have input on how we are allocating our research dollars? Dr. Varmus. Mr. Istook, there are a number of ways in which I would like to respond to your comments. Mr. Istook. Sure. Dr. Varmus. As far as the formal consultation process is concerned, there isn't any formal process that we go through. However, the data of the sort that you're presenting--I haven't seen this table before--but other kinds of information, of course, is not only accessible to us, but we look at it quite closely. As you know, in the past we provided to the Congress cost of illness reports, and we're of course following the epidemiology of disease throughout the Nation very, very closely, because we are concerned about these figures. They do feed into the overall priority setting process. I haven't seen this table before, and I'd have to question some of the numbers that you're quoting. Because---- Mr. Istook. These are from HCFA, by the way. Dr. Varmus. The HCFA numbers, I'm sure are correct, but the numbers that relate to percentage of disease spending are somewhat perplexing to me, and I'm sure perplexing to Dr. Klausner, since he previously was receiving almost 20 percent of the NIH budget and is now only receiving 5 percent. Mr. Istook. Certainly any errors we want to rectify. Dr. Varmus. There may be some corrective---- criteria for funding allocations Mr. Istook. Sure, we may correct information. But the ratios, of course, still indicate that a significant question of at least $1.5 billion of the application. Dr. Varmus. I think we would be remiss if we were allocating our dollars solely on the basis of Medicare payment. Obviously, the economic burden of disease is one of the things that we take into consideration when we think about how our appropriations are spent. If there were a major disease we were not studying, we'd be quite troubled. But as you know, there are many other criteria that we have to consider in putting together our budget. One is the other kinds of burdens posed by the disease, because they're not all financial. The age at which the disease occurs--disease of children, disease of middle age, disease of adults, of aged adults--makes a difference. The degree of morbidity, the longevity of the illness. But then we have to consider many things other than the illness itself, because, of course, much of our money is spent in research that's very difficult to categorize as belonging to one disease or another. And one of the places we always run into trouble in these discussions, and it's a trouble that's inherent in the process of setting priorities and explaining what we do, is that much of our research is an effort to understand the workings of cells and organisms that may not apply to any single disease, yet of course, the public has a right to expect us to be able to categorize what we spend in understandable terms. Mr. Istook. Which calls into question why even allocate among any disease at all if research is just going to be of such general application? Dr. Varmus. Well, because some research is, classifable. If we do a clinical trial to treat a certain condition, we can say we're spending money on that disease in that case without appreciable ambiguity, even though as you know, sometimes such clinical trials do lead to developments that affect other illnesses as well. But that's a by-product. I think we end up with the difficulty we've been in before: that, for us, scientific opportunity and the submission of applications to study certain questions end up being a very significant driver of where our money is spent. We don't expect there to be a one to one relationship between any cost accounting and the place where we spend our monies. I find myself more responsive to a complaint that there is a promising opportunity that we're not seizing than I am to the notion that there is a less than uniform correspondence of one component of our priority making to the way we spend our money. reducing health care costs Mr. Istook. Of course when you have, it's hard to find any other disease that has a one to one ratio. And yet you've got one disease that has a 100 to 1 percentage or priority ratio. I'm concerned, especially, we're spending tremendous amounts, of course, through NIH on research. But it doesn't seem to me that one of the purposes is to try to reduce not only the burdens, but the cost of health care, to patients, to their families, to citizens, to taxpayers, to all the people that are being hit with tremendous health care costs. And our research doesn't seem to take into account that national priority of trying to reduce the burden of health care costs by making sure that research is focused on the diseases that are costing so many people so much. Instead it is grossly focused on a disease that, although terrible, is not more terrible than many other diseases, and certainly does not represent the same degree of threat to nearly as many people in this country as other diseases, such as cancer and diabetes. Dr. Varmus. Well, let me take issue with a couple of things you've said. One is that the goal of our research is not solely to reduce health care costs. In fact, sometimes the outcome of our research is to increase costs. In some areas that does happen. We like to point to advances that in fact do save money, but they don't all save money. Sometimes we have an advance that decreases human suffering, but does so at the cost of increased medical expenses. Secondly, I would take issue with the question of the populations at risk. And let's talk specifically about AIDS, because that's obviously what's on your mind. AIDS is currently the leading cause of death for individuals between the age of 25 and 44. It's a disease which has tremendous impact worldwide. Every child growing up in America, every parent is concerned about HIV. Peoples' attitude toward life is affected by it. It's a new disease. It's a disease which continues to spread in certain populations here, even though the infection rate has begun to stabilize. We do have some therapies for it. It represents an enormous challenge, which we have already seen pays dividends in thinking about other ailments. We discussed this before, and I understand that money we spent on other diseases also has ramifications beyond the narrow disease confines to which the monies are classified. But I think the pervasive nature of infection with HIV, its involvement of every organ system, has produced for us challenges that have had particularly broad ramifications in all of medical science. Mr. Istook. Thank you, Dr. Varmus. I will work with you and try to get more information from you on how many people and how much input actually goes into deciding the allocation of the research dollars within NIH, and whether we need a much broader and more inclusive process to make those determinations. nih priority setting process Dr. Varmus. I would like to make just one very brief comment if I can. Mr. Istook. Sure. Dr. Varmus. We are preparing, for the public and for the Congress, a booklet that describes how we go about the priority setting process. As you'll see, many, many constituencies are involved in that process, and my response to your request for information about formal interactions was accurate. But those influences are felt, just not through a formal process---- Mr. Istook. Sure. You'll give us the information on the informal part. Mr. Porter. I might say to my colleagues that everyone, except Mr. Stokes, who had to leave, has had an opportunity to ask questions this morning. Dr. Varmus will be here with each of the Institute directors for seven full days of additional hearings. And would be available to answer any questions, as well as the directors themselves. Dr. Varmus, we'd like to thank you very much for your testimony this morning. You've enlightened us a great deal. We appreciate the wonderful job you do at NIH. You and the Institutes are truly national treasures, and we appreciate your strong leadership there. The subcommittee will stand in recess until 1:30 p.m. [The following questions were submitted to be answered for the record.] [Pages 43 - 197--The official Committee record contains additional material here.] Wednesday, February 26, 1997. NATIONAL CANCER INSTITUTE WITNESSES RICHARD D. KLAUSNER, DIRECTOR, NATIONAL CANCER INSTITUTE ALAN RABSON, DEPUTY DIRECTOR HAROLD VARMUS, DIRECTOR, NATIONAL INSTITUTES OF HEALTH DENNIS WILLIAMS, DEPUTY ASSISTANT SECRETARY, BUDGET, DEPARTMENT OF HEALTH AND HUMAN SERVICES Mr. Porter. The subcommittee will come to order. We're pleased to welcome Dr. Richard Klausner, the Director of the National Cancer Institute, this afternoon. And Dr. Klausner, I'm going to forego an opening statement and so are my colleagues on this side. And why don't you simply proceed. Introduction of Witnesses Dr. Klausner. Thank you, Mr. Porter, members of the committee. It's a pleasure to have the opportunity to speak to you. Before I start, let me introduce, you know the people on my right, but on my left is Dr. Alan Rabson, the Deputy Director of the National Cancer Institute. Opening Statement This past year, we recognized the 25th anniversary of the 1971 National Cancer Act. And it's been for us an historical year as we sought to evaluate this Nation's investment in cancer research and assess the fruits of that investment. This fall, we were able to announce that for the first time since we began to track the constant rise in cancer mortality over 60 years ago, we had encouraging news. Sometime around 1990, we appeared to have reached the peak in the mortality rate and for the past five years, the overall age-adjusted mortality rates have fallen for all cancers. And that's shown here, you can see what we've been able to observe for the last few years. [See figure 1.] [Page 200--The official Committee record contains additional material here.] Dr. Klausner. Every 2 percent drop represents 10,000 to 15,000 lives that would have been lost. These include for the first time the most common causes of cancer death, including lung, colorectal, breast, prostate, bladder, head and neck and others. We believe that these encouraging results are the results of the investment we have all made. They are probably the result of multiple factors, including prevention, especially declining tobacco use among American adults, early detection and better therapy. The burden of cancer, as you all know, is not shared equally among all in our society. African-Americans, for example, experience a 20 to 30 percent excess rate of cancer death compared to white Americans. However, the latest mortality data included again for the first time a significant drop in the cancer death rate in African-Americans. We can see that here. In fact, you can see from looking at this that the percentage drop appears to be larger over the past five years in the African-American community than among all Americans, suggesting if those hold up that this terrible gap in survival may be closing. [See figure 2.] [Page 202--The official Committee record contains additional material here.] Dr. Klausner. Today over 10 million Americans are cancer survivors. The majority of these were diagnosed over five years ago. In recognition of the many unanswered questions that long- term survivors face, there is a need to do research to answer questions about medical and psychological consequences, of delayed recurrences, second cancers, and long-term effects of treatment. As I announced last year, we're initiating several funding initiatives, in this area. Our fundamental goal is to develop effective interventions to reduce the incidence, mortality and morbidity of cancer. There is probably not going to be any one intervention or even any one type of intervention that will successfully conquer cancer, or the many diseases, in fact, that we call cancer. Our approach must be and is open and broad-based, identifying those at risk and modifiable risk factors, for developing sensitive and predictive means of early detection, and learning to finally correctly diagnose each cancer so that the diagnosis predicts the course of the disease and dictates the choice of therapy. Cancer is a disease in which one of the trillions of cells in our body gradually changes over time. That cell is a crucible in which the interacting players of genes and environment meet and produce the alterations that drive the behavior, in this case the misbehavior, of each cancer. The ability to look at genetic changes in cancer cells offers us an interesting twist to the search for external causes of cancer, a type of reverse epidemiology. Scientists are now exploring whether the fingerprint of particular types of carcinogens can be found within the DNA of the cancer cell, much like the thief that leaves incriminating evidence at the crime scene. And to help us use the effects of environmental carcinogens to identify the culprits. Such an approach has recently been demonstrated for one of the carcinogens, benzopyrene, found in tobacco smoke, as well as a carcinogen that causes liver cancer, and is found contaminating certain foods, for sunlight and for vinyl chloride. cancer prevention Prevention in part explains the drop in cancer mortality rates, and prevention will play an increasingly important role in our approach to cancer in the future. Prevention studies range from evaluating behavioral intervention against tobacco use, and for healthful diets to pharmacologic interventions that include drugs that block the interaction of hormones for breast and prostate cancer, to anti-inflammatory drugs and their ability to prevent the development of colon and other GI cancers, to vitamin derivatives to prevent aerodigestive and other cancers. In fact, now we're testing 24 agents in over 78 clinical trials aimed at preventing cancer, in approaching cancer not as a single event, which it's not, but as a long and potentially stoppable process. The identification of infectious causes of cancer provides another type of prevention opportunity. Based on major recent breakthroughs at the NCI, we have made a commitment to proceed with the development and testing of a multi-valent vaccine against cancer-causing strains of human papilloma virus. These are the viruses that cause cervical cancer. This is the first such effort to vaccinate against an agent solely for the purpose of preventing cancer. Early detection remains a critical part of increasing cancer survival and enhancing the possibility of a cure. And I expect we'll be discussing this issue in the question period. clinical trials The final component of the decreasing cancer mortality is improved treatment. Clinical trials are the means by which we test and establish the best treatment for cancer. We have continued to work with partners to assure that patients have access to clinical trials by strengthening our cancer clinical trials agreement with the Department of Defense, and conducting a new agreement with the Veterans Administration to integrate the entire VA medical system into the NCI clinical trials and cancer centers network. We have embarked on a strategic plan to restructure our clinical trials information system, to create a modern informatics base developed in conjunction with the FDA and the International Committee on Harmonization, to develop electronic systems for data on adverse events and the use of common toxicity criteria. A single entry clinical data reporting system will greatly facilitate these trials, and pilot testing for the system will be completed by April. These efforts will improve the speed and accuracy of reporting, produce resource savings, and remove impediments of burdensome and cumbersome paperwork. Critical to enhancing access to clinical trials is available and useful information. We're currently working with patient and consumer groups to rewrite the NCI PDQ information system to be more inclusive of all trials, to be more user friendly and comprehensible and accessible. The NCI clinical trials evaluation program is currently sponsoring over 750 active clinical trials, including almost 260 phase one trials this year to test new drugs and new therapeutics. Such new approaches include viruses engineered specifically to kill cancer cells, gene therapy, immunologic approaches to cancer, photon based therapy, and new small compound drugs directed against the cancer cells or the blood vessels that nourish those cancers. In addition, hundreds of other trials are conducted at NCI cancer centers and through other funding mechanisms. This past year, 12 new drugs were approved by the FDA for use in cancer. And we anticipate over 30 new investigational drug applications in 1997. In the biotechnology industry, over 40 new agents are in clinical trials for cancer. And cancer is the largest beneficiary of this burgeoning industry. Notable results of clinical trials of the past year include the demonstration of a 30 percent reduction in mortality for adjuvant therapy in stage C colon cancer, translating into approximately 4,000 lives saved a year. And as these benefits may also translate, extend to stage B patients, the mortality reduction may prove to be even greater. Interferon has been demonstrated to be of benefit in at least a subset of patients with advanced melanoma. Remarkably improved survival from combination chemotherapy with radiation for nasopharyngeal cancer resulted in a cooperative trial being stopped early because of the positive results. Other examples illustrate the incremental advances being made, each adding to improved survival for patients with multiple types of cancers. These trials examine new agents, new combinations of therapy, new ways of delivering therapy such as neo-adjuvant treatment where chemotherapy, for example, is given before rather than after surgery, in order to improve surgical success and even allow less extensive surgery. One recent therapeutic advance, let me just illustrate, how cancer therapy is being altered by our new understanding of the molecular characteristics of cancer. Recently, investigators at the National Cancer Institute have been studying a particularly aggressive form of lymphoma. And with the previous treatment, using five drugs, we see that about 50 percent of the patients were cured. Those that were not cured relapsed within about the first year. [See figure 4.] [Page 206--The official Committee record contains additional material here.] Dr. Klausner. The question was, why 50 percent? What did those other patients have? Well, it turns out virtually all those other patients had a mutation and alteration in one particular gene, p53, whose loss of function is involved in over 50 percent of human cancer. So it was actually two different diseases. Now, they developed a new drug regimen, and now we're seeing that for this type of cancer, over 90 percent of patients, including this other category, which we had previously lumped together, are either being cured or at least look like they have long-term remission. breast cancer--molecular markers This illustrates a principle that's guiding a fundamental transformation in oncology. We can begin to identify the defining characteristics of any cancer, leading us to precise and informative diagnoses. Let me give you one example. Breast cancer. One of the most difficult therapeutic decisions we have to make now is an early stage breast cancer without node involvement. Who needs chemotherapy? Who needs adjuvant therapy? Some fraction of these women will relapse or develop evidence that their cancer has spread. And it's very important that we learn to look at these cancers that we've been lumping together and recognize that there will be molecular signatures that will distinguish a cancer that needs a particular therapy from one that doesn't. This has recently been published, and this shows using two molecular markers that were discovered through studies on understanding the basic properties of moving through the cell cycle, something called cyclin-E and an inhibitor called p27. And notice these differences. This is the outcome for women with early stage breast cancer, and these are those cancers that have high levels of one of these and low levels of the other. And you see what happens. It's clear that these women are the women we need to focus on for adjuvant therapy. [See figure 5.] [Page 208--The official Committee record contains additional material here.] Dr. Klausner. Whereas, look at the outcome for that subset of women which have low E levels and high p27 levels. Again, getting a feeling for how this is going to change in the future. The molecular profile of the cancer cell will define the actual targets for therapy, therapy that will be designed rather than arrived at empirically as we have done for the past 20 years. It is this molecular distinction between cancers that will allow us to tailor the correct therapy to the correct diagnosis. Because we've made great strides in beginning to understand how we look at the molecular fingerprint of cancer, we've recognized in addition that we can actually accelerate this process. We can do much better. For that reason, the NCI has embarked on an ambitious project to identify all or almost all the genes expressed in cancer versus normal cells. We call this the Cancer Genome Anatomy Project, and its goals are two-fold: to produce a full index of expressed genes for normal, pre-malignant and malignant cells, to help support the development, dissemination and application of a whole new generation of technologies that will alter our approach to detection, to diagnoses and to choosing therapy. This project, which we call CGAP, both builds on and is complementary to the Human Genome Project, and is being done jointly through collaboration between the intramural and extramural programs. CGAP has been developed with explicit annual milestones, and will be, and already, we believe, is, building a national resource that everyone can tap into via the World Wide Web, and this is the Web page for this new CGAP, you can go to it, click on any particular cancer, and what we hope eventually to fill this with is a description of all possible genes, how one would approach asking diagnostic detection and therapeutic questions. [See figure 7.] [Page 210--The official Committee record contains additional material here.] Dr. Klausner. This will be the way that we will learn to detect cryptic cancers, such as ovarian, pancreatic, stomach and others. Again, CGAP involves a collaborative effort with the National Library of Medicine, the Department of Energy and with a series of industrial partners who are co-funding this. There of course are many other initiatives that I would be delighted to share with you. But the challenges and opportunities clearly before us are great. To address these, Mr. Chairman, the budget request for the NCI for fiscal year 1998 totals $2,217,482,000, an increase of over $61 million. I am pleased to be able to appear before the committee, and look forward to answering any questions. [The prepared statement follows:] [Pages 212 - 220--The official Committee record contains additional material here.] mammography Mr. Porter. Dr. Klausner, let me first say that we believe you're doing a wonderful job at NCI in providing leadership not only for your own institute but for many of the other institutes in how you approach the research that you fund. Let me also apologize for being late. I was in a meeting with the full committee Chairman and had every intention of starting us off at 1:30 and was unable to do so. So I apologize to you and Dr. Varmus and everyone in the room. The topic was raised briefly this morning with Dr. Varmus, but I want to begin by discussing the ongoing controversy about mammography guidelines for women in their 40s. NCI initially recommended mammography for this age group, and your predecessor later withdrew the guidelines. You convened a consensus development conference on the subject in light of recent research findings. That group concluded that the evidence was not strong enough to recommend guidelines, and that it should be the individual choice of a woman and her doctor. The press reports that the conference was acrimonious and even raucous. The impression given in the popular press was that you disagreed with the findings of the consensus conference. Some groups charge that you are now changing your mind and supporting the findings. Dr. Klausner, I'd like to know not only your own personal views on this, but the course of events in the recent past and what plans there are for the future to address this very, very serious issue. Dr. Klausner. Absolutely. I think this is a very important, very confusing and, as we've seen, very contentious issue. I think it's the NCI's responsibility to speak clearly about the evidence that we have, to provide guidance to women and their physicians about decision making, guidance that's based upon a clear and balanced description of evidence. And as Dr. Varmus said this morning, the National Cancer Advisory Board, I will be working very closely with them, they have a subcommittee now, we will be working with all due speed in order to provide just that, to provide guidance for us, so that we will, as quickly as possible, communicate a very clear message about what information women and their physicians should use in terms of making decisions about when to begin screening mammography. The question is not whether to do regular mammography screening, the question and the controversy is about when. We will be coming out with what we believe will be very clear statements that will provide guidance so that individuals and physicians can make decisions about this difficult issue. Let me just clarify by simply repeating the things that I've said over the past month, including what I said at the time of the consensus conference. The consensus panel, in looking at all of the latest data, said that in their opinion, they did not think a single uniform recommendation to begin screening mammography for all women in their 40s, was warranted by the data. I think that is not an unreasonable position to take. And what I said is that I agreed with the sentiment of that conclusion. My concern that I said at the time was simply with, and this is important, the wording, the balance and the tone in the draft report. Because I want to make sure, if we are to say that women and their physicians need to be informed to make an educated decision, I want to make sure that we provide the most balanced and clear and least confusing answer to the questions of evidence, to the questions of the evidence for benefit, to the questions about limitations, and the question of risk. And that was where I think some of the confusion comes about who was agreeing and disagreeing. I thought their conclusion was defensible. I was concerned that the draft report, and it is still a draft report, that the draft report did not have the clarity and the balance about the evidence versus the limitations to actually allow women and physicians to make the decisions that they were recommending. Perhaps I can try to spend a few minutes trying to clarify why this is such a complicated, contentious and difficult problem. Let me just say that whatever guidance the NCI provides, I believe, as I've said all along, must be based upon available evidence. I think the National Cancer Institute must base its statements in science and what we know. And as I said at the time and continue to say, while many of us want extremely clear-cut, yes or no, black and white answers to often difficult problems, we cannot nor should not produce certainty or say that there is certainty where there is not. So where are we? Why is this so complicated? There is complete agreement from the data that's available that women 50 and above should have regular screening mammography. There is wide agreement that women below the age of 40 should probably not be recommended to having regular mammography. So we're left with 40 to 49. What happens? How do we know? But why don't we look for data. There have been 8 randomized clinical trials from around the world over the past 30 years that have looked at over 180,000 women who were invited to the trials to begin screening--and this is very important--at some time during their 40s. The average age of women receiving mammograms during those 8 studies is 48. But at some time during the 40s. None of those studies alone have convincing statistically significant data, have enough deaths from breast cancer to reach a conclusion. So all the data, all the studies have been put together through a process called metanalysis to try to see, do they all say something together. When one does that metanalysis, which is fraught with some uncertainties and difficulties, one, and I think there's general agreement on this, that there is approximately a 15 to 17 percent reduction in mortality for beginning screening mammography at some time in the 40s. The data does not address 40, or 40 and 3 months or 45. And of course, one of the problems with the controversy is the way we frame the question. Nothing sudden happens to a woman when she turns 50. And certainly, nothing sudden happens to all women when they turn either 40 or 45 or 50. By asking for a yes/no, black/white question that at this birthday, suddenly there is benefit, we get into this very confusing and contentious argument that evidence and data could not directly address, because in fact it does not fit anything we know about the biology of risk of breast cancer, or breast cancer or the performance of mammography. So there is going to be uncertainty. There will always be some period in which you move and move gradually from when there does not seem to be a benefit that outweighs the limitations and the risks to a period where it clearly does. I think to argue overly about trying to come up with a precise age for all women will keep us in an argument that does not move us beyond an unanswerable question to one that provides useful guidance to women. One size won't fit all. And I think the guidance we will come up with will be based upon the evidence and hopefully will be very useful and clear. I think we can strive for clarity, even when there's not certainty. I think that's what we will be doing over the next month. screening Mr. Porter. Dr. Klausner, correct me if I'm wrong in this, and I may well be, but if this consensus panel had said, and you had agreed, that women should all be screened beginning at the age of 40, have mammographies, then wouldn't that become a guideline that would be widely adopted, particularly in the Medicaid program, for example, and when you say that this is an issue that has to be determined on a case by case basis, aren't you really saying, though, that poor women won't necessarily get screening that might detect cancer early and perhaps save their lives? Dr. Klausner. Well, remember, the difference between a technique being capable of detecting cancer, even detecting it early, and that translating into a benefit, is something we try to determine by doing studies so that we actually make our decisions based on evidence. My feeling is, if there is evidence that supports benefit in the 40s and we don't have anything more precise than that, but that that evidence would support the decision, for some women it may make sense earlier in their 40s, for some women it may make sense later in their 40s. I think that then we can provide that guidance to make sure that those decisions are supportable. This is the type of issue that we will be grappling with over the next couple of weeks to months. I hope, and I think it will be very soon, we will work very quickly, so that the position of the NCI is clear, but does not go beyond what we are comfortable that the evidence actually tells us. Mr. Porter. But if I understand correctly, you're giving a scientific view, and this issue has tremendous public health consequences. For example, women over 50, I believe, the guidelines show that they will get regular mammography. And those under 50 in public programs probably will get nothing. And what you're saying is that at some point, perhaps in their 40s, they need this additional prevention. But if the guidelines don't provide for it, you can be sure that the funding won't be forthcoming, for poor people. Now, for rich, for a wealthy individual, they can go to their individual doctor and the doctor may well say, well, sure, you're 40, but we think you need this. Dr. Klausner. Well, again, I wouldn't want to prejudge what the guidance will be. I think that's unfair to the NCAB process that we're doing now. We're very aware of all these issues. We want to make, we want to provide guidance that will be clear and will be helpful. Right now, I believe it's 40 states require insurance companies, now we're talking about insurance companies, to pay for mammography, I believe it's over the age of 40 or over the age even of 35. And four more states are considering such legislation. ncab subcommittee Mr. Porter. You say you're going back now to develop this. How long will it take and are additional studies needed to develop the responsive guidelines? Dr. Klausner. There is a question whether there's need for more studies. And I believe there certainly is a need for more studies in the early detection of breast cancer and new technologies. And perhaps we can talking about that. But for the process that we started yesterday with the National Cancer Advisory Board, no, we are not looking for new studies. We will be working, there is a subcommittee that has been announced, announced this morning. And they will be working with all due speed. And their expectation is certainly within one or two months to have completed their recommendations to the National Cancer Institute about what message the NCI should communicate to women and providers about this important issue. Mr. Porter. Thank you, Dr. Klausner. Mrs. Lowey. Mrs. Lowey. Thank you, Mr. Chairman. And welcome, Dr. Klausner. I want to express to you my personal appreciation for the outstanding leadership you have provided at the National Cancer Institute. I can assure you, as former Chair of the Women's Caucus, as the daughter of a victim of breast cancer, as the mother of two daughters in their 30s, I share the anxiety of women across America about the issue of mammography screeing guidelines and we appreciate that this advisory board is meeting. And we are hopeful that there can be clear guidelines. But most importantly, I would hope that in the absence of a consensus, that the whole issue of insurance can be resolved and that insurance must cover mammograms. I think we're all agreed on that. Dr. Klausner. Yes. other detection technologies for breast cancer Mrs. Lowey. It seems to me that we've got to provide women in their 40s with clear guidance. I'm hoping that this panel can do just that. However, I'm concerned, that when you look at the statistics, in women under 40, 25 percent of the cases of breast cancer are not detected by mammograms. So I would like to follow up on my colleague's comments to talk about the possibilities of additional research on other techniques. Improvements in mammography quality, greater access to mammograms, certainly have contributed to the decrease in breast cancer mortality. And there's no question that mammograms save lives. And it's the most important screening tool for cancer that we have. However, as you have explained to me and to others, there are fundamental reasons why mammogram technology would never be as accurate as we would like it to be. And mammograms are limited in their ability to pick up aggressive tumors. My concern is, what are we doing about it? Where do we go from here? What alternate technologies is NCI working on that may allow us to detect an aggressive tumor in its earliest stages? Is a blood test for breast cancer, such as the PSA test for prostate cancer, a viable goal? Are there other technologies that hold promise? Even in women above 50, I believe that 10 percent of those tumors are not detected. And again, as a woman, it's very frustrating to many of us to get a mammogram and speak to a friend who then, because of self-examination a week or two later, discovers a tumor. So perhaps you can enlighten us on where we're going from here. Dr. Klausner. Sure. Let me just say, the statistics that we have suggest that it's women under 50, where about 25 percent of cancers are missed. And then in older women, it drops to about 15 to 10 percent that are missed. And as you point out, while mammography is clearly capable of being and is a life saving technology, let me emphasize two things. First of all, in the age groups where we know that regular mammography results in a 30 percent reduction in mortality, still not all women, far from all women, are using, or are availing themselves of access to mammography. And we need to make sure that all women do have access to mammography. Only about 50 percent of women above the age of 50 are having regular mammography. So we need to do much better with that. We also realize the limitation, a 30 percent reduction in mortality, which is very important that we can ascribe to regular mammographic screening. We can turn it around and recognize that 70 percent of breast cancer deaths in women that never have mammograms will still happen in women that have regular mammograms. So mammography is not perfect. It's the best we have right now. But we need to do much better. detection technologies for breast cancer This year, the NCI will be investing over $40 million in studies related to imaging, imaging, as an approach to detection in breast cancer. And I'll come back to molecular approaches like a PSA. These include improving mammography. And we all believe that the most important avenue for improving mammography now is a technology called digital mammography, where instead of using film, you create the image directly through a computer through a variety of sensors, of electronic sensors. And then you can use very sophisticated new techniques of image analysis, can also have telemammography, where you send the images to Centers of Excellence. And we believe that that's a very important area. And much of our investment in mammography development is in this new area of digital mammography. There are lots of other areas of detection technologies for breast cancer. They include technologies that don't include radiation, such as magnetic resonance, both magnetic resonance imaging and something called magnetic resonance spectroscopy, to look at the characteristics of any possible lesions. There are other techniques, such as PET, SPECT, optical imaging, ultrasound, microwave, photon migration. There's really a proliferation of new ideas. And in fact, as I think I've mentioned to you, we've just constituted a new think tank, headed by Dr. David Bragg, to advise us on new opportunities in technology detection. We are also proposing for the first time to establish a standing clinical trials group for diagnostic imaging. So we have available to us an infrastructure that will allow us to test clinically new ideas and new approaches in detection technology for breast cancer and other cancers. And we are actually bringing that to our board next week. So there is a lot that we are doing. But as you said, there are other possibilities for detecting cancer besides just imaging. What do we do when we detect something is important. One of the problems with mammography is most of what we detect is not cancer. And even when we detect something, we're not always sure what to do about it. The answer there I believe is going to come from what I began with, the sort of approach of the cancer genome anatomy project, that will allow us to look at all of the products of cancer cells, and of different types of cancer cells, so that we can learn as quickly as possible, are there PSAs for breast cancer. And when we detect a lesion, will that lesion be able to be ignored? Because while we call it cancer by looking under the microscope, it may not ever do anything. Such as in Ductal Carcinoma In Situ, we don't know which fraction we need to do something about. These are the important ways that we need to look at the future, move forward, so we can improve this limited but important technology. funding allocation decisions Mrs. Lowey. If I may, Mr. Chairman, just following up on that briefly, you mentioned that $40 million was currently being spent on various techniques, mammography, improvements in mammography, etc. Grants are currently reviewed, there's peer review of all grants. However, there are thousands and thousands of grants that are rejected. One of the questions I've had is, how do you determine what percent of the dollars are put in mammography technology or in other forms of technology or in prevention, or in cures? There are many eager scientists out there working in all of these areas. How do you make these determinations? We all know, and perhaps Dr. Varmus knows one, who recently joined the Strang Clinic. He was doing work on brain research, and now is at the Strang Clinic because of a particular grant, and has made major advances in that direction. Often, the scientist will be enticed to pursue a certain field because of the availability of dollars. Most of us, including our Chairman, wish we could double and triple the amount of money, if it could prove productive. So perhaps you can shed some light on that. Dr. Klausner. Well, you're asking an important but, of course, very difficult question. We need to make sure that we're covering in essence all of the bases. We can't choose between prevention or detection and treatment and understanding the basic biology. It's a constant juggling, a constant balance that relates to opportunities, as Dr. Varmus has talked about. When we have a new opportunity, researchers rush in. And that is a very good use of dollars. Because we know there's an idea, there's an opportunity, there's an inspiration. We're closing in on an opportunity to get a definitive answer. It is a very dynamic process. And coupled with that is that we depend upon the larger community to come up with their ideas, they're thinking about this all the time. They produce proposals that then are reviewed for their quality and for their importance, for what they can achieve. And our approach is to allow the distributed wisdom of the entire scientific community to, in essence, interact with us, so that we maintain a balanced portfolio. Because we need to approach this and all of these problems from all possible angles. And often we don't know, as you know very well, we don't know exactly where a new advance is going to come. I know you hear that again and again from us. But it is, it has to be a very dynamic process. Mrs. Lowey. Thank you, Dr. Klausner, and thank you, Mr. Chairman. Mr. Porter. I want to apologize to my colleague, Lou Stokes. We started the year by saying that we would recognize the members in the order in which they arrive at the hearing. But we also said that where you are a ranking member on another subcommittee and have other responsibilities, we would give that member preference. And Mr. Stokes, in VA-HUD, has had a very busy day and had to leave this morning and didn't get a chance to ask his questions. And I'd like to call on him next for that reason. advances in minority health Mr. Stokes. Thank you, Mr. Chairman. Since I didn't get a chance to pose any questions to Dr. Varmus, may I also pose some to him? Mr. Porter. Sure. Mr. Stokes. Dr. Varmus, let me welcome you once again before our subcommittee. It's always a pleasure to have the chance to talk with you. The NIH programs funded by this Subcommittee are absolutely essential to improving, prolonging and protecting the health and well-being of the American people. As you are keenly aware, the health of African-Americans and other minorities lags dramatically behind that of the general population. What major advances in diseases and disorders that disproportionately impact African-Americans and other disadvantaged minorities can you report to the Subcommittee this year? Dr. Varmus. Mr. Stokes, that's an important question and one to which I've given a lot of thought. Because you know we share this concern, that even when we make advances, we still are failing to close the gap between the health of minorities and the health of majority populations. But what I don't want to give you a list of the things that we're trying to do. Because that's not satisfactory. But I think this year I can point to a number of advances that affect minority populations in particular, or have special meaning for minority populations. Because the diseases are common in those populations. Let's start with sickle cell disease. You heard a couple of years ago that we were making significant progress there, because of the drug I mentioned this morning, hydroxyurea, which has a very positive effect on the outcome of the disease, and reduces the episodes of sickle crisis by about 50 percent. In the past year, there's been evidence that bone marrow transplantation can also have a very beneficial effect in quite a significant number of patients. It's a more laborious procedure, but it has been done both in children and in some cases, in fetuses, and had remarkable effect. The experiments with fetuses, I should say, were not done with sickle cell disease, but the same procedure could be applied in sickle cell. And the second area I want to draw to your attention is the area of stroke and hypertension. There has been progress in hypertensive medication over the last several years that has a definite effects on the minority population. Because as you know, African-Americans in particular have a very incidence of hypertensive disease. The advances in treatment of stroke that you'll hear about from Dr. Hall again will have particularly beneficial effects on the minority population because of the high incidence of stroke in that population. You would be right to point out to me that one of the deficiencies thus far in the application of the new treatment of stroke, with tissue plasminogen as an activator, is the need to educate physicians and patients of the urgency of treating stroke. And in many cases, the disparity in health of minority populations can be traced to less aggressive care. And this is one of those situations where it will be particularly important for physicians in rural areas, and physicians treating minority populations to become aware of the advances that have been made in the treatment of stroke. There have been advances in diabetes, another disease which disproportionately affects the minority populations. Understanding some new genes that are involved in the generation of the diabetic state, and continued advances in the long-term management of diabetes. Again, as you would be quick to point out to me, it's important that we get that message out to the provider community and to the patient community, so that we can adapt readily. funding for nih Mr. Stokes. How important, Dr. Varmus, is the research that's done in these various areas throughout the National Institutes of Health? Dr. Varmus. Crucial. Every advance that I've described to you is dependent upon NIH sponsored research. Mr. Stokes. That then brings me to my next question. To my understanding, last year NIH received a percentage increase across the board, did it not? Dr. Varmus. Yes, it did. The NIH increase was 6.9 percent, 6.5 percent in program. Mr. Stokes. Now, did offices such as the Office of Research on Minority Health also receive correspondingly an increase, or percentage increase? Dr. Varmus. Let me point out to you, Mr. Stokes, that that office is not the primary source of funding for minority programs. That office is intended to coordinate the activities, provide stimulus to activities in the institutes. We spend well over a billion dollars a year on projects that we can identify as being highly oriented toward minority health. A very, very small fraction of that goes to the Minority Health Office. Dr. Ruffin's job is to provide a stimulus to those programs. And I believe he does that very effectively. So the increase in spending for minority programs has gone up. minorities and cancer Mr. Stokes. Let me switch to Dr. Klausner for a couple of questions before my time expires. Dr. Klausner, it's always a pleasure to see you. Your cancer mortality by race and gender chart indicates a significant decline in cancer among black men as compared to the rest of the population. Can you elaborate for us on this, that is, which cancers accounted for this decline, what role did prevention play--that is access to health care, early detection and so forth? Dr. Klausner. That's a very good question. These new numbers, in fact, this is figure 2, which shows the difference between men and women, black and white, you can see the enormous increase in the previous 20 years in the mortality rate, especially black men, from cancer, and then what's happened over the past five years. We've just gotten these numbers. We're very encouraged by them. And we have gotten groups of people together to try to analyze exactly what are the components. We see the drop in mortality across a number of cancers, colorectal, lung, bladder, prostate. We're trying to understand these. Because I think that's going to be very important. Here we have an opportunity to see a change in the direction we want to go. We need to understand what we're doing right, if indeed it's something that we're doing right, so that we can stimulate that. And we have groups of people now working on the different sites, as well as the different changes among different racial and ethnic groups, so that we can try to understand this data. And that's the first thing that happens, once you get surveillance and epidemiologic data. We now know this, and we need now to try to understand what's behind it. office of special populations Mr. Stokes. How is that reflected in the budget before us? Is there built into your budget some means for us to be able to detect how you want to build upon this type of progress? Dr. Klausner. Well, as I think I mentioned last year, last year in the spring, I was about to receive a report from what's called a Special Actions Committee specifically about what the NCI should do in terms of its research programs vis-a-vis special populations. And over this past year, we've acted on many of those things. We've established a new Office of Special Populations. I think you know Dr. Otis Brawley, I think he's doing a spectacular job. And what he's doing is systematically going through all of our programs. He has an Advisory Committee as well. He in fact this spring will be making a series of priority recommendations to me. One of the first things that we never had that we're now doing is to create an information base so we know exactly what is going on, what the needs are. It will be setting up a special what we call Progress Review Group of experts to come in and advise us on what are the areas of need coupled with what we're doing. This year, our programs directed at minority programs have increased. There are over 110 projects and programs specifically oriented towards minority populations. And in fiscal year 1998, the budget for that will increase to about $115 million, that is specifically looking only at issues in minority populations. I can go through many of these. But I think the major point is that now we have this office to coordinate these activities. It is a real priority for us. And I think the recommendations, considerations and activities in that office are going to be very important. cancer survivors Mr. Stokes. You mentioned, Dr. Klausner, that over 10 million Americans are cancer survivors. What is the racial and ethnic percentage distribution of these survivors? Dr. Klausner. I do not know the answer to that, but I will get that. [The information follows:] The Racial and Ethnic Percentage Distribution of Cancer Survivors Of the approximately 10 million Americans who are cancer survivors, approximately 91% are white, 7% are black and Hispanic and 2% are other minorities: Asian, Hawaiian, American Indian, etc. five-year survival rates Mr. Stokes. What is the current five-year survival rate for the five leading cancers in African-Americans? Dr. Klausner. The five leading cancers for African- Americans include, lung cancer is the number one, prostate cancer, colon cancer, breast cancer, and I believe pancreatic cancer is the fifth. The five-year survival rates for lung and pancreatic cancer are and have been and remain dismal. The five-year survival rates are increasing for the other cancers. I may misquote if I try from memory to give you the exact five- year survival rates. But what I will say, we still continue to see a significant disparity between the five-year survival rates between African-Americans and white Americans. We see a disparity in almost all these cancers in terms of the stage of diagnosis and in terms of the outcome. For example, breast cancer incidence among women over the age of 50 is lower among African-American women than among white women. That's the corrected incidence. And yet mortality rates are about the same. So again, we've seen in each of these cancers, there's now for the first time an improvement. So we're seeing it move in the right direction. Mortality rates are higher. Survival rates are lower for each of those, for colorectal, for breast and for prostate. For lung and pancreas, again, I don't think there's a significant difference in survival, as far as I know. Mr. Stokes. I see that I am out of time, Mr. Chairman. Mr. Porter. Yes, actually you are. Mr. Stokes. All right, thank you, Mr. Chairman. Mr. Porter. Thank you, Mr. Stokes. Mr. Miller. nih reauthorization Mr. Miller. I'm sorry I missed this morning with Dr. Varmus. In my area of Florida, the Sarasota, Florida area, I don't have a center in my area or district, but Moffitt is not too far away. So I was there this past fall when they celebrated their anniversary, along with Congressman Young of our committee, who is very involved with it because of this committee and because of Defense money that flows into cancer research, and also Congressman Bilirakis who is from that area. So we are all there together, which makes me want to ask the question, where do we stand on reauthorization of NIH? NIH is not authorized right now, is that correct? Dr. Varmus. Well, we still have authorization under the original Public Service Act. Mr. Miller. Right. Dr. Varmus. Last year, a bill was passed by the Senate, after being written by Senator Nancy Kassebaum's committee, but it wasn't taken up by the House, by the corresponding House committee. This year, we are hoping to go through the authorization process. We're working at the staff level to try to make that happen. Mr. Miller. Is there a sense that it may be taken up? Dr. Varmus. Yes, I think it's very likely. Mr. Miller. It's Congressman Bilirakis' committee? Dr. Varmus. Yes, that's correct. In the House. angiogenesis Mr. Miller. But at any rate, I've always been impressed with what they've been doing at Moffitt. I have visited often. They've come a long way. I happened to see you on ABC news Monday evening, and it raises questions and level of interest about you, you have a very difficult job. You have to cover all the bases of prevention and treatment and detection, and where you allocate your resources. Then all of a sudden, in this case, ABC news picked out one area. And I wonder, what impact does national media has in program selection? You have hundreds of programs. And this one on that special that you were commenting about Monday evening, is this---- Dr. Klausner. I believe this was on angiogenesis? Mr. Miller. Yes. Dr. Klausner. Yes. I didn't see it, but---- Mr. Miller. You came across very positive and very focused. Dr. Klausner. Oh, thank you. Mr. Miller. And very photogenic on television. Dr. Klausner. Well, I think the media has tended to pick up things that the scientific community views as interesting or hot. And this is clearly one of those examples. If I can say something about angiogenesis. While we talk about how each cancer is different, one of the things we've realized about all cancers is that in order for them to grow beyond a certain point and to spread, and that's what kills people, that they spread, is that they need to make sure that they establish their own blood supply. The blood supply isn't there for them. And so cancers, in order to kill people, have to be able to create a new blood supply, which is really pretty extraordinary. And that has led many investigators to recognize a blood supply specific for tumors. It's called angiogenesis for birth of vessel, and is a remarkably attractive target for anti-cancer therapy. Some have even claimed that if all these tumor vessels are the same, maybe all we'd have to do is develop a therapy targeted against the blood vessels. Others say that there will likely never be a single treatment for cancer may not be so accurate. I think we need to be cautious about that, as I think I was on that show, because there may be many types of blood vessels for different types of cancer. But the point is, this is a whole new approach to the treatment of cancer. And the early studies which are in animals look extremely promising. Right now, the NCI is supporting I think somewhere between 10 and 20 new agents that are being developed that are directed either at killing the blood vessel cells or at clotting the blood vessel, or at preventing the blood vessel cells from growing, or at stimulating those cells to kill themselves. There's a whole bunch of different approaches. We are in fact very excited about this area. Being excited is wonderful. It helps us keep going. And we'll just have to see how well this looks. But we are putting this new approach on a fast track for development. And in fact, I've just recently asked for there to be a special meeting at the NCI so that we can talk with the investigators, with people who are excited, as well as skeptical about this, to come together and help advise us along with the industry, how we push forward developing these new agents into clinical trials. Dr. Varmus. May I comment just briefly about this? Mr. Miller. Yes. Dr. Varmus. This is a good illustration of an area in which research toward one remedy, that is cutting off the blood supply to a cancer, is also research on other kinds of therapies. Those therapies that are designed to increase the blood supply to organs like the brain and the heart and the kidney and peripheral muscles, because the same principles that are involved in trying to interfere with blood vessel growth to tumors are being exploited to enhance blood vessel growth to the heart, to the brain and to other organs affected by diminished blood supply that frequently accompanies aging. areas impacting on cancer Mr. Miller. On that line of thought for just a minute, I know Mr. Istook was talking about it this morning, the question of how much money goes to different diseases. Some people question what AIDS gets on a per capita basis to the persons exposed to AIDS, they think it's far too much money compared to cancer. Part of the explanation that Dr. Varmus has made, and I agree, is that, as you just made here, research applies over all areas, it's not just targeted. Can you, Dr. Klausner, identify areas that research outside of NCI have had a direct impact on types of research? For example, AIDS research, immune system, that has been able to draw from that to be beneficial in the cancer area? Dr. Klausner. Oh, absolutely. We wouldn't be able to make the progress we think are making in terms of cancer, in any sort of vacuum. And we rely totally on the entire enterprise. Let me just give you one example that was just published last month that I'm particularly intrigued about, coming from work looking at diabetes and at the development of fat cells. It turns out that there's a critical gene, and this gene is like the gate that determines, as primarily a single gene, whether a cell becomes a fat cell. It's called PPAR gamma. And this is work that's been worked on by Ron Evans and Spiegelman. And what they found is that, they found this particular receptor, and have found drugs that stimulate this receptor. And in fact, some of these drugs have recently been approved by the FDA for treatment of adult onset diabetes. Now, what does this have to do with cancer? It turns out, the most common type of sarcoma in adults are liposarcomas, that relates to the lineage that relates to fat cells. It turns out what's been recently published, just a month ago, is that all of these sorts of tumor cells have this receptor. And when you give this very non-toxic drug, the tumor cells stop growing, differentiate to just be fat cells. Now, this is just an experiment in the lab. But in fact, they are now moving and we're talking with them to move very quickly to clinical trials for this currently relatively untreatable form of cancer, these sarcomas. And this is just one example. It goes on and on. The fact is, we are a very integrated community, and that's very good. Mr. Miller. You sound very optimistic about the direction of cancer research, more optimistic than ever, through so many different areas. We see a light at the end of the tunnel, maybe. Dr. Klausner. We certainly see a lot of light. Mr. Miller. Thank you, Mr. Chairman. Mr. Porter. Thank you, Mr. Miller. Ms. Pelosi. environmental links to breast cancer Ms. Pelosi. Thank you, Mr. Chairman. I too want to join with my colleagues in welcoming you, Dr. Klausner, and thanking you for your leadership. I personally want to thank you for the time you took to come to the Bay area last summer to meet with researchers and breast cancer activists in our community about our high rate of breast cancer. We were all very appreciative of the opportunity to have you come out and speak with our group, but also for you to listen to our concerns regarding the possible environmental links to breast cancer. As you know, that has been one of the questions I keep posing to our distinguished scientists who come before us, is the answer in the lab? Yes. Is part of the answer outside? Let's see. Dr. Varmus, in fact, testified this morning that the precise changes that occur in genes during our lifetimes are telling us how environmental agents like tobacco and sunlight cause cancer by inducing mutations, and how normal mechanisms for correction of DNA can fail, allowing harmful mistakes to persist in our genetic material. Is that correct, Dr. Varmus? Dr. Varmus. Correct. Ms. Pelosi. I did better than I think I did with my Transportation Committee and the cloning story. As you hopefully both know, and I know Dr. Klausner does, the San Francisco Bay area has one of the highest breast cancer rates in the world. You're aware of the great concern. Dr. Klausner. Yes. san francisco bay area Ms. Pelosi. And that there is a concern we have that this high rate is linked to environmental factors. Report language in the fiscal year 1997 bill urges the NCI to work with community groups and the National Institute on Environmental Health Sciences on this concern. I have a question about the NCI's report to this language in the budget justification. You cite the Long Island breast cancer study project as an example, and I commend my colleague, Congresswoman Lowey, for her success with that project. The studies from the Bay Area cited in the response are not studies of breast cancer in the Bay Area. And only one, which is not funded by the Government, looks at the epidemiology of breast cancer. Does the NCI intend to study the San Francisco Bay Area with regard to the possible environmental link to breast cancer? I would just, as you answer, also consider in our area possible exposure sources to radiation are plentiful. If you would answer that with a current assessment of the possible role of radiation as an environmental factor in causing breast cancer. Dr. Klausner. Yes. We've made it very clear that we're interested in supporting studies in areas where there appears to be an excess of any cancer, but certainly breast cancer, that cannot be explained by known risk factors. And in fact, I have met, subsequent to coming out to San Francisco, with researchers from that area who came to the NCI to talk to them about grants that they could put in and our interest in funding such studies. But they have to put in the grants, and we'll see what happens. What is going on now in the San Francisco area is to analyze the data to actually try to understand whether there is, in fact, an excess and how much of an excess, when one takes into consideration known risk factors. All of the evidence that we have suggests that modifiable factors, whether it's diet or environment, change the risk of breast cancer. We see that from migration studies, we see that from the differences in incidence of breast cancer in different areas of the world, and especially, as I said, when people move. It's been extremely difficult, despite many, many studies, to pin down specific risks from the environment. It doesn't mean we should stop, we should keep going. I happen to think, as I said in my opening statement, that we need a new approach, such as this reverse epidemiology, where we can look at the breast cells themselves to try to see whether breast cancers in particular areas have a different pattern of DNA damage that might tell us that there's a type of carcinogen that those women are being exposed to. Certainly, as we've learned over the past year, when we reanalyze the data of local or regional variation in breast cancer incidence, when we correct for known risk factors, and there are, as we know, multiple known risk factors, even though we don't understand all of them, then those regional differences, not entirely, but largely, go away. Seventy percent or more of those differences no longer exist. And this was published last year from researchers at the NCI. Currently, there are studies at Stanford University specifically to do the same thing in the San Francisco Bay Area. We really need to know that. We need to be able to subtract out known risk factors in order to really get hints that there may be regions that would be amenable to the type of epidemiologic study that would be hopefully useful in tracking down environmental culprits. Ms. Pelosi. So the status of the study would be, there's an opportunity for a grant, should the grant application be made. But if this Stanford---- Dr. Klausner. This is actually already going on, and we're actually just waiting for the result of this now. Ms. Pelosi. I understand. But is that a preface to what---- Dr. Klausner. No, absolutely not. Ms. Pelosi. You said--what I heard, and I might have misunderstood, was that this would decide whether this would be---- Dr. Klausner. I think in order to interpret and understand epidemiologic studies, we need to make sure that we understand the full range of risk factors, so that when we're trying to correlate, the way epidemiologic studies go, you observe peaks of disease and try to correlate that with something you can measure, an environmental exposure, radiation, diet, etc. So you really need to make sure you have a full data set to make sure those correlations are going to be informative. Ms. Pelosi. I see, okay. So I should tell our folks back home to get their pencils out and---- Dr. Klausner. I think they've already heard that message and are doing that. Ms. Pelosi [continuing]. That the ball is in their court, and that's where the initiative will come from now. Dr. Klausner. Yes, ma'am. breast cancer survival Ms. Pelosi. I appreciate your response. Thank you, Dr. Klausner. With relation to the continued funding of mammography and the question that has been before the committee this afternoon, in the interest of time, I won't go into that, but to associate myself with the concerns expressed by our Chairman and others, and the statements of Mr. Obey when he said that whatever the decision is about what age, etc., that it should be science- based. But I would add to that, when it is a question that it should come down certainly in favor of women's health. Because it is so that although there's a lower rate of incidence of breast cancer among younger women, there's a lower survival rate, as well, is that not so? Dr. Klausner. Yes, there is a somewhat lower survival rate for women who are diagnosed with cancer at a younger age. There is some, it's either a subset, and probably is a subset that changes those statistics of what appears to be more aggressive cancer in younger women. clinical treatment Ms. Pelosi. In the past year, dividing the world now since this morning into culminations and inspirations, and I just wondered if there were any culminations in the clinical treatment of breast cancer, is culmination too high a standard to put on that, in the past year? Dr. Klausner. We'd have to ask Dr. Varmus for exactly his definition. We can get a reading from the Office of General Counsel, I guess, about the exact definition of a culmination. Ms. Pelosi. Last year we went through this on the word breakthrough. Dr. Varmus. I've never felt so influential, Ms. Pelosi. Ms. Pelosi. Well, you are a man of words, is that not your original training, Dr. Varmus? Dr. Klausner. There have been advances in the clinical treatment. And we are anticipating the results of some important studies in treatment, just over the next few months. But I will hasten to add that these advances are incremental. They are not the dramatic changes that we would like to see. prostate cancer Ms. Pelosi. The same thing for prostate cancer as well? Dr. Klausner. I think for new therapies for prostate cancer, we have not seen any results in the past year that suggest that we are learning to improve mortality through new therapies, therapies that we hadn't had before. Whereas, in breast cancer, we do have upcoming results of, as I said, neo- adjuvant therapy, the value of giving chemotherapy before surgery, with the idea that you can reduce the size of the tumor, perhaps even then significantly reducing the type of surgery that needs to be done. breast cancer--abmt We are finishing accrual, finally, for the first study to look at autologous bone marrow transplantation in advanced breast cancer. And we expect early results by August of 1998. We have a series of results that will be coming out soon, or that have come out, that all suggest that more intensified chemotherapy or combinations of anti-hormonal and chemotherapy improve disease-free survival in different subgroups or survival in different subgroups of women with breast cancer. What this adds to is unfortunately a slow but a clear incremental set of advances in our understanding of how to approach each woman with breast cancer in terms of making therapeutic decisions. access to care Ms. Pelosi. Thank you, Dr. Klausner. In closing, Mr. Chairman, I just want to associate myself with the concerns also expressed by Congressman Stokes. I see a big change in what we're hearing presented by the NIH and the NCI from several years ago before this committee. And I truly believe that what you do there shouldn't be a trickle-down so that minorities and women, for example, eventually reap the benefit of research that you do on white males as concerned as I am about white males as well. But all that I hear tells me over and over again for the need for universal access to quality health care. Because prevention, I keep saying it, early detection and prevention are so essential. Access to quality health care, if that were increased in the minority community, I'm sure it would reduce the incidence of some of this disease, as well as not only enriching personal lives, but costs to our economy as well. Thank you, Mr. Chairman. Dr. Klausner. Can I make one quick comment? Mr. Porter. Yes, surely. Dr. Klausner. About that issue of access to care that relates to what Mr. Stokes asked me. The NCI and the Department of Defense completed a study looking at the outcome of prostate cancer in African-Americans versus whites, where the outcome in general is quite different, as we've said. But now within a system of equal access and equal care, and the outcomes were the same. I think that's a very, very important thing that we've recently learned. And it reinforces that. I also want to thank you for hosting me in San Francisco and introducing me to a restaurant that I've gone back to many times. [Laughter.] Mr. Porter. Thank you, Ms. Pelosi. Mr. Istook. Mr. Istook. Well, if you come to Oklahoma, we'll give you good barbecue. [Laughter.] I was going to inquire, Dr. Klausner, Mr. Stokes beat me to it, you had in your testimony of course the reference to the significantly larger, higher incidence of cancer and cancer mortality in blacks. I share his interest in getting further information from you, not only on the situation, but on the allocation of resources to that. Because that's a very, very major differential that I know you'll want to reflect in your research allocations. I did want to inquire, I'm also, as Mr. Bonilla is, on the Defense subcommittee. And there are certainly certain aspects of medical research that get significant funding from that. One major one is breast cancer. Where women in the armed forces certainly supply a, base is not the right word, but a population that can be utilized in those studies, for that matter, they could also utilize men in the armed services for prostate cancer research. Dr. Klausner. Right. coordination with dod Mr. Istook. My question on that is, can you describe to me what level of coordination there is or is not, where you think it's sufficient, where you think it may be deficient, in the coordination of cancer research with the significant monies that are being spent on that through the Defense budget? Dr. Klausner. I think that's an excellent question, and I am very pleased with the level of interaction and communication that we have with the Department of Defense, especially under the leadership of Dr. Joseph. As you know, we established last year a model system, which is an integration of the DOD health care system with the NCI clinical trials system, so that all phase two and three therapeutic trials for the NCI, that there is access to those trials for anyone within the 8.3 million member. It's not just uniformed individuals, 8.3 million member health care system. We are going to have a day or day and a half retreat I believe beginning March 18th with the Department of Defense specifically to look at how to extend that program and to further coordinate and integrate our research efforts and planning efforts in cancer. So I think the interactions have been really excellent. And we're learning a tremendous amount from this new interaction we have in terms of clinical trials in cancer. Mr. Istook. I would appreciate, I'm sure there's some documents that describe the relationship, that there's always concerns about overlap in grant application process and research. And you may decide you want to fund a particular program, but they may be interested in funding the same one. There's a lot of elements in coordination. Dr. Klausner. I'd be happy to provide that. Mr. Istook. That would be much appreciated. [The information follows:] Coordination Efforts With DOD NCI staff has maintained close contact with the DOD staff of the Breast Cancer Research Program (BCRP) since its inception in 1993. An NCI representative is a member of the BCRP Integration Panel, which is responsible for advising the DOD on the overall direction of the Program and its investment strategy, and provides a second-level review for grants, much as does NCI's National Cancer Advisory Board (NCAB). Other NCI scientists have served as members of many of the scientific review panels convened to review grant applications to the Program and as ad hoc consultants to the Integration Panel at several programmatic meetings. Using the NCI data base resources NCI has performed a portfolio analysis of all its grants and contracts with a breast cancer component. This information includes number of active grants and contracts and level of funding in each of the tracking categories in use by the DOD's grants administration unit. This information is also provided to members of the Integration Panel at the yearly meetings when grant funding recommendations are made to the DOD. The purpose of this information sharing is to avoid unnecessary scientific overlap and duplication and to maximize resources for breast cancer research for both NCI and the DOD Breast Cancer Research Program. Further coordination is provided through the NIH Inter- Agency Breast and Gynecologic Cancer Working Group, which was established by NCI in 1993. This group, which is chaired by an NCI staff member, serves to coordinate the research of numerous agencies in breast and gynecologic cancer. Representatives from all NIH Institutes with an interest in this area, as well as representatives from DOD, DHHS-Office on Women's Health, Uniformed Services University of Health Sciences, EPA, FDA, and NIOSH attend monthly meetings of this group, which serves as a clearinghouse for information dissemination and scientific exchange. The NCI has recently established a Breast Cancer Progress Review Group. The Review Group will examine the field of breast cancer research and the current NCI efforts in this field. The results of this analysis will be made available to the DOD Integration Panel. professional judgment budget Mr. Istook. I also, I recognize of course that each institute, as you indicated before, receives benefit from the research in other institutes. And there is a lot of crossover in that. Nevertheless, everybody is jealous of their own funding and wanting to maximize that, that they know they can focus on areas most likely to benefit their particular focal area. I wanted to inquire, and you've probably got this in some documents that you can get to me as well, if the NCI funding were at a higher level, what are the areas in which you would want to increase the cancer research funding? And that could be by type of cancer, that could be by some other descriptive term, but what would those be? Dr. Klausner. Well, we're asked to provide an annual, essentially professional judgment budget, the so-called bypass budget. And I'd be happy to provide this to you. But actually, the way we wrote this bypass budget last year, and now we're working on a new one this year, is exactly in terms of delineating new priority opportunities that if there was a sufficient increase of funds, what we would be able to fund. We described them in terms of fairly exact budgets, milestones, accomplishments, explanations, and where the opportunity is. I'm happy to provide you with a copy of this bypass budget, and I think it does explain that process. Mr. Istook. If you would, and I'll certainly look at it. If there's some very summary fashion overview of what funding is, since it's getting near the NCAA tournament, we ought to say what funding is on the bubble. [Clerk's note.--Information submitted was too voluminous to be printed and is available in Committee files.] Dr. Klausner. I'd be happy to actually give that to you in terms of the types of priorities that we identify. opportunities Mr. Istook. Right. There's nothing you'd want to give a quick overview on? Dr. Klausner. Oh, yes. The way we did it, we first stepped back and established a set of criteria for what was what we call an extraordinary opportunity. And we had a very extensive process of asking the community at large to feed in what are extraordinary opportunities, what we could say reasonably if we had an unexpected increase in available resources, what we might be able to accomplish, that would push forward cancer research. So we went through that process. And these were clinicians, epidemiologists, basic scientists. And overwhelmingly, there was a confluence on five areas that met those criteria, that we were ready to go if we had the new investment. There wasn't just a fantasy, we were ready to go. And they were areas such as a new approach to developmental diagnostics, how to actually make real this new possibility of molecular diagnostics for cancer, new detection technology, so that we actually can detect things very sensitively and know what we were detecting. Cancer genetics, an important problem. And in cancer genetics, how to develop the field of the interface between genetics and the environment and diet. And a fourth area was the need for animal models. Or for what we call pre-clinical models, from some of the advances that Dr. Varmus talked about, there's a whole new way that we can look at organisms, very simple organisms to fairly complex organisms, such as the mouse, to create real understandings of the processes of cancer. So those were some of the examples. They were really infrastructure needs that in fact we feel would advance all cancer. Mr. Istook. Sure, I appreciate that. And I guess Dr. Varmus, this probably is best for you, the same process that he described of saying where the next steps would be with funding, is that something that each institute does in the same fashion, essentially? Dr. Varmus. Not exactly the same fashion. One difference is that the Cancer Institute always has a bypass budget, which provides them with a chance to think about what they would do with a great deal more money than they're likely to get, given the current constraints. But as I mentioned this morning, I don't believe you were in the room, I was talking about how we put together the request for new money in what I call the areas of NIH research emphasis. That's done by having each institute spend some time with its constituents, its scientists on the outside and the inside, coming then to me with a list of things they would like to emphasize as new research priorities, and reevaluate those together. And we build a series of budgets at different levels of increase, at which we would spend different amounts of money on longer lists of those projects as the amount of money gets greater. So we are trying to prioritize within those available new opportunities. Mr. Istook. Okay. And whatever the most parallel document might be from the other institutes, I would appreciate getting a copy of that from the others, too. That would be helpful. Dr. Varmus. All right. [Clerk's note.--Information submitted was too voluminous to be printed and is available in Committee files.] Mr. Istook. Thank you very much. Thank you, Mr. Chairman. Mr. Porter. Thank you, Mr. Istook. Ms. DeLauro. ovarian cancer Ms. DeLauro. Thank you, Mr. Chairman. Welcome, Dr. Klausner. Just three or four questions. First of all, I'm very excited when we have the opportunity to talk about what you are doing with the genome anatomy project and the focus on ovarian cancer. In last year's report language, the committee asked NCI to provide funding for ovarian cancer research under SPORE. Just a question on whether or not that's been done. Dr. Klausner. Let me go back and talk a little bit about our advances in ovarian cancer. I think Dr. Varmus did an excellent job of describing what we're doing. I just want to reemphasize what he said, that almost half of 60 clinical trials are looking at new therapies, new agents, from gene therapy to immunologic therapies. And as he said, for the first time, we have agents, that are far from perfect, that are showing responsiveness in advanced ovarian cancer. We have just opened what we think will be an important trial in looking at bone marrow transplantation and stem cell replacement with much more intensified chemotherapy for ovarian cancer. But as you pointed out, the problem with ovarian cancer is that it's a secret cancer. It's hidden. And the majority of cases are not diagnosed until they are advanced, when our ability to cure is much more limited, as you pointed out. That's one of the reasons we put ovarian cancer in the first year of the cancer genome anatomy project. We've already begun to make what we call the libraries from ovarian cancer cells, so that we can in a systematic way search for tags, molecules, that can act as flags for us, that will provide us with better detection, hopefully earlier detection, as well as new insight into how to intervene in ovarian cancer. I think that's really going to be a very important investment. Let me also say that there was another advance that I think is going to be important for ovarian cancer recently reported, and that is the first evidence that one can observe pre- malignant changes in ovaries. Now, for a long time, that's never been seen. These are in individuals at high risk. That is going to be very important, because it's going to give us the opportunity to ask the questions, what are the cells and what are the events that initiate or move forward the progress of the changes that result in ovarian cancer. I think that's an important research advance. Now, in terms of the SPORE, we did not fund a new SPORE in ovarian cancer. The reason is, the SPORE, or the Specialized Program in Research Excellence program is a new one. As a program, it's experimental. And our advisors have advised us that the program should be reviewed. And we plan to review it. There's much to say that these programs can work very well. So this is not any idea that we're not going to continue this. But we really felt that this specific mechanism required a careful review so we would learn from the first several years what is the best way to organize and fund a SPORE, and whether the SPORE mechanism is the best mechanism for this type of transitional research. Ms. DeLauro. What's the timing on this? Dr. Klausner. I think our plan to do that is either next year or the year after. One of the reasons is that we've just completed a very extensive complete review of our whole cancer centers program. I'd be happy to talk about that. And most of the SPOREs are within NCI cancer centers. human papillomavirus Ms. DeLauro. Also with regard to last year's report language, it encouraged NCI and the NIAID to collaborate in sponsoring basic and clinical research on HPV diagnosis and prevention. Can you tell me if this has been done? Dr. Klausner. Yes. A lot has happened with HPV--there's several things. First of all, there are at least, I think, six clinical trials going on now or about to go on, on therapeutic vaccines aimed against HPV or HPV gene products. These are vaccines attempting to mobilize the immune system for patients with cervical cancer. Ninety percent of cervical cancer is caused by a series of subtypes of HPV. As I mentioned in my opening statement, there have been some recent advances in moving towards what may well be an effective vaccine against oncogenic or cancer-causing forms of HPV. And we are working closely with NIAID, and in fact, researchers from multiple institutes. This is another example where researchers are involved in vaccines from the Child Health Institute and others. And we have made a commitment that we will move forward to develop a multi-valent vaccine aimed at attempting to vaccinate against the subtypes that are responsible for 80 percent of cervical cancer. office of cancer survivorship Ms. DeLauro. NCI has established, you said, a new office for cancer survivorship? Dr. Klausner. Yes. Ms. DeLauro. What kinds of activities will be performed there? Dr. Klausner. That office is to coordinate a whole range of activities related to the long-term medical, psychological, psychosocial and biologic consequences of cancer, including looking at second cancers, late recurrences, the effects of the current therapies that we use, psychological aspects of being a cancer survivor, cost and health outcomes issues. There are four initiatives already. We had a meeting in November, we brought together a large number of people. They created within a month a very good report, which I'd be happy to provide for you, which laid out what a research agenda would look like for long-term survivorship. I then gave the staff about a month to act on that, to create a series of initiatives. We have four types of initiatives, including a proposal for an RFA that we'll be bringing to our board next week for a whole series of research programs aimed at answering quality of life issues, and that whole range of issues I just described, as well as providing supplemental funding to cancer centers, to cooperative groups, to SEER registry system, and to other national and international registries so that we can quickly get answers to the issue of long-term effects of cancer and survivorship. Ms. DeLauro. Let me just say that I'm sure all the members on this committee want to work very closely with you on some of these issues--the issue of HPV and what that means in terms of cutting back, and in terms of cervical cancer. You have such good information. I continue to look forward to working very closely with you in seeing how we can move the agenda along as quickly as we can. Thank you very much. Dr. Klausner. Thank you. Mr. Porter. Thank you, Ms. DeLauro. We have myriad questions for the record that we would ask that you address for us, Dr. Klausner. By all accounts, you're doing an excellent job at NCI, and the obvious intellect and enthusiasm and energy you bring to that endeavor is just amazing to us. And we very much enjoy working with you and seeing the progress that you are making. So we thank you for your testimony this afternoon, and appreciate your candor and directness in answering all of our questions. Dr. Klausner. Thank you very much. Mr. Porter. Thank you so much, Dr. Klausner. The subcommittee will stand in recess briefly. [The following questions were submitted to be answered for the record.] [Pages 244 - 418--The official Committee record contains additional material here.] Wednesday, February 26, 1997. NATIONAL EYE INSTITUTE WITNESSES CARL KUPFER, M.D., DIRECTOR EDWARD McMANUS, DEPUTY DIRECTOR JACK McLAUGHLIN, Ph.D., DIRECTOR, DIVISION OF EXTRAMURAL RESEARCH CAROL LIPSON FIVOZINSKY, BUDGET OFFICER HAROLD VARMUS, M.D., DIRECTOR, NATIONAL INSTITUTES OF HEALTH DENNIS P. WILLIAMS, DEPUTY ASSISTANT SECRETARY, BUDGET, DEPARTMENT OF HEALTH AND HUMAN SERVICES Mr. Porter. The subcommittee will come to order. We are pleased this afternoon to welcome Dr. Carl Kupfer, the Director of the National Eye Institute. Dr. Kupfer, it's very good to see you. I think I'm going to have you to myself. But why don't you proceed with your statement, and then we'll go into questions. Introduction of Witnesses Dr. Kupfer. Thank you, Mr. Chairman. Perhaps before I begin I might just introduce those to my left who are representing the National Eye Institute also. To the far left is Ms. Carol Fivozinsky, who is our budget officer. Next to her is Mr. Ed McManus, who is the deputy director. And to my immediate left is Dr. Jack McLaughlin, who is the associate director for extramural programs. Opening Statement Mr. Chairman, the National Eye Institute continues to support research on the vast array of blinding eye diseases, but today I would like to focus on some of the exciting new areas of research that really impact upon the concerns amongst our older Americans. It's a condition which is the main cause of visual disability and blindness. At present, there are 1.7 million Americans over the age of 60 who suffer from severe visual impairment and blindness, and by the year 2030 this number will be increased to about 6.3 million. This is a condition called ``age related macular degeneration,'' and then the term ``age-related,'' that tells you why there's going to be such an increase as our baby boomers, who are just reaching age 50, will continue to go into the 60 and above age group. We are pursuing a number of very exciting areas, and I'd like to just very briefly tell you what they are. In the laboratory, we are very interested in the evaluation of growth factors, and these are factors that can rescue cells and allow regeneration to take place in the central nervous system and the retina, which is affected by age-related macular degeneration. The retina is part of the central nervous system. The disease affects the macula, which is that part of the retina we use for straight-ahead vision. We use it for reading, for driving, for sewing. And, therefore, the individual who has age-related macular degeneration is unable to do these activities, but fortunately can still get about and ambulate, although the impact on quality of life is very severe. We are very much interested in an item that Dr. Klausner brought up, and that is blood vessel growth. Just as blood vessels are important to maintain the integrity of a cancer, and if you could reduce the amount of blood vessels, you can kill the cancer. There are eye conditions--age-related macular degeneration being one and diabetic retinopathy being a second--where new blood vessels form. And we are actively engaged in looking at factors that prevent proliferation of new blood vessels--we, and people in the Cancer Institute, and the many other institutes who are interested in preventing abnormal blood vessel growth. We are pursuing techniques for the introduction of genes into the retina, and this has been accomplished in experimental animals, and I think in the next two or three or four years we will begin to see these experiments done in patients. We are very much interested in retinal cell transplants. This, again, is going to be primarily done in experimental animals for the foreseeable future, because there are many very important aspects of this type of work, including graft rejection, that must be overcome before we can assure that a clinical trial is worth doing. And, finally, there is a condition in which the cell seems to commit suicide, and a number of diseases, including glaucoma and macular degeneration, appear to share this problem. We want to know what regulates this activity and how we can turn it off. From a clinical point of view, we are well into our Age- Related Eye Disease Study, which involves some 4,700 patients, and from this study we will be able to assess the aging process of a retina, the potential risk factors that may predispose to the development of age-related macular degeneration. We're very much interested in measuring the quality of life, and we do have an instrument, a questionnaire, that enables us to assess this very quantitatively. And, finally, there is a clinical trial component to look at the effect of certain vitamins and minerals as to whether they can be of benefit in slowing down the degenerative process. We are also beginning two new studies in which we're evaluating the genetic factors in macular degeneration. There are a number of families in which two or more members do have macular degeneration, either in the same generation or in two generations, and we're looking very aggressively at what the genetic factors might be. I don't want to forget to mention that we are also very much interested in the infant and the young child. We recently announced the results of our retinopathy of prematurity study in which freezing the outside of the eye has reduced blindness considerably, now that we're able to measure the vision at age five-and-a-half and six years. As far as young Americans are concerned, we've had a very interesting experience with a pilot study in which patients with uveitis who are on large amounts of drugs, which do have adverse side effects, can have those drugs reduced by the introduction of a purified protein derived from the retina is actually fed to the patient. The National Eye Institute is requesting for 1998 a budget figure of $330,955,000. Mr. Chairman, I'd be happy to answer any questions. [The prepared statement follows:] [Pages 422 - 425--The official Committee record contains additional material here.] professional judgment budget Mr. Porter. Thank you, Dr. Kupfer. I'm inclined to want to ask you first about the budget number. We understand that the request, including the OAR transfer, would be roughly $340.4 million, up about $8 million over the fiscal year 1997 appropriation. And I'd like to know what, in your professional judgment, your budget should be. In other words, what could you reasonably really use? How much promising research is there in the area of the eye? And won't you, in fact, because of inflation, be actually working with less money in the next fiscal year if we were to fund you at the $340 million level than you have to work with right now? Dr. Kupfer. I did mention in my opening statement those areas that are very promising that have to do with age-related macular degeneration. And, of course, they impact on other retinal diseases, such as retinitis pigmentosa. And we would go ahead and take advantage of these research opportunities, no matter what. In fact, in the last three or four years we have increased the amount of money in age-related macular degeneration from $5 to $17 million, and the present level of support of retinal research is about $70 to $75 million. [Clerk's note.--later corrected to ``$16''] But there are other opportunities. For instance, just in the last two weeks a gene for glaucoma was discovered, and the exciting thing about this is that usually when we find the gene, we aren't quite sure what it does, because we first have to find out what the gene produces in the way of a protein and determine what the protein does. In this case we not only know where the gene is; we can identify the gene, we know what protein it produces, and we know what the protein does--it clogs up the out-flow channels in glaucoma. And we can immediately apply this within the year to screening families that have this form of juvenile glaucoma-- that is, they develop the blindness within the second and third decade of life--and identify quite convincingly those individuals who are at high risk of going blind. So this is an area that should immediately be followed up very aggressively in terms of how does this finding apply to open-angle glaucoma, which is the main form of glaucoma throughout the United States and the world. In particular, that happens to be a very major problem amongst African-Americans. It's about six times more common in African-Americans than Caucasians. [Clerk's note.--``to seven'' later added.] So there are other opportunities. In cornea research we now have for the first time identified channels in the cornea through which water is transported. And, of course, the whole trick in keeping the cornea clear is to keep it free of fluid, and therefore the ability to see the channels where water is continually being pumped out of the cornea becomes a very important point in preventing the cornea from becoming opaque. In cataract there are new findings that should be put to hypothesis testing because we want to slow down the development of cataract. I mentioned before, if we could just slow down the development of cataract by ten years we'd reduce by about 45 percent the number of people who need surgery. [Clerk's note.--``to 50'' later added.] Right now we, as taxpayers, support about $5 billion to do the 1.6 million cataract surgeries every year, and that's a major economic impact. Even though it's one of the most safe operations and most effective operations, it still represents a major economic impact. So there are a number of opportunities, and I would say that we would pursue all of them at a slower rate. With additional resources, the rate could be increased. glaucoma gene Mr. Porter. I always enjoy the interplay between the budget you really would like to have and the one the President has handed you, so I like to ask these kinds of questions. We remember the painful retirement of Kirby Puckett from baseball last year because glaucoma had irreversibly damaged his right eye before it was detected. Now recent scientific findings may result in new tools for early diagnosis of glaucoma. Researchers in Iowa have located a gene that causes a particularly virulent form of glaucoma which strikes young people, as you said. They expect to develop a test for the gene within a year. This seems to be different from most cases when genes are discovered and years of work lie ahead before there is an impact on patients. Once tested, glaucoma patients could be diagnosed early and treated before any vision loss had occurred. Does this test also hold promise for people with more common forms of glaucoma? Dr. Kupfer. Yes, sir. First, as far as the juvenile type, it's going to be a very effective way of really preventing blindness from ever occurring, because for this group, the use of a straightforward operative procedure before the disease really has taken away vision, will basically prevent the blindness from ever occurring. In the case of open-angle glaucoma, I think we're going to have to see what additional genes are involved in addition to the one that has just been found, and I think in the next year or two or three we will identify those additional genes. This finding has really spurred on the researchers. We have several groups working very hard in trying to identify additional genes. So I think there will be a major impact on this disease. Mr. Porter. So that most eye diseases that are genetic are not single-gene conditions; they're more likely to be multiple? Dr. Kupfer. Yes, sir. I think it is very clear that glaucoma, age-related macular degeneration, retinitis pigmentosa are multiple-gene diseases. We've got to find all the genes involved. [Clerk's note.--Reference to ``retinitis pigmentosa'' later struck and ``diabetic retinopathy'' added.] Mr. Porter. And if you had more money, you could presumably find them faster? Dr. Kupfer. Faster. Yes, sir. neuron survival Mr. Porter. Your justification describes a protein found in cells that lie behind the retina which encourages neuron survival. The therapeutic potential of this protein is being explored for a variety of conditions in which neural cells die, such as stroke, traumatic brain injury, and Parkinson's disease. This seems to highlight the difficulty of ascribing research to one disease or another. When you're asked to estimate your total expenditures for a list of diseases, how would you categorize the research on this protein? Would it be research on eye disease or Parkinson's disease, or stroke? Dr. Kupfer. Well, if we do it on the basis of what seems to have the greatest impact, the experiments that have been done on the cells which are affected by Parkinson's disease show clearly a survival of these cells. They do not degenerate in tissue culture. So I would say this is probably going to have initially a major impact on Parkinson's disease. As a matter of fact, this research was done in collaboration with the investigators in the Neurology Institute. We are trying to see what role it plays in cell survival in the retina, and, of course, that is being pursued very aggressively. radial keratotomy versus laser technique Mr. Porter. In past years we've talked about RK surgery as a method to correct near-sightedness. Now physicians are heavily marketing a laser technique that is intended to correct myopia. What kind of clinical trials or approvals did this procedure undergo before marketing began? Has it been compared to RK in terms of safety and effectiveness? And what is your scientific opinion of this procedure and its effects, both in the long and short term? Dr. Kupfer. You may remember, sir, that when radial keratotomy, RK, first appeared on the scene--which is now perhaps 15 years ago--we were approached by a number of investigators in the community that said, ``We are very concerned about the safety and efficacy of this procedure, and we would like to submit a clinical trial.'' We expedited the review. It was a very good review, and we supported the clinical trial and actually have ten-year data on the outcome of radial keratotomy. So from both a scientific point of view and from a patient information point of view, the surgeon can tell the patient what to expect in terms of outcome. This research data base does not exist with the laser studies to the same extent that it does with RK. These studies were done without support from the National Eye Institute. We were very interested in supporting animal studies and did so, but the clinical studies were supported primarily by the manufacturers of the lasers, and it is difficult to assess the long-term effects of these procedures because the longest data now is about two years. So I think we will want to see what the long-term effects will be. However, I do want to add that FDA has reviewed these studies and has given approval for the use of the lasers. fda approval Mr. Porter. When FDA has these matters before them, do they contact you for data that you might have? Dr. Kupfer. Yes, sir. As a matter of fact, we usually have a member of the National Eye Institute on their outside review panel. We have been working with FDA over the past five years and working with the private sector, the pharmaceutical companies, the device makers, and academia, trying to bring together the four components to make the translation from the laboratory to the clinic and eventual FDA approval a little more secure in terms of designing the very best clinical trial possible and then helping to see that it's carried out well. And I think gradually we are moving in this direction, and I have great hopes that we will see more collaboration between FDA, National Eye Institute, the private sector, and academia. macular degeneration Mr. Porter. In your testimony you mentioned that 1.7 million people are affected with macular degeneration today, and that you estimate that by--I think you said the year---- Dr. Kupfer. The year 2030. Mr. Porter [continuing]. 2030 it would be something like six million. Dr. Kupfer. Approximately 6.3 million. Yes, sir. Mr. Porter. We're hearing from groups that are very concerned about macular degeneration that they say 13 million people are affected today. Why is there a difference in this estimate? Dr. Kupfer. When we quote the figure 1.7 million, we are saying that these are individuals who actually have severe visual disability or are legally blind. The larger figure are those who are at risk of developing age-related macular degeneration, and a certain subset of those individuals will go on to develop severe visual impairment, but not all of them. Mr. Porter. Mr. Stokes? Mr. Stokes. Thank you, Mr. Chairman. Dr. Kupfer, it is nice to see you again. Dr. Kupfer. Yes, sir. glaucoma gene Mr. Stokes. It is always a pleasure. Doctor, according to your budget justification, approximately three million Americans have glaucoma, and at least half of those who have glaucoma are unaware of their condition. As many as 120,000 people now are blind from the disease. Recent articles report that the gene associated with glaucoma was recently identified by NEI-supported investigators. What are the major implications of this finding with respect to early treatment and detection of glaucoma? Dr. Kupfer. The gene that was found and cloned and the protein product that it produces and what it does, primarily applies to a subgroup of glaucoma that's called juvenile glaucoma because they develop during the first two decades of life. In those individuals who are in families--and this is inherited as a dominant characteristic--we can now, within the year, test members of the family and determine very clearly whether they will go on to develop glaucoma or not. The important thing is that when these individuals develop glaucoma they develop such high pressures in the eye that they can go blind in a matter of months, so early diagnosis is absolutely critical. And if we can diagnose them early, we can do a surgical procedure to produce a new channel through which the fluid can leave the eye, and there's every expectation that they will then never get into trouble again. Now, the real impact is how is this gene related to open- angle glaucoma, which accounts for about 85 percent of all the glaucomas, and that is being very actively pursued. I think that it will be found that this gene does play a role in open-angle glaucoma, but there are other genes also involved, and those are the genes we are looking for now. retinopathy of prematurity Mr. Stokes. What major progress do you have to report to our committee with respect to research on retinopathy of prematurity, the blinding eye disease that affects premature babies? What is the extent of this problem? Dr. Kupfer. At the present time it has been estimated that about 4,000 infants weighing 3.3 pounds or less are born every year. And of those, it's estimated about 700 to 750 will become blind. We now can probably reduce that figure to about 400 by the treatment of freezing the outside of the eye. We now have five-and-a-half year data on the first cohort of premature infants from a clinical trial begun about seven years ago, and we know that to actually prevent blindness, to restore good vision and keep vision, we can do that in about 25 percent of the children. And others may not have good vision but have useful vision. So I think that we really have made major strides; however, we haven't stopped. We are continuing two other trials, one that deals with providing oxygen but at a very constant level. Technology has now enabled us to monitor the arterial oxygen levels continuously in premature infants lying in an incubator, so we can be sure that the level of oxygen stays constant. There is the hypothesis that it's not just the level of oxygen but the changing level of oxygen that may be a risk factor in inducing retinopathy of prematurity. And then there's another trial that is looking at the question whether there are other environmental factors that may contribute to the retinopathy of prematurity. So we are very actively and aggressively pursuing this in conjunction with the Child Health Institute and with the Nursing Institute. biology of the brain Mr. Stokes. Doctor, as you know, the NIH has included the biology of the brain among its special emphasis areas, and, of course, you, Doctor, over the years have focused attention on the eye as the window to the brain. What major research studies are underway at the Institute with respect to the biology of the brain? And, tell us--what are the implications of this work for furthering advances in neuro-degeneration and spinal cord injury. Dr. Kupfer. I think that the seeing part of the eye, the retina--and perhaps I could just illustrate that with this figure. This is a cross-section of the eye, and the light comes through the cornea and is focused by the cornea and the lens onto the retina, and the retina is actually part of the brain. It's part of the central nervous system. [The information follows:] [Page 432--The official Committee record contains additional material here.] So that the connection between the retina and the brain, which we call the ``optic nerve,'' is quite comparable to the spinal cord. In fact, they are the same level of complexity and conveying roughly the same sort of information from the periphery to the central nervous system. The research that is then going on in the optic nerve has a bearing on spinal cord injury, and this research is primarily looking at what growth factors are necessary to allow cells of the central nervous system to regenerate similar to what happens when one has an injury to a peripheral nerve. Those peripheral nerves usually regenerate. We're trying to determine what is the difference between a peripheral nerve, which can regenerate, and a central nerve track that cannot. Growth factors are involved. Genetic control is another. These central nerves will regenerate in a very, very young infant, but somewhere along the line the genetic control to allow regeneration to occur stops. And we want to know how to reactivate it. We're interested in therapy of various drugs that will stimulate the development of central nervous tracks. So this is a very major area of work. In addition, all the diseases that affect the retina-- retinitis pigmentosa, age-related macular degeneration, the juvenile dystrophies, they also need to be studied in terms of growth factors, gene replacement, transplantation, all the sorts of studies that underlie neuroscience at the present time. Mr. Stokes. Doctor, considering the importance of this area, how much is included in the fiscal year 1998 budget request for the work in this area? How much are we currently investing? Dr. Kupfer. I think in terms of the retinal disease, we're investing about $75 million. This will probably increase in fiscal year 1998 because we want to take advantage of these research opportunities and we will move funds in that direction. Mr. Stokes. I think I have exceeded my time. Thank you, Mr. Chairman. transplanted retinal cells Mr. Porter. Thank you, Mr. Stokes. Dr. Kupfer, the press has reported that surgeons in Chicago have transplanted retinal cells from aborted fetuses in an attempt to treat macular degeneration. Is this an approach you believe holds promise? Dr. Kupfer. Mr. Porter, this technique has been used in various parts of the world during the last five to ten years. It has been used in Sweden. It has been used in India. I think this may be the first report in the United States. My feeling is that we have so much more to learn in terms of what must be done for a transplanted tissue to survive, that perhaps these types of clinical studies may be a bit premature. We are pursuing this in the laboratory very aggressively, and we will continue to do so. I think that there is a high probability in the next five, ten, fifteen years, that we will learn the surgical technique of transplantation, how to prevent rejection of the transplant, how to maintain the transplant long enough to begin to develop connections with the retina and the brain, and then how to reorient these transplants so they can actually convey information that's going to be meaningful to the brain. These are very major problems that have to be overcome before I think this sort of surgery will be useful. fetal tissue Mr. Porter. Is there evidence that fetal tissue is less likely to be rejected than adult tissue? Dr. Kupfer. Yes, there is, sir, and I think that was the reason that the fetal tissue was used. But, nevertheless, I think there is still the possibility that fetal tissue may remain viable for much longer than if it were adult tissue, but eventually I think it is going to either be rejected or it will develop into a scar and not be functional. That would be my prediction at the present time. macular degeneration Mr. Porter. Cigarette smoking has been shown to increase the risk of developing macular degeneration. Are you working with the CDC and the Cancer Institute to include that warning in their cancer control messages about the dangers of smoking? Dr. Kupfer. These are results that recently came to our attention through three different studies. I think that, given the fact that cigarette smoking is a disaster for lung cancer and for cardiovascular disease and several other things, adding this additional piece of information is desirable, but I think it doesn't quite have the same urgency as those other areas. But we are in contact with CDC through our National Eye Health Education Program, and I know the Cancer Institute is aware of these studies. Mr. Porter. Was it an NEI study that linked nutritional supplements like selenium and vitamins to a slowing of macular degeneration? Dr. Kupfer. Slowing of macular degeneration--I think that the present clinical trial in which we are using some vitamins and minerals is the first systematic attempt to see if these are of any benefit. marijuana use for glaucoma Mr. Porter. This morning we discussed the debate about possible medical uses of marijuana. One disease for which marijuana is claimed to have a therapeutic affect is glaucoma. Is there a scientifically-validated basis for these claims? Dr. Kupfer. In the early 1970s it was found that smoking marijuana reduces the pressure in the eye in normal individuals. Following that, a number of patients with glaucoma did report that their pressures did go down when smoking marijuana, and this was observed to be the case by eye care professionals. There were a number of animal experiments done during the early 1970s. In 1978 we actually issued a request for applications to study this in patients. No applications came forth, so we really do not have any strong scientific basis on which to make a judgment. I hasten to add that we do have a very large armamentaria of drugs that have been approved by FDA that do lower intra- ocular pressure and do not have some of the very serious side effects that marijuana does have. But we would be prepared to conduct clinical trials if there was an interest upon the part of the research community and individuals with glaucoma. private foundations Mr. Porter. You suggested last August that your Institute and the Foundation for Fighting Blindness should jointly plan their research agendas to direct research funding more effectively. Is this a departure from usual practice at NIH, or is it common to coordinate research agendas with private foundations? Dr. Kupfer. I think it's becoming more and more common, sir. As a matter of fact, one of the models that I'm most familiar with began with the Diabetes Institute, and that was a collaboration between the Diabetes Institute and the Juvenile Diabetes Foundation, where they jointly funded research grants. We now have that same relationship with the Juvenile Diabetes Foundation, and we would like to have that same relationship with the Retinitis Pigmentosa Foundation. The reason for that is that, although their resources are not as extensive, they have much more flexibility than we do, and therefore they can do certain things that we cannot do, and we want to look for areas where we can complement each other in that nature. I think we're going to see more of this rather than less. I don't know, Harold, if you want to make any comment about the---- Dr. Varmus. I have urged Institute directors to take seriously propositions from private organizations. We offer one very important component that is often difficult for them to provide, and that is an extensive, well- established peer review system that allows them to make the best possible use of the dollars they receive from donations and volunteers. Mr. Porter. How would you plan to coordinate your research portfolio, since you place heavy emphasis on investigator- initiated research rather than Institute-generated research? Dr. Varmus. Well, we would not want to subscribe to a program that we didn't think was in our interest, and, through discussions that have been held with a number of funding organizations, we have been able to agree that there are initiatives of mutual benefit we both would agree would be to the advantage of both sponsors and that we'd be happy to sponsor. Dr. Kupfer. One could see at least two occasions. What we're doing with the Juvenile Diabetes Foundation is to co-fund RO-1s, research grants that we've reviewed but do not fund. They're very meritorious, but we do not have adequate funds to fully fund them. And the Juvenile Diabetes Foundation looks at these, makes their own decision. We notify the grantee that if they are going to accept this grant it's going to be co-funded, so that they are fully prepared, and then we move ahead. The second area is to supplement our fellowship support. There are opportunities where to bring individuals into a particular area, a supplementation of the NIH fellowship might be helpful in an individual, for instance, who has a very large debt and would need some additional financial resources. The private foundations can do this. We cannot. nutritional supplements for retinitis pigmentosa Mr. Porter. You're conducting clinical trials of a nutritional supplement to halt the progression of retinitis pigmentosa. Vitamin A has already been shown to delay the progress of RP. Reports suggest that, if successful, this treatment could allow patients to retain useful vision for their entire lives. How can a nutritional supplement stop the progression of an eye disease? Dr. Kupfer. Perhaps I could answer that by first going back to the first study that you alluded to. The first study actually used Vitamin A or Vitamin E or a combination of the two or a placebo, and it was felt, on the basis of many, many animal studies, that both Vitamin A and Vitamin E would be of value, Vitamin A because it is part of the molecule in the retina that captures the light, rhodopsin; Vitamin E because it's an antioxidant and is supposed to stabilize membranes. And the photoreceptor is made up of thousands of membranes, so it was felt that this would be very valuable. As it turned out, the Vitamin A was of benefit, but the Vitamin E was not of benefit and actually caused an acceleration of the degenerative process. So one must be very, very careful in testing these in a very well-controlled clinical trial, so the recommendation from that first study was that Vitamin A is of benefit, and we have an explanation. The second trial is additional assessment of nutritional ingredients, and we will see how that turns out. Mr. Porter. And if this therapy turns out to be successful, it would be very low-cost, would it not? Dr. Kupfer. Yes, it would be, just as Vitamin A is very low cost. Yes, sir. long-range research plan Mr. Porter. Your Institute is in the early stages of developing your next long-range research plan. What would you consider the most significant ways the vision research field has changed since your last plan was released? Dr. Kupfer. I think the areas of neuroscience, of genomics, the tracking down of genes, and the role of immunology are probably the three major changes. Automation has played a very major role. High-speed computers have allowed us to do things we weren't able to do. I think we're going to see research done in a very different way in the next decade than we have previously. I think we're also seeing that collaboration is absolutely essential. This article on finding the gene in glaucoma must have had 15 authors, and I think this is not unusual. Many of these articles require the skills of many, many different groups, and I think we're seeing more coordination of research activities, and I think we've got to shape our research grant support in that direction. cataract surgery Mr. Porter. Apparently, many people who have cataract surgery must have a second operation because the cataract forms again as a response to the residual lens cells remaining after the surgery. What share of those undergoing cataract surgery face this problem and how much could be saved if drugs or better surgical techniques could prevent the formation of the second cataract? Dr. Kupfer. Yes, sir. It has been estimated that about 25 percent of the individuals who undergo cataract surgery have this proliferation of cells that occlude the vision, and therefore a laser treatment is necessary to sort of punch a hole in this membrane. If we assume that there are about 1.5 million or 1.6 million cataracts done a year, and about 25 percent of those, that's about 300,000 to 400,000 develop this problem, and the average cost, with hospitalization and return visits, is about $1,000. We're talking about $300 to $400 million. contact lenses Mr. Porter. How many Americans are contact lens wearers? Do we know that? Dr. Kupfer. That's a very good question. The problem with the answer is we know how many people purchase contact lenses, but we don't know how many people are wearing them. It has once been said there are more contact lenses in the top bureau drawer than in the eyes of people. I would guess--and I could correct this when I look at the transcript--somewhere between 5 and 10 million people are wearing contact lenses. [Clerk's note.--later corrected to ``24.''] Mr. Porter. And are there any long-term studies of the effects, the possible negative effects of wearing such lenses? Dr. Kupfer. Yes, sir, there are. Many of the studies have dealt with what was the original type of lens, the hard lens, and they have given way almost completely to the soft lens. The hard lenses do have some complications after about 15 to 20 years of wearing, but the soft lenses so far are being watched very carefully. The main problem with soft lenses is that they are so comfortable that people forget to take them out at night and will sleep with them--in fact, may keep them in three or four days--and then corneal ulcers can develop, and that's a major complication. vision conditions needing more research Mr. Porter. We talked about glaucoma and the tools to detect and prevent it. We seem to have a much more limited stockpile of weapons against other eye diseases. For which vision conditions would you say we know the least about treatment and prevention? Dr. Kupfer. In terms of the public health impact, it's age- related macular degeneration. Of the cases, 90 percent are what we call ``the dry type.'' That is, there is breakdown of the retina very slowly. The wet type is 10 percent. That's where new vessels develop. But it's that 10 percent that causes legal blindness. And we can only treat successfully about 15 percent of those patients, so we really do not have an awful lot to answer. That's our major concern at the present time. Mr. Porter. And that, in a sense, is a result of being successful in other fields and having people live longer and healthier to later ages and then develop diseases like age- related macular degeneration. Dr. Kupfer. That is it completely. Mr. Porter. Or Alzheimer's disease. Dr. Kupfer. That's right. Mr. Porter. Well, we thank you very much, Dr. Kupfer, for your good testimony. I'm going to ask Dr. Varmus if he would stay just a moment, because I have several questions left over from this morning that I'd like to pose to him. But thank you for your good testimony. Thank you for your excellent work at the National Eye Institute. You do a wonderful job there and we appreciate the candid and good testimony that you give us and insights into what is being accomplished in your field. Thank you very much. Dr. Kupfer. Thank you, Mr. Porter. angiogenesis and cancer Mr. Porter. Some of these questions probably are for Dr. Klausner, but since he's not here---- Dr. Varmus. We can call him back. He's still in the building. Mr. Porter. I thought you might be able to answer them. We talked earlier about reducing the blood flow to certain cancers. Dr. Varmus. Right. Mr. Porter. And the promise that that has. I wonder if you know whether that is NCI-supported research that led us to where we are? Dr. Varmus. Most of it is. Yes. There are actually two approaches that are being taken. One is based on the idea that the process of blood vessel formation, like so many things that go on in the body, is a ying and yang process. There are factors that promote blood vessel development and there are factors that inhibit it. Dr. Judah Folkman at Harvard, who is one of the pioneers in this field and a long-term NCI-supported investigator, has, for example, identified at least two or three compounds, natural products of the body--indeed, in some cases natural products of tumors--that can inhibit blood vessel growth and have been used in treatment of tumors in animals, and have, indeed, been proposed for clinical trials. The other avenue is to make use of clotting mechanisms to induce thrombosis, clots, in blood vessels that lead to tumors. I'm not sure who sponsored those experiments. There was a paper recently published in the journal, ``Cell,'' describing the use of this approach in an experimental tumor in an animal, in mice. We could find out for you who supported that. consolidated aids appropriation Mr. Porter. Dr. Varmus, your budget again proposes a consolidated appropriation for the Office of AIDS Research. I know you're obligated to support the President's budget request, but could you tell me if the approach we used in fiscal year 1997 for AIDS funding was workable? Did our language prevent you from doing anything that you wanted to do in managing AIDS research? Dr. Varmus. It did not prevent us from doing anything. The budget was, of course, allocated according to the plan worked out by the Office of AIDS Research. It was slightly cumbersome in its operation, in that the money went to the institutes, back to the office, then back out to the institutes, but it was a paper transfer and it worked efficiently and everybody was happy. aids transfer authority Mr. Porter. Do you and Dr. Paul intend to use the transfer authority we gave you in this fiscal year to move AIDS funds between institutes? Dr. Varmus. You're referring to the 3 percent transfer authority? Mr. Porter. Yes. Dr. Varmus. At the moment we don't have any expectations of using it. As you probably know or will soon know, we have identified a number of projects that will be funded by use of my 1 percent transfer authority, assuming that the committee is willing to approve that request. None of those are in the AIDS area. I believe one of the reasons we've had so little need for it is that the planning process was carried out right up to the time when the allocations were made, and, as a result, I think the appropriations were appropriate. And, given Dr. Paul's discretionary budget, I think in toto we were able to operate effectively without using this transfer authority. If there is a need as an emergency later in the year, we, of course, would employ the transfer authority. earmarks for diseases Mr. Porter. I wish I'd had an opportunity to say this earlier, but I want to put it in the record. Dr. Varmus, we fight hard to keep our bill and our report free of disease earmarks. We've heeded your warnings that this is destructive to the scientific enterprise, and I'll continue to fight to preserve this principle, despite what is a growing rebellion in some quarters of the Congress. I have to say the President's pronouncements last year pledging specific dollar amounts to spinal cord injury research, for example, have the effect of undermining these kinds of efforts. How can you and the scientific community expect Congress to continue ``letting science decide'' when the President of the United States seems to be leading a charge in the opposite direction? That's more of a statement than a question. Dr. Varmus. Thank you. Mr. Porter. I think that it does us a great deal of harm for the White House to work in the direction that takes discretion away from science, from you in determining the proper allocation of funds, and we would like to give you the maximum discretion in doing that. While all of us have strong feelings, as does the President, we do our very best to try to keep them out of the bill and only in the report where they belong. Dr. Varmus. I perhaps should say, Mr. Porter, that there was a happy confluence of events in that circumstance, because there have been some recent developments in the study of central nervous system injury that allowed us to make extremely good use of those additional allocations. priority setting Mr. Porter. In each year that I've been chairman of the subcommittee, I've been approached by advocacy groups concerned that NIH spending in certain diseases is out of balance with its incidence and associated health care costs, and I think Representative Istook raised some of those questions earlier. Some feel that political pressures are applied to NIH spending decisions. Can you lay out for us your response to these concerns? For example, when the committee provides more funding for NIH than was requested by the President and we ask your advice in allocating the increase, what guides your decision about distributing the funds among the institutes? Dr. Varmus. You ask me to do that here or for the record? Mr. Porter. No. Here. Dr. Varmus. There are several things. I have to say, Mr. Porter, as we think through priority setting, it is an imperfect process. When we're given money to spend on research, we have to depend upon subjective estimates and our judgment, and ultimately I suppose we come back to the idea that those of us who have been entrusted with positions such as director of NIH or director of an institute have the judgment that allows us to make the best possible guess about how the money can be well spent. When we have an increased amount of money, there are two kinds of things that can be done. One is simply to fund more grants than we could otherwise fund. As you know, we have a list of grant applicants with different priority scores. Currently, in some institutes, grants that received extremely high priority scores, perhaps ranking among the top 20 percent, but with scores that indicate a very high degree of excellence as perceived by the study sections, don't get funded, and we are able to fund those. That's just a simple lowering of the threshold so that we have a higher success rate. The other thing that happens is in the programmatic allocations by each institute--an allocation that is made differently in different institutes. Some institutes will fund the top 80 percent of their grant applicants and then look at the distribution of grants among programs and decide to reach lower in the priority list among grants to make sure that there's adequate support in various areas. Others divide the grants by program and fund to certain levels within each program. Regardless of how that's done, when additional money is available the director of the institute, in consultation with outside experts, with members of his program staff, with his National Advisory Council that's composed of both consumers and scientists from the outside, will decide whether to go further in funding certain programmatic areas. Now, when I say ``program,'' I'm referring both to funding in certain categories--be it basic research or disease-specific research--or sometimes it means providing more funding for certain kinds of mechanisms--for training grants, for construction. shared instrumentation You will recall that we've had discussions here before about the amount of money we're able to spend on extramural construction or on shared instrumentation. Shared instrumentation is a very useful item to talk about, because, as you're aware, we cut back on our support for shared instrumentation. I, myself, believe that's one of the most potent ways we can advance science, especially at centers where equipment does get used by a large number of individuals. And that's one of the things that tends to get cut when the money is tight, because we're not funding an individual investigator; we're funding the purchase of equipment that services many different investigators. But when we have more money, we're liable to say we will support the shared instrumentation grants or other endeavors that benefit a group of investigators. areas of special emphasis Mr. Porter. I thought I heard you earlier in the day refer to budgeting at various levels--in other words, I'm interested in at what point you do this. Obviously, you've worked out a budgeted 2.4 percent increase. Do you also have in place where you might go if the funding were at 4.8 percent or 5 percent or---- Dr. Varmus. Yes, I do. Mr. Porter. It's all done in advance? Dr. Varmus. This year, in particular, I went through, in painstaking detail, with each institute director the kinds of projects they would identify as falling within areas of special emphasis, areas where they could foresee--as, for example, Dr Kupfer could see increased interest in glaucoma as a consequence of cloning the glaucoma gene this year. He would tell me that there were three or four areas which he would like to expand because of new, recent discoveries or because of some pressing scientific need or because of a resurgence of a disease. I have a list of initiatives that the institute directors would like to advance. As a result of our discussions, I have, by a semi-subjective and semi-informed process, developed my sense of what the most urgent items and the most productive items on that list are likely to be. And I, in order to sustain our commitments and also initiate some new endeavors, have tried to put together a budget that's fair to the various institutes, fair to our existing grantees, and still allow initiatives to be started for various budget levels, not knowing where the actual outcome will lie. So I have some sense of how much we'll be able to put into these new projects if we have various levels of support. Obviously, if we had this professional judgment budget, we would be able to support virtually all of the initiatives. If we have a more modest budget that is constrained by the budgetary issues we've agreed exist, we will support fewer of those or support them with less money than we might otherwise do. royalties for drug products Mr. Porter. Dr. Varmus, we've been approached about a legislative provision that would extend five additional years of market exclusivity to unpatented drug products which are the subject of a CRADA with NIH. In return, the pharmaceutical companies would pay a royalty to NIH to enhance appropriated research funding. What is NIH's view of this proposal? Dr. Varmus. Well, we're willing to look at it, but I've only heard it described in the kind of detail you just provided. And until we see it in further detail, I would be hesitant to endorse it. We would be perfectly willing to work with whomever is proposing it and look at the details of the proposition. government performance and results act Mr. Porter. Thank you. From Department documents, we understand that NIH has determined that it will need to ask OMB for permission to develop an alternative approach to the Government Performance and Results Act performance measures for its research activities. Understanding the difficulty of establishing performance measures for investigator-initiated basic research, what alternative measures are you considering? And what approaches to GPRA are the other Federal science agencies contemplating, if you know? Dr. Varmus. Yes. Well, I do know something about that. As you know, Neal Lane and I chair the Fundamental Science Committee of the National Science and Technology Council, and about two years ago, in preparation for the implementation of GPRA, we gave some thought to how the agencies that do fundamental science would be able to evaluate their programs in accord with GPRA. In thinking through this process on the behalf of NIH, we came to the conclusion that we could develop some quantitative measures for our activities in support of training and in support of facilities and other infrastructure, so we plan to do that, to develop a logarithm that will allow us to make some judgments about how we're doing in those areas. But, as you point out, with respect to fundamental research it is a good deal more difficult. There are a number of qualitative measures that we can imagine. We can imagine descriptions of specific scientific advances as a way of portraying what we do. We can talk about the impact of our science on industry, on the biotechnology and pharmaceutical industries. We can talk about how basic science has benefitted clinical practice. We can talk about the impact of our research on improved health, on the reduction of hospital days or on the development of procedures that have been shown to be effective in the treatment of various diseases. There is the possibility of some more quantitative measures. I, myself, find them rather unsatisfactory--for example, patent applications, citation indices, and other measures which I think are less instructive and less pertinent to what we do than actual descriptions of discovery. managed care Mr. Porter. This morning you touched on this question. I have been concerned for a long time about the changes in our health care delivery system that are leaving our teaching hospitals without the resources that they need, because in many instances managed care plans simply bypass those kinds of facilities because of their higher cost. I'm also concerned as to what managed care organizations will do to contribute to the cost of biomedical research. I think you've had some discussion with representatives of the managed care industry recently about this. Can you fill us in, in a general way, on what you see? Dr. Varmus. Sure. We've met twice now with representatives of Kaiser Permanente, the Puget Sound Health Care Program, and several others. Mr. Porter. Did you initiate those meetings or did they? Dr. Varmus. Well, I guess we did at one level, but there were a couple of preliminary conversations, some of them initiated by Dr. David Nathan, who is the head of my clinical research panel. But I asked them then to come to NIH. But it was clear from our preliminary conversations that they were interested in having these conversations. As you know, the managed care industry includes a number of organizations that have been in existence for a long time, have a strong research record, receive NIH money, do interesting research, and have connections in many cases to academic health centers. And we see those connections strengthening. Managed care organizations have much to offer the NIH. They have large stable patient populations that are easy to track, and particularly useful from the perspective of epidemiology and health services or outcomes research, or for the conduct of clinical trials. I think there's a difference in overall program in that managed care organizations, for fairly obvious reasons, are less interested in the fundamental research than we might be, but we have many areas of shared interest. And it's to their advantage, I think, to form partnerships with us because they know that their staff appreciates the chance to participate in research, they recognize that there are benefits to the kinds of research we're describing for their planning and for benefitting patients who are enrolled. partnerships with managed care organizations One of the things that we recognize as a joint concern is how they make their contribution to research without being penalized in what is currently a fiercely-competitive market. Therefore, one of the players that needs to be brought into this discussion, but has not yet been brought in as actively as I would like be done--the employers who are the ultimate purchasers of these health care plans. If we were to persuade a managed health care provider to join with us and to provide some of the resources necessary to carry out more clinical research at our academic health centers, it would be necessary to pass on some of those costs to those who pay for the health care that's provided. We believe that the benefits accrue both to those who are in those health care plans and to the Nation at large, and that either by force of persuasion of the employers who pay for these plans, or perhaps by persuading Congress to help us in finding ways to achieve means to ensure that health care plans include some allocation for research, that we can achieve the benefits that I think are to be gained by the managed health care revolution. Mr. Porter. Let's say that Congress did that. Let's say Congress directed all managed care plans to allocate 1 or 2 percent of their revenues to research. What effect would that have in directing research? And maybe you can talk generally about where we are in reference to basic research as opposed to research that tends to be more directed toward a specific end. Dr. Varmus. Well, I believe that money would be most appropriately spent largely on clinical activities, and I believe that because that is what the managed care organizations are going to be interested in, in part because a very significant part of the erosion of support of academic health centers has affected clinical research. Not all of it, because, as you know, patient care revenues that have traditionally gone to academic health centers have frequently gone into either a departmental fund or a dean's fund, which ends up supporting both basic and clinical research. So I want to emphasize that the loss of revenues has affected both basic and clinical activities. But I think the expectation would be that whatever is provided from the managed care industry would go largely to clinical activities. What I then imagine happening is that proposals that could be jointly funded by the NIH and by managed care would be supported through both avenues. I've not thought through in great detail exactly how that would be done, whether it would achieve the kind of partnership, we just discussed, with some of the voluntary organizations--for example, the Diabetes Foundation--or whether we would prefer to work with separate pots of money with managed care industry picking up some proposals and us picking up others. research partnerships Mr. Porter. It seems to me that we are--Dr. Kupfer referred to this--we are increasingly looking for partnering in one way or another with foundations or even with industry, and that at some point we end up with a great deal of research that is directed to specific ends and less perhaps resources than we ought to have on basic research. Is that possible? Dr. Varmus. I wouldn't jump to that conclusion, Mr. Porter. Mr. Porter. Good. Dr. Varmus. Because if you look at the research in basic sciences these days and look at the acknowledgements in research papers, as I frequently do as someone, of course, looking for acknowledgement that NIH helped to support the research, what you find almost inevitably is support from a variety of institutions. In fact, since it's frequently the case that NIH is the major supporter, it sometimes seems to me that the attribution to NIH is somewhat buried among a long list of foundations and other organizations that have provided support for post- doctoral training and for fairly modest amounts of money, but we all have supported the research. So virtually everything that's done these days is a partnership, and the question is whether you allow those partnerships to be brokered independently by the investigator who has gone out to six places to get the money, or whether the investigator can go to one place and get support for a project from two organizations at the same time, as we do in the case of some of the projects co-supported by the Juvenile Diabetes Foundation and certain institutes at NIH. Mr. Porter. Dr. Varmus, thank you for your patience and for your very candid and direct answers to all of our questions. We will now stand in recess until 10:00 a.m. tomorrow. Dr. Varmus. Thank you very much. I appreciate your interest. [The following questions were submitted to be answered for the record.] [Pages 446 - 494--The official Committee record contains additional material here.] Thursday, February 27, 1997. NATIONAL HUMAN GENOME RESEARCH INSTITUTE WITNESSES FRANCIS S. COLLINS, M.D., Ph.D., DIRECTOR, NATIONAL HUMAN GENOME RESEARCH INSTITUTE ELKE JORDAN, Ph.D., DEPUTY DIRECTOR KATHY HUDSON, Ph.D., ASSISTANT DIRECTOR FOR POLICY COORDINATION JAMES C. VENNETTI, EXECUTIVE OFFICER ERIN S. BURGESS, BUDGET OFFICER HAROLD VARMUS, M.D., DIRECTOR, NATIONAL INSTITUTES OF HEALTH DENNIS WILLIAMS, DEPUTY ASSISTANT SECRETARY, BUDGET, DEPARTMENT OF HEALTH AND HUMAN SERVICES Mr. Porter. The subcommittee will come to order. We begin our hearings this morning with the National Human Genome Research Institute and Dr. Francis Collins. Dr. Collins, welcome. Nice to have you here as an institute now. Why don't you introduce the people who are with you and then proceed? Introduction of Witnesses Dr. Collins. Thank you very much, Mr. Porter. Sitting at the table, beginning at my left, Mr. James C. Vennetti, who's the Executive Officer; Dr. Kathy Hudson, who is the Assistant Director for Policy Coordination; Ms. Erin Burgess, Budget Officer; Dr. Elke Jordan, the Deputy Director; Dr. Harold Varmus you are familiar with, and Mr. Dennis Williams from the Department. Opening Statements It is indeed an honor to testify for the fourth time in front of this committee, but the first time as the Director of the National Human Genome Research Institute. I have to keep thinking before I say those words, or I tend to get them wrong. In reality, the former NCHGR, the National Center for Human Genome Research, is now the NIH's newest research Institute. On January 14, after consultation with you and other Congressional leaders, Secretary Shalala signed documents that gave the National Center for Human Genome Research a new name and new status. We are proud the NCHGR has been recognized for its successful leadership of the Human Genome Project, the accomplishments of its cutting-edge intramural laboratories, and its active policy research programs. As an Institute, NHGRI looks ahead to completing the Human Genome Project and to playing a leading role in 21st century health science based on understanding the instructions encoded in our DNA. In my statement, I could enumerate milestones and accomplishments of this grand adventure called the Human Genome Project over the last year and project some of the future ones, and don't worry, I will. But I also thought it would be appropriate to put this into the context of human health. Because as a physician, clearly my excitement about this project is what it will do to benefit human beings, to alleviate suffering, and to avoid illnesses which currently plague so many. prostate cancer So I would like to tell the committee about an individual named Robert. Robert is currently 64 years old. At the age of 54, he was diagnosed with prostate cancer. This was for him in some ways a surprise, and in other ways not. Both his father and his paternal uncle had previously been diagnosed with prostate cancer and they had both died of it. So finding his own diagnosis at age 54 was perhaps less surprising than it would have been to others, although certainly a very young age to have that diagnosis. Now, Robert was treated at the Johns Hopkins University surgically and is currently doing well some 10 years later. However, his son was recently diagnosed at the age of 42 with prostate cancer. Families of this sort are not rare, although they are uncommon. In a collaborative effort between Johns Hopkins and the National Human Genome Research Institute, an intense effort was made to try to figure out what is at the basis of this inherited predisposition to prostate cancer. There had been indirect evidence for three or four years, based on studies of large families, that there was something going on in the way of a hereditary factor. Last November, we published in the journal Science that in fact there is a specific gene on chromosome 1 named HPC-1, for hereditary prostate cancer gene number 1, which if misspelled, or mutated, carries an estimated 80 percent likelihood of conferring prostate cancer on an individual by age 80. And the age of onset for such individuals is skewed towards a considerably earlier age than the general risk of prostate cancer. Now, prostate cancer is a terribly common disorder. Three hundred and forty thousand men will be diagnosed with that disease this year and more than 40,000 will die from it. It is this early onset type that is particularly of concern. It is estimated that some quarter of a million men have mutations in this gene called HPC-1, and that identifying those individuals might potentially be of great value by warning them of their high risk. Now, let me hasten to say, we have not yet identified the precise gene involved. We know its neighborhood. We know the company that it keeps. And an intense effort is underway now to identify the gene itself. This same strategy that mapped this gene in Robert's family was applied this past year to also map a gene for Parkinson's disease in a large Italian family to chromosome 4. A great advance, I think, in terms of understanding a disorder which has been very frustrating and puzzling. And up until recently, there had not been much evidence that genes played a role. And now it's very clear that at least in that family, they do. inherited disease research Similar advances have been made in mapping genes for diabetes and multiple sclerosis. And in fact, in collaboration with the Johns Hopkins University, the NIH has now set up a Center for Inherited Disease Research with the National Human Genome Research Institute acting as the lead agency within NIH to facilitate this kind of mapping of genes for complex disorders. The NIH recognized that this is at the forefront of what we need to accomplish, and that many investigators don't have the technology in their own local institutions to do this, but would like to be able to. And we're looking forward to this being a very important addition to NIH's powerful set of tools to further the business of identifying genes that contribute to disease. I might also say, we have a new initiative within NHGRI partnering up with Howard University and with the Office of Research on Minority Health to specifically look at the genetic underpinnings of diabetes and prostate cancer in African- Americans. Requests for proposals have been issued for both of those and one of those studies on diabetes is now getting underway. And I have personally been very pleased to play a role in getting those efforts underway, given that those are both disorders which disproportionately affect African- Americans. And clearly, there may be genetic causes for that. finding the genes In order to take the situation that Robert's family is now in, where we know the general neighborhood of a prostate cancer gene, and go to the gene itself, one needs the next step. And here is where the Human Genome Project's tools, which are already available, and happily you didn't have to wait until the project was done, have played a major role. So the area around HPC-1, which normally would have taken a matter of a couple of years to develop a map of, already has a very detailed map, because the Human Genome Project has now mapped 96 percent of the human chromosomes to a level of specificity that we thought would take us until 1998. Furthermore, once you have the neighborhood, you not only want to know where the milestones are, you want to know where the genes are. Because each one of those genes is a potential candidate for a gene that's involved in prostate cancer. A major step forward occurred last October with the publication in Science magazine of the first gene map of human DNA. Associated with the article is a very useful Web site with 16,334 of the estimated 80,000 genes placed in rather precise intervals on human chromosomes. So that for the gene hunter, there was about a 20 percent chance, as of last October, that the gene you're looking for has already been placed in the spot you're searching, and that saves you a huge amount of time. I think positional cloning, this business of finding genes that are responsible for disease, continues to accelerate as a consequence of this. Last year some 21 disease genes were identified, the best year yet. And I think that number will continue to grow in a very gratifying way. complete dna sequence But the sequence, all of the DNA, is what we now really want. And of course, that is the ultimate goal of the Human Genome Project. And I'd like to tell you also that this is coming along quite well. This past year saw the completion of the complete DNA sequence of yeast, and the completion about a month ago of E coli, the bacterial organism which has served as the work horse for a very large amount of microbiology research over the course of many decades. That particular sequence was accomplished by a grantee of the Human Genome Project, is already in high demand, and is available on the public data base run by the National Library of Medicine. Our partnership with the National Library of Medicine in all of these databases, including the World Wide Web page I cited a moment ago, has been critical to the availability of this genomic information. NLM is also, I think very appropriately, being sensitive to the possibility of using these databases as educational tools. The gene map Web page that I mentioned had 500,000 hits on it in the first two months. And the estimates are that more than half of those were from high school students who were looking to learn something about human genetics. And this Web page is set up in a fashion that makes it very accessible to them, and a very useful educational tool. I might add, as the DNA sequencing is now ramping up, and we have initiated six pilot projects around the country, which by the end of next year should have produced something like 100 million base pairs of sequence. A great deal of enthusiasm is coming forward for this effort from private industry. For instance, I was gratified to see that the CEOs of the biotechnology industry organization last year chose the maps from the Human Genome Project as the thing that they most wanted to celebrate as having done the most for their industry, an unusual step, because they usually choose some more defined effort that's come from a particular company. beyond the first sequence Furthermore, we are very much now in the process of thinking about what shall we do when this sequence is in hand in 2005, or maybe if all goes well, a little sooner than that. Many people have compared the determination of the human genome sequence as something analogous to deriving the periodic table of the elements for chemistry. The periodic table for biology might have 80,000 entries, one for each of the human genes, instead of the 100 or so elements of the chemical table. But the parallel is a useful one to consider, because it sort of puts into context what a table of genes does for you. It provides you with that basic chart of the elements of the human organism, and then a great deal of exciting activity can follow in terms of figuring out how these genes talk to each other, interact to make a cell or a tissue or a whole organism. ethical, legal and social implications So back to Robert. I have tried to sort of outline here briefly some of the accomplishments of the last year. What about Robert? Well, Robert has another son. I told you he has one who has been diagnosed with prostate cancer at 42. He also has another son who's just turned 40. And of course, that individual is anxious, as is Robert, about the future. I think it's fairly likely that in the course of the next year or two, the HPC-1 gene will be found and Robert's son will have the chance, if he desires to know the information, to learn whether he is at similarly high risk or not. And he might not be, of course, the transmission of this disease is not 100 percent. It's probably in the neighborhood of 50 percent that this son would have the same risk as his father. But of course that then raises the question, is that a good piece of information to know? And this again raises all of the ethical, legal and social issues which come out of genome research. I ran across a quote recently from Winston Churchill, which I'm fond of, because I think some people have argued that the ethical considerations are so severe that we should really slow down this research. And I completely disagree with that logic, because I think this research holds within it the promise of curing so many human ills. Churchill said: ``My faith is in the high progressive destiny of man. I do not believe we are to be flung back into abysmal darkness by those fearsome discoveries which human genius has made. Let us make sure that they are our servants, but not our masters.'' Well, our effort to make sure these discoveries are our servants, not our masters, is the ethical, legal and social implications program, the ELSI program of the Human Genome Project. And in the past year, a number of important things have happened. The Task Force on Genetic Testing, which has been meeting for almost two years, has produced its principles and very recently published in the Federal Register a set of implementation recommendations, which are being submitted for public comment. These recommendations involve a number of new initiatives to look at the issue of testing, to make sure that it's done accurately, that the results can be trusted, and also that there is some oversight about when a test is ready to leave research and move into clinical practice. In the area of health insurance discrimination, I think we all should celebrate the Kassebaum-Kennedy bill, which does on its list of issues which health insurers should not use to take away coverage or to set exorbitant premiums, list genetic information. Just the same, there are areas that are not covered by that legislation, particularly for individual policy holders. And we are very interested in providing information to the degree that we can to assist the process of closing those loopholes. In the area of employment discrimination, there is some optimism that employers would not be at the present time able to use genetic information to discriminate. And I think that is something to be hoped for, because clearly, your DNA is not something you get to choose. And to have your DNA used to deny you a job seems inherently unfair. But to really prevent that, a legislative approach is needed. And we held a conference last October, out of which came a series of very specific guidelines which have been submitted for publication, which we hope will be looked at. That was a conference organized by the National Action Plan on Breast Cancer in collaboration with the ELSI working group, and I think produced a very useful document. Finally, the area of education, particularly of health professionals, continues to be one that we have enormous interest in catalyzing. Increasingly, individuals are going to their doctors with the latest copy of Time or Newsweek, saying, does this refer to me? Should I have this test for breast cancer? And soon it will be questions about testing for prostate cancer. And most physicians are not well prepared to answer those questions. In collaboration with the American Medical Association and the American Nursing Association, a coalition for health professional education in genetics has been started, and will have its first full meeting in about 10 days. We're very optimistic that that will be an effective way to pull together a whole host of primary care provider disciplines, allowing them to work together to achieve better literacy for health care professionals and genetics on a short turnaround. So Mr. Chairman, even without this week's revelations about Dolly, we live in exciting times. The Human Genome Project is proud to be at the center of a revolution in biomedical research. The promise for better health that the Human Genome Project provides is beginning to be realized in some quarters, although most of that promise lies ahead, and most of what I've been talking about are more in the area of inspirations than culminations. But I'm glad once again to be able to tell you that we are ahead of schedule and under budget. The request for the National Human Genome Research Institute is $202,197,000. And I'd be happy to answer your questions. [The prepared statement follows:] [Pages 501 - 504--The official Committee record contains additional material here.] finding the gene--the end of the beginning Mr. Porter. Dr. Collins, thank you for that wonderful statement. The average person reading the newspaper and let's say they read about HPC-1 and that you've found it, probably thinks to themselves, we now can cure or prevent prostate cancer. And I wonder if you could carry the concept of finding HPC-1 further and tell us what is required or may be required to get to the actual point of being able to change the gene or to cure the disease from what you have found. Dr. Collins. Thank you for the question. I think there is a great concern that many of us have that media reports of gene discoveries may sound like cures for disease, when in fact it is only a step down that path. Finding the gene is sort of the end of the beginning. Without the gene in hand, one is often really feeling in the dark, to try to understand the disorder. So for HPC-1, when the gene is identified, hopefully in a year or two, it will almost immediately, if it seems to be a good thing, allow the possibility of diagnostic testing to identify the men at highest risk. And that kind of testing would not ordinarily be done except for individuals with a strong family history of the disease, because applying it across the board might pick up many false positives. Basically, finding the HPC-1 gene would put prostate cancer in the circumstance where breast cancer is now, with BRCA-1 and BRCA-2 being a few years ahead of HPC-1. That testing alone for prostate cancer could be quite a valuable advance. This is a disease where early detection is the mainstay of cure. And we have a blood test, the PSA test, which detects early evidence of tumors. But it's almost too sensitive, in that it finds things that you're not quite sure what to do about. If you could combine that test with a genetic susceptibility test, you might have a more valuable predictor about who really needs an intervention. But I will not be satisfied, nor should anybody else be, by simply having the ability to do diagnosis. The discovery of the gene should tell us something fundamental about how is it that a prostate epithelial cell becomes malignant. That same gene, one would expect, may turn out to be involved in the more common variety of sporadic prostate cancers. One can't be sure until you get there, but that's a likely outcome. That's certainly been the case for many other cancers. Learning about how that gene functions, what its biological niche is, should provide new insights into therapies. And that's where you really want to go, and I think that's the nature of your question. Those therapies might come in the form of a gene therapy, although that is probably going to be quite difficult for an organ like the prostate, and especially if it turns out that this is one of those genes where if you don't correct it in every single cell, the cells you miss will go on and form the cancer anyway. On the other hand, understanding how the gene works might give you much better ideas about drug therapy, as protease inhibitors have arisen out of understanding the HIV genome. That sort of designer drug pathway is a very appealing one. But it is a pathway whose timetable can never be predicted. And so I can tell you these views of what's coming in the future, but the one thing I can't tell you is how many years between where we are now and where we really want to be. And anybody who sort of tries to make those predictions I think is speaking beyond the information that they have. There are so many things that are unpredictable about this. But it is the way to get there. And we're on the road. budget increase Mr. Porter. You said, and we applaud the fact that you are ahead of schedule and under budget. That's the best news that appropriators can hear. How would you respond to a question that said, well, if you're under budget and if NIH as a whole is only getting a 2.6 percent increase, why is your Institute scheduled for an 8.3 percent increase? Dr. Collins. One of the reasons I guess is that ramp-up of the Human Genome Project to full funding has never quite been achieved. And I understand the reasons for that. Starting a new program at a time of fiscal restraint has been quite a challenge. I think the Congress has been very generous in their enthusiasm for this project in appropriating what has come our way so far. And we understand those restraints. I do think that we are now in a circumstance, having succeeded at the mapping phases for the most part of this project and now beginning to ramp up the sequencing component, where we in many ways are significantly budget limited. We know what to do, we know pretty much how to do it. How soon we get there will be a function of how much budget we have available. We could go faster at this point, in fact, if it were possible for the budget to ramp up more than it has. In the current proposal, in the President's budget, I think we have done well on the basis of the NIH initiatives. Some $14 million, which is almost all of our increase, comes out of those specific initiatives, particularly in the area of genetic medicine, which Dr. Varmus and the rest of the NIH leadership have identified as being the highest priorities for payoff in fiscal year 1998. So I think the answer to the question would be, if we're going to basically deliver the products that the Congress wants, that the public seems to want, we could actually do better if this budget continues to ramp up. If we're truncated, we can continue to sort of do what we've been doing. But it will take us longer to get there. Another part of this is we are beginning to spend a small fraction of our effort looking at what happens after the human genome sequence is done. It would be very unfortunate to sort of get there and then realize we should have been planning for the next step. So we are doing that planning, and we've issued a couple of requests for applications this year for people to begin to look at whole genome technology and for developing a ``genome attitude'' towards biology on a larger scale. And I think that's a very important part, but a small one at the present time, of our portfolio. finishing faster--finding a cure Mr. Porter. Is the real answer then that there is a certainty that more money will get more results with respect to the mapping project, and that therefore, the likelihood of bringing real progress to prevention and curing of disease is more likely with the money spent at a higher rate earlier than in other places? Dr. Collins. You could argue that every year that goes by that we don't have the complete human genome sequence we are missing out on opportunities to cure disease. You could certainly argue that every year that goes by, people are wasting a lot of money getting bits of sequence that wasn't already available for them. And people have tried to add up what that amounts to, and especially if you include the private sector, that may be as much as a half a billion dollars every year that's spent on activities that won't be necessary when the Human Genome Project is done. cloning--scientific opportunities Mr. Porter. Dr. Collins, you were present yesterday when Dr. Varmus addressed the Dolly question. Dr. Collins. Yes. Mr. Porter. I wonder if you would like to expand on that answer, or add your own viewpoint to it, and see what you think about cloning. Dr. Collins. Sure. When I came to this job as Director of the National Center for Human Genome Research, which is what we were called then, I did so with some trepidation. But after I had been here a year or so, it occurred to me that many of the aspects of my own training had actually prepared me pretty well for this position in terms of having a background in physical science, being a physician trained in genetics. Only this week did I realize another part of my background was appropriate, and that is that I grew up on a sheep farm. [Laughter.] So from that particular context, and mindful of Mark Twain's remarks: ``There is something fascinating about science. One gets such wholesale returns of conjecture out of such a trifling investment of facts.'' That seems to be happening rather broadly this week in the press. Nonetheless, I think what was reported and I guess is being reported in Nature today, but has already been talked about very broadly, is a fundamentally exciting scientific achievement. And I completely agree with Dr. Varmus' analysis of some of the scientific opportunities that this offers in terms of understanding development. For me as a geneticist, this notion that the DNA sequence of a differentiated cell could be convinced to sort of go back and start over again as a fully undifferentiated embryonic state is remarkable. I think most of us would not have guessed that would happen. It sort of says that the whole array of genes are like an orchestra, and in a particular cell maybe only some parts of the orchestra are playing. But the whole orchestra is there. And if you can figure out how to sort of shut off the playing for a little while and then start it back up again, you can get the whole orchestra to perform. And that is fundamentally really interesting. I think the possibilities, some of which Harold mentioned yesterday, about being able to use this kind of de-differentiating process medically are very intriguing ones. I would also say that in terms of the ethical issues, we should make it very clear that the use of this technology to clone human beings is unacceptable. Repugnant is the word that Dr. Varmus used yesterday and I agree with that. On the other hand, to rush in and criminalize a certain aspect of scientific research without careful thought would be unfortunate. And I applaud the President's decision to involve the National Bioethics Advisory Commission, a group that I think is very well positioned to look at this issue over the next 90 days and come back with some observations about possible options of what might be done. So I think although in many instances, when you have a media event around science, you worry a little bit that it's going to scare the public off. This observation has engaged the public in conversations that we might not otherwise have had. And I think the reverberations of this observation, provided it can be duplicated, of course, we will all be interested to see the first confirmation of this report. But provided that is so, I think something has really changed in science, in the way we view biology. And that is something to be welcomed. Mr. Porter. So you're expressing some scientific skepticism that this is actually good science, or you want to at least have it proved that it can be done repetitively? Dr. Collins. I think any new observation that is as fundamentally revolutionary and unexpected as this ought to be confirmed by another investigator. I have read the paper reporting this. It looks very solid. I don't see anything wrong with it. It seems quite well founded, and I suspect it will be possible to reproduce. Although it is clear that this was a very difficult thing to do with only 1 lamb actually being born out of almost 300 that were attempted. So there must be some enormous inefficiency in the process. One of the things I'll be very interested in is to see whether Dolly ages prematurely. There is a history of arguments about the molecular basis of aging and is it in fact something that is acquired as a cell divides over and over again and acquires mistakes in the DNA? Is that what eventually causes the process to run down and the cell to die? Now, Dolly's single original cell, typically in the one cell stage, had already gone through six years of life. Is it going to be the case, therefore, that her longevity is affected? That will be a very interesting thing to follow. Mr. Porter. With your background on a sheep farm, maybe this is where you can---- Dr. Collins. Go back to my roots here. [Laughter.] Mr. Porter [continuing.] Add something to the research. Mrs. Lowey. genetic testing--breast cancer Mrs. Lowey. Thank you, Mr. Chairman. And thank you, Dr. Collins. The possibilities of the work of your institute are certainly overwhelming. And it is certainly a privilege for us to play some small role in helping advance the important research you're doing, and I want to thank you. And I look forward to working with you on the whole area of employment discrimination, and I am delighted that those findings will be published. As you know, I have been working on that whole issue, and I'm looking forward to your presentations on the legislative remedies. Because I have to participate in another hearing immediately, I just want to, and I know what we'll be discussing the areas of employment discrimination with regard to genetic testing, etc., I would like to just ask you, since we gathered last and you reported to us on your BRCA-1 and BRCA-2 findings, have there been any additional findings in that regard, any other additional research that you'd like to share with us? Dr. Collins. I appreciate the question, and I very much appreciate your leadership in the area of genetic discrimination and legislative initiatives to do something about that. I appreciate what you're doing about employment this year. I think the opportunities are quite good to solve this problem at the Federal level. BRCA-1 and 2 research is in sort of an incredible flurry of activity, now that the genes have been in hand for a year or two, some of the best labs in the country have turned their attention to trying to figure out what they do. Mouse models have been made for both of those, where the BRCA-1 and BRACA-2 genes have been knocked out to see what happens. At the present time, it's not clear that the mouse models show the same risk of cancer, at least not in the first few months. But still, those models are likely to be quite useful in understanding the mechanisms and how these genes contribute to cancer of the breast and ovary. In terms of understanding how the protein products of these genes work, there have been at least two, and one hears rumors of a third, experiments that show other proteins in the cell that interact with the BRCA-1 protein and therefore probably work together with it to do whatever its normal function is. And that is one of those clues that starts you into a pathway which might be very useful in understanding how these genes do their work and how they don't succeed when they need to in somebody who has an alteration. In terms of understanding the clinical consequences of alterations in this gene, the Washington Area Ashkenazi Jewish study has now been going on for a year, and the results of that study have been submitted for publication. I'm not at liberty to describe them. But this particular study looked at 5,300 men and women, collected their family history and obtained a blood sample to find out whether or not they are carrying one of these genetic alterations. One in 40 of those individuals was carrying a mutation in either BRCA-1 or BRCA-2, about the expected number, based on previous studies. And obviously, the main payoff that we are waiting for from that study is to find out what really is the risk to such an individual? Is it as high as the 85 percent that has been proposed in other studies? This study I think gives a better window on that, because it's less likely to be a biased estimate, and hopefully those results will come forward very soon. Mrs. Lowey. I appreciate that. Because I believe you shared with us two facts, among many other facts, but number one, it's still a very small percent of the cancers. Dr. Collins. Yes. Mrs. Lowey. And number two, or perhaps I should ask you this in the form of a question, when you're saying 1 in 40, are you determining at what age that cancer appears, so after a certain age, the incidence of cancer increases in every population? Dr. Collins. Sure. Mrs. Lowey. So that if you're identifying that gene to be 1 in 40, you're not making determinations at this point whether that person will get that cancer at the age of 40, 50, 70 or 80. Or are you? Dr. Collins. I may not have been completely clear. The 1 in 40 is the frequency of finding an alteration in BRCA-1 or 2 in a Jewish individual, regardless of their cancer history. What the study is trying to determine for those individuals who do have those alterations, what is their likelihood of getting cancer and at what age. Is it an early age of onset, which some of the other studies have suggested, and if so, by how much. We don't have the answer, but in the coming months, that should come forward. genetic testing--counseling and control Mrs. Lowey. And has there been any progress made on counseling and control of these tests? Because many of us are concerned, and we talked about that last year, about the commercialization of these tests and what goes with it, and what kind of consistency is there in the counseling with those tests. Dr. Collins. Well, there are a number of answers to that question, certainly a number of centers are looking at counseling, trying to figure out what is an effective way to deliver these services. There is a Cancer Genetics Studies Consortium which is funded jointly by the National Human Genome Research Institute, the National Cancer Institute, the National Institute for Nursing Research and the National Institute of Mental Health that has banded together about 11 researchers to share their experiences doing genetic counseling for both breast cancer and colon cancer. And a lot of useful information has come out of that consortium with at least four publications in prominent journals to guide the rest of the world in terms of how to present this information so that it is absorbed and understood and put into practice. The other thing you're referring to, though, is really sort of the marketing of the tests themselves. There has been, since we last met in this room, the marketing announcement of a company in Utah of a test for BRCA-1 and 2. It cost $2,400 to have a particular sample analyzed to see if there is a mutation present. And it is available to individuals outside of research protocols, which up until fairly recently was where most of this testing was being done. So that's raising questions about whether this is premature or not. Various statements have been made on that topic, and they don't all agree with each other. The National Action Plan on Breast Cancer has a published statement saying that it's unfortunate to have such testing done outside of research protocols when we're not sure yet what the clinical utility is. But at present, there is no Federal oversight to prevent that. The Task Force on Genetic Testing, which I mentioned in my opening statement, has very much been looking at this issue. And they have actually made the recommendation that the Secretary of Health and Human Services establish an Advisory Council on Genetics and Public Policy to review such tests and to make such judgments about whether or not they are appropriate for taking up a role as part of general clinical medicine. It will be very interesting to see how that's received. Mrs. Lowey. Well, thank you, and I look forward to continue working with you in this area. And I thank you, Mr. Chairman. And I do apologize. Dr. Collins. Thank you, Mrs. Lowey. Mr. Porter. Thank you, Mrs. Lowey. Mr. Miller. cloning--international cooperation Mr. Miller. Thank you, Mr. Chairman. Dr. Collins, I always look forward to your presentation, you're so excited about it. A couple of questions. The Dolly question. Were you caught off guard by that? Was that unexpected, or is that type of research being done here in the United States? Dr. Collins. I was totally caught off guard. This was a result that I think was not expected to succeed. There were preliminary experiments by the same group published a year or so ago, where they were able to take sheep embryo cells and take out the nucleus and then put it back into an oocyte and produce a lamb. But that was less surprising. An embryo cell is sort of programmed to be an embryo cell. The idea that you could take a mammary epithelial cell from the udder of a sheep and convince it to behave that way, that is the profoundly surprising part of this. And I think most people would not have expected that to work. Clearly, the group that did this work kept it very tightly under wraps. A strong effort was made not to have this leak out prematurely. So no rumors had been circulating. This kind of research is certainly done in this country, although it is in sort of the animal husbandry area, which is a separate discipline from the folks that are looking at, say, mouse models of human disease using molecular biology. But it has certainly electrified the community. You cannot walk down the hallways of a research building in any university in this country, I don't think, without being engaged in a conversation about Dolly this week. Mr. Miller. Was that in an animal husbandry department? Dr. Collins. It's animal science, I guess, it's in an institute in Scotland which is privately funded, and involves a biotechnology company as well. Mr. Miller. Is that an embarrassment, to have this-- [Laughter.] Dr. Collins. Oh, I can't be embarrassed. I guess as a scientist, I've always been sort of a fan of the notion that science is an international activity. Certainly the Human Genome Project is. And we tend to celebrate exciting advances wherever they come from. future health care delivery Mr. Miller. When I get a chance to speak to young people, one thing I say is, there are two areas that are so exciting, what the future holds. And it's hard to comprehend what it's going to hold. One is the whole area of telecommunications and computers, which is mind-boggling how far we've come in the past 10 years. I'm not sure where we're going. But the other area is the area you're in. And it's hard to comprehend what medicine is going to be like. I was speaking to a group, I was even relating that to a group of employees at a hospital last week, health care delivery is going to be very different 10, 20 years from now. How could you describe the potential of the way health care is being delivered 10 years from now? We're on the verge of so much that's happening. People will still grow old, parts will wear out, but the ideas of cancer and all that, how could you describe what a health care delivery system will be like 10 years from now? Dr. Collins. I'll give it a shot. As my old professor of medicine kept reminding me, the death rate will still be one per person. [Laughter.] We have to have realistic expectations, but I do think there will be stunning advances in the next 20 or 30 years in understanding the basis of the common diseases that so frequently cut people down prematurely, things like cancer and diabetes, hypertension, schizophrenia. This very long list of disorders which we currently can describe the symptoms of and often treat the symptoms of, but whose underpinnings have not really made themselves known. Obviously, as the geneticist, I will tell you that a significant route to getting to those underpinnings will be our understanding of the genetic contribution to those disorders. We all are walking around, it's estimated, with 5 to 20 genes that are misspelled and that are sort of lurking there, waiting to potentially cause us trouble. You may have a different set than I do, but we all have some. There are no perfect genetic specimens, not even in these hallowed halls of the Congress, I'm afraid. So the possibility of uncovering those misspellings becomes quite real over the course of the next 10 or 15 years, with the Human Genome Project producing all of these tools. And with that will come the ability to make individualized predictions about risk. Now, if I knew I was at risk for colon cancer more than the average person, that would be something I'd like to find out about, as long as I was sure it wasn't going to be the end of my health insurance, because I know that colon cancer can be cured if it's detected early, while it's still a small, benign polyp. So you will see, in I would say the next 10 years, you wouldn't have to wait longer than that, the emergence of individualized programs of preventive medicine based on this kind of genetic susceptibility testing, to allow people to design programs for themselves, focused on staying well. And not just one size fits all, everybody should do the same thing, which is what we often do, but individualized programs based on your own susceptibility. Obviously, that depends on the kind of testing. It has to be voluntary, and I would hasten to say this is the sort of thing that some people maybe won't want to know, and shouldn't have to know. But I suspect for disorders where interventions are available, a lot of people will be interested. Now, the therapeutic side of medicine is also going to be going through remarkable changes in the next 20 or 30 years. Whether those come from gene therapy, a field which is still in its infancy and therefore it's hard to tell what kind of kid it's going to be when it grows up, or comes from drug therapies that are really designed to target the precise problem. We were talking about therapies for HPC-1 a minute ago, I'm not sure which therapy will develop and I don't care, as long as it works. And I think there's a good likelihood that you will see many of those things, not tomorrow, not next year, but in the next 20 or 30 years. Furthermore, medicine will probably become very much influenced by the computer revolution that you mentioned. Things like telemedicine will become much more familiar parts of everyday medical care. I think that's good. I think we have to be cautious about how we oversee that, so that we don't lose the human touch. As a physician, I will argue very strongly that a very important part of medicine is that human touch. And if everything we do ends up being robotized, we've lost something really important and we should resist that. designer drug strategies Mr. Miller. You mentioned, one area that you mentioned is protease and how the Genome Project had a relationship to that. I see Dr. Fauci is coming up next right behind you. Dr. Collins. Yes, he might disagree with that. [Laughter.] Mr. Miller. But what areas have we already seen a relationship to bring out that's available, the relationship for example of protease? What areas are we farthest along as far as providing treatments available on diseases? Is protease a good illustration of that? Dr. Collins. I used it as an example of a designer drug strategy, whereby understanding the genome of HIV, and that was not the Human Genome Project, but that was AIDS researchers working very hard to try to understand this very frustrating, difficult virus, learning that it did make this particular enzyme, this protease, and then figuring out what kind of small molecule could be designed to effect that activity. Then you see this revolution that seems to be happening over the course of the last year, where potentially the course of the illness has been significantly altered. And I'm sure Dr. Fauci will talk more about that. That's the model, the designer drug strategy. Another example that I guess I would give is in the area of cholesterol management. We have learned a lot about why it is that some individuals have early heart attacks by understanding this disease called familial hypercholesterolemia, which turns out to be rather common, and it's an alteration in a receptor that normally binds to LDL, which is one of the molecules that carries lots of cholesterol. Understanding that genetic alteration led to insights by the Nobel laureates, Brown and Goldstein, which have now put in our hands a whole generation of cholesterol controlling drugs, which are actually very effective. In situations where individuals in the past really didn't have many options other than diet control, which didn't work well, these are now very treatable conditions. It's another model where gene understanding led to insight about pharmacological therapy and then to the control of a disease which had really been quite resistant. There are others, but that's a particularly attractive one. I might say, another area of future medicine will be the business of predicting what kind of drug should this person get for this disorder, based on their genetic endowment, pharmacogenetics, as it's sometimes called. It may be that some drugs work particularly well for some people and less well for others. It may be that the toxicity of drugs is determined to some degree by the genes of the host. If we understood that better, and there's a great effort to do so in many pharmaceutical companies, then we could individualize therapies, to avoid the toxic side effects and maximize the benefit. Mr. Porter. Thank you, Mr. Miller. Mr. Wicker. Mr. Wicker. Thank you, Mr. Chairman. Dr. Collins, let me ask a question about cloning. And let me just observe, Mr. Chairman, that you have figured out a way to get the television cameras here, just tell people, as you did yesterday, that we're going to talk about cloning, and CNN will show up. And I saw Dr. Varmus last night on Headline News talking about cloning. Mr. Dickey and I have been whispering about these technical terms that Mr. Miller's been using. We're very impressed. [Laughter.] Cloning--Potential for Hoax Mr. Wicker. I want to try to ask a real layman's question. The Chairman, asked a question about skepticism. And I believe Dr. Varmus used the word science fiction yesterday in talking about this very serious subject. First of all, do you think there's a chance this Dolly experiment might be a hoax? Are you convinced beyond a doubt that it is real? Dr. Collins. I think it's unlikely that it's a hoax, looking at the data and seeing that this is a paper produced by several authors, not just one, certainly the data as presented does indicate that Dolly's genes appear to be identical to the genes of the sheep that donated that mammary epithelial cell, so there wasn't a mix-up of some sort. I guess I would say it is never possible to sort of look at a published paper and say absolutely for sure this could not be a hoax, but it doesn't seem to have that flavor. I guess what I was saying a moment ago was that science always should be confirmatory. When you have a new result, particularly a surprising one, other people should--and believe me will--be going out to see whether they can reproduce that result. So I think it's very unlikely that it is a hoax. Mr. Wicker. I have an article about you from the Chicago Tribune. It describes you as a lanky, laconic physician, chemist, geneticist, country music singer, and motorcycle buff. And we should now add former sheep farmer. [Laughter.] Cloning--Why a Sheep Mr. Wicker. Is there anything about a sheep, and you wouldn't know this from having been a farmer, but as a scientist and geneticist, something about that particular mammal that you think made it an easier candidate for this type of experiment? Dr. Collins. I don't know if there's something unique about it. Certainly one of the motivations for using sheep for this experiment is there's a great deal of interest in using sheep, particularly the ability to put genes into the mammary glands in order to make proteins in sheep milk, which could then be purified and used as pharmaceuticals. So there was a drive from the point of view of the biotechnology industry to try to achieve this in a sheep and not in, say, a horse. There are a couple of interesting things about sheep. You can operate on the sheep uterus without inducing labor. You can't do that in most other mammals. So there's been a long experience of doing fetal surgery with sheep, which may in some way have played into this. There's a lot of veterinary experience dealing with the sheep reproductive system, because it seems to be more tolerant of interventions during gestation. Outside of that, I'm not sure that this could not somehow have been done in some other large mammal. It just happened that this group that was doing it was most interested in that particular mammal. Mr. Wicker. Well, you mentioned a horse. And I was thinking a race horse, you know. [Laughter.] Dr. Collins. Well, you can be sure people in Kentucky are talking about that this week. Mr. Wicker. Undoubtedly. I appreciate what you and Dr. Varmus have said about the ethical considerations. There are very profound considerations that go into this. But the human is a mammal. And I just want to hear your comments, if you can clone a sheep, and if somebody had the money to pour into the project, is it totally science fiction to assume that a human being could not be cloned? Cloning Humans Dr. Collins. Harold, do you want to jump in? Dr. Varmus. I just want to clarify my reference to the term science fiction yesterday. I did not use that term to say that it would not be possible to do similar experiments in humans. What I was pointing out was that there was a lot of science fiction composed around this idea. And that from the point of view of most scientists, this is not where the interesting component of the current experiment lies. The interest lies in the use of animal models, the or understanding of how genes are turned off and on, and the possible exploitation of that for benefit. Mr. Wicker. Okay, but I really am interested, though, in the answer to the question. Dr. Varmus. We acknowledge the possibility that it is possible. I made that clear yesterday. And with not very expensive equipment. However, your question about sheep is right on the mark. We don't really know whether this is a special case. It's impossible to evaluate how easy it was in the sheep, because remember, starting with an adult cell, it was only 1 case out of almost 300. Now, in someone else's hands, that might have been 1 out of 5,000, in which case it probably wouldn't have happened, because it's too difficult to do. Perhaps in other species, it will prove to be more efficient or less efficient. I think we don't know. And when Dr. Collins referred to the importance of confirmation of the observation, one of the things that will be interesting is not simply confirming the observation with sheep, but looking in other agricultural animals or for that matter in the mouse. Dr. Collins referred to some interesting notions about aging that could come from these experiments. And it will be very important to try to do this kind of experiment in the mouse. I point out to you that what is called a clone is not strictly speaking a clone--in fact, less identical than identical twins. The reason for that is that when this experiment is done, you are putting the cell into an environment where there are mitochondria, the small DNA- containing organelles that exist in the cytoplasm--I'm sorry to use the terminology, but---- Mr. Wicker. I'll get Mr. Miller to explain that later. [Laughter.] Dr. Varmus. So there is other DNA, there is DNA outside of the nucleus, in the cytoplasm of our cells, which is in Dolly, but was not in the donor. That's important. So it's not truly a clone. Moreover, as Dr. Collins mentions, the cells that came from the donor have been through many, many duplications. In the course of those duplications, there were almost certainly mutations introduced into the DNA. We don't know the effect of those mutations. But it makes Dolly different from the fertilized egg that gave rise to the donor. Human Embryo Research Mr. Wicker. Okay. Let me just ask a quick question, for either one of you. The case of Dr. Mark Hughes. I wonder if you could comment on that. He was forced to leave NIH because it turned out he was using Government equipment to conduct human embryo research in violation of the so-called Dickey-Wicker amendment. In that case, I understand it was disputed who alerted NIH. And I just wonder, how confident we can be that other situations like this don't exist and what steps are being taken to make sure of this? Dr. Varmus. Perhaps I should answer that, Mr. Wicker. Obviously, as in the case of any law, all we can do is look for offenders and be sure that people understand the law. There is no doubt that Dr. Hughes understood the law. It was explained to him by many people, including myself. The intramural NIH research program was fully aware of the law. Anyone who had applied to the NIH for grants to do work that could involve human embryo research not only was informed, but had signed a statement saying that they knew that in receiving money from the NIH, they were not to use any of that money to do that kind of work. We have put reminders in light of the evidence about Dr. Hughes on our Web site. The Department of HHS has sent to all institutions that receive our grants reminders about your amendment as well as other restrictions on the use of our money. We've made every effort to be sure that our grantee institutions and our grantee scientists understand what the law is, and we expect them to follow it. Mr. Porter. Mr. Dickey. Mr. Dickey. Thank you, Mr. Chairman. I apologize for not being here yesterday. It wasn't because the cameras were here. I know I'm kind of a shy guy and I'm sometimes afraid of the cameras, but it wasn't for that reason. I'm concerned overall, and I've expressed to you my concern about the Dickey-Wicker amendment. And I think I've settled that. But I'm concerned overall that we might not be progressing toward cures, and we might be distracted by giving appropriations to more areas. Can you help me with that? Is that question clear? Dr. Varmus. No. Mr. Dickey. What I'm concerned about, as I look at the expenditures, we're taking money away from heart disease, and cancer and so forth. Or stated another way, we have money that we're sending to other areas of responsibility like diabetes, for example; we could be taking that money and bearing down more toward a cure. Tell me how I'm wrong in that perception. Dr. Varmus. Again, I'm not quite sure where you get this idea that we're taking money away from those areas. All areas of research could be aided by additional funds. There are various ways to evaluate whether the amount we're spending in different areas is appropriate; it may seem appropriate to some and not to others. We believe that the money that we spend is all directed toward alleviation of human suffering, and that the calculus that one uses to determine what is correct may vary from calculator to calculator. But it's not the case that there is money being taken away from the areas you've mentioned. Every area you've mentioned is an area that has received increases over the last several years. Not always equal to the increases that are received by every component of NIH for example, as we discussed earlier, the Genome Center, now Institute, has been ``ramping up,'' in Francis Collins' words, more rapidly, because it began from a very low level. A very similar argument could be made for the funding of AIDS research, which for a time ``ramped up'' quickly. Now it receives the same increase as every other area of NIH. Breast cancer research was ``ramped up'' some years ago as were Alzheimer's, and tuberculosis research, in response to specific needs. We've been funding research on diabetes and heart disease and cancer for many years, at quite generous levels. We believe that we respond to the scientific opportunities and that great progress is being made in all the areas that you mentioned. So I would take issue with the general contention that we are taking money away from these areas of serious medical concern, and I'm not quite sure where you think the money is going where it's not deserved. Maybe you could be more explicit about that for me. Mr. Dickey. I just got the impression, and I just watched it, diabetes is one particular thing that I've gotten concerned about because of a friend of mine's loss of his daughter, 32 year old daughter. I think it was heart complications of diabetes that caused her to lose her heart functions. Now, I get this idea (and I don't think I can support it factually) that we are, that some things are old hat and we're making progress; however we're not really going to war in certain areas. Heart disease, for instance, let's see, $28 billion was spent out of Medicare for heart disease, covering some 17 million, 18 million patients. Now, I don't see an intensity of that going at the heart disease, and saying, we're closer, we're closer, we're closer. Is that an accurate observation? Dr. Varmus. I don't believe it is, sir. And I say that for a number of reasons. One is that we've made tremendous strides in the treatment of heart disease and prevention of heart disease over the last 20 or 30 years. So the mortality rates have fallen by about 50 percent. That doesn't mean that we're there. There's still a very high burden of disease, especially with the aging of the population. We have a number of very important initiatives, and you'll hear about them next week. We spend over $1 billion a year on a variety of research on the heart and the vessels. As you know, much of the heart disease that we have in our society is due to diseases of the vessels. You could read yesterday's testimony about the intensity of research on the process we call angiogenesis. That's a word, Mr. Miller, that refers to our understanding of how blood vessels are generated. [Laughter.] It is a very, very important new field of research, because if blood supply to an organ like the heart or the brain is impaired, obviously what we would like is a way to replenish the blood supply by making new blood vessels. And we've learned largely from research in cancer new ways to do that. Mr. Dickey. Let me interrupt you, because I'm afraid my time's run out. From what I understand, NIH over the last 10 years appropriation has increased 98 percent. Diabetes, from that appropriation, diabetes has increased only 32 percent. Maybe that is a way of describing what I'm trying to say. In other words, just taking diabetes, it hasn't increased, as we increased your appropriation, diabetes has gotten a lesser---- Dr. Varmus. Well, I don't know, I'd have to look at the source of those numbers. It probably is the case that if you look at the numbers over that long a period, you may see a lower than average increase because a number of things have expanded in a very major way because of the growth of the genetic enterprise or because of the growth of our expenses to respond to the AIDS epidemic or in response to Alzheimer's, which has become an increasing problem. But I think if you look at diabetes research broadly and analyze the way in which diabetes research is being affected by other disciplines, you will get a different picture. Let me give you one very pertinent example. The kind of work that Dr. Collins and the Genome Institute have done has allowed in the last year the isolation of two genes that have been studied for totally different reasons that are responsible for two inherited forms of diabetes called maturity onset diabetes of the young. These are remarkable opportunities, inspirations, if you will, for understanding diabetes at the fundamental level. I will also point out to you that we have made tremendous progress in diabetes. You can read the transcript of Dr. Kupfer's performance yesterday, and you'll see that we now have the means to treat diabetic retinopathy very effectively. One of the problems in caring for diabetics at the moment is persuading patients and physicians to respond to the new information that we've accrued over the last several years by studying the long-term complications of diabetes. As the death of your friend's daughter illustrates, we know that diabetes affects blood vessels and nerves and kidneys and eyes. We also have learned that careful control of diabetes, which is difficult to achieve and requires patience and hard work, has a major effect in reducing the morbidity of the complications of diabetes. So a large part of the problem in diabetic morbidity has to do with taking the discoveries that have been made with NIH research and getting them applied in the clinic. Mr. Dickey. I really believe that my support of what you're doing has a lot to do with the intensity of the commitment. And I just don't want you all to let up. I mean, you all are scientists and I'm where I am. But I'm just saying, it's the intensity, and it's just pushing forward. It's the cure that we need to go after. Diabetes is only an example. Dr. Varmus. I appreciate your comments. And I hope you'll come to hear from Dr. Gordon and Dr. Lenfant, who will address some of these issues. Mr. Dickey. As long as there aren't any cameras. [Laughter.] Thank you, Dr. Varmus. Mr. Porter. Thank you, Mr. Dickey. Before I call on Ms. DeLauro, I want to say that the situation is a very unfortunate one that we are running out of time. And we have asked Dr. Fauci if he might stay a little bit later. The Chair intends to go until 12:30 with Dr. Fauci. And Dr. Varmus, I am feeling that we are not allowing sufficient time in some instances. And I would ask that we consider perhaps bringing back yourself and certain institute directors later in the year, if we feel we really haven't had a thorough opportunity to look at the situation in each of those institutes. Dr. Varmus. We would be delighted to do that. Mr. Porter. I know how valuable your time is, and I don't want to burden you, but I also don't want members of the subcommittee to feel they haven't had a real opportunity to discuss things that are on their minds with you. Ms. DeLauro. Genetic Discrimination and Privacy Ms. DeLauro. I'm very supportive of what this project and this institute is about, in terms of what it means to our ability to identify therapies or cures in the long-term. I think it's one of the most important efforts that we have taken. One of the concerns that I have is there are about 40 million people today who are not covered by health insurance in this country. We've got tremendous advances in medical technology like the human genome map. What concerns me is that in the future you may have someone who tests positive for a mutated gene that could yield breast cancer at some point in their lifetime, and they will not be able to get any kind of preventive care in order to avoid that disease. You have a landscape with insurance coverage today that potentially may make it very difficult, once we've got this wonderful discovery, she may be left without any recourse, unable to deal with it. I mean, the question is, and I'm struggling with the question here myself, with what you are doing and what you are able to uncover in the Human Genome Project, will it help or hurt individuals with little or no health care coverage in the future? That may not be specifically what you are about, but we're dealing with what science is uncovering and what is happening to the people at the other end of the process. Dr. Collins. It's a very serious matter. We are, among all Westernized, civilized countries, the one that seems most willing to let the largest fraction of our own population be in a circumstance where they can't get access to health care. And you really do look at that and wonder, how did this happen. I don't think that the genetic aspect of medical care is particularly different from the rest of medical care. If you're not covered, you're not covered, and that's a serious tragedy, and one which I think this Congress seems interested in addressing, albeit maybe not in the overarching way that was discussed a couple or three years ago. Ms. DeLauro. I get scared about pre-existing conditions. Dr. Collins. Well, sure. There are two areas that we can and should start to fix, even within our existing flawed health care system. And I sort of think of these as the two pillars of a building. And one of them is privacy and the other is avoiding discrimination. The avoiding discrimination pillar, in order to really be robustly protective, requires Federal legislation to make it illegal for health insurers to use genetic information to deny coverage or to set exorbitant premiums. And Kassebaum-Kennedy moves in that direction in a very gratifying way, if you're in a group policy. For individual policies, it's much less protective. Efforts are underway in the current Congress to do something about that as for instance, Congresswoman Slaughter announced yesterday legislation that I think highly appropriate. Discrimination comes in other flavors besides health insurance. Employment issues need to be addressed as well. The other pillar is privacy and confidentiality. Not only should third parties not be able to use this genetic information against you, they really shouldn't be able to see it unless you tell them it's okay. And if you have one of those pillars without the other, the building still falls down. We really need a way to protect medical records in this country. Right now, it's ridiculous. If you start counting up the number of people that can look at your medical records, you sort of get tired after 100, because it just keeps getting bigger and bigger. And there is no meaningful control of that process. Clearly that is an area of great concern amongst the public and in the Congress. There are at least three bills this year that are being introduced or will be shortly. My own view is that you can't take the genetics part of the medical record and set it in a separate category and say we're going to apply protections to that and not worry about the rest. Because which part is the genetic part? Every disease has a genetic component. Everything in your medical chart, if you want to look at it with really a hard, cold eye, you could say there is some familial contribution. It's not possible to separate the information. So to solve the privacy issue for genetics, we have to solve it for the whole medical record. And I certainly think that ought to be a very high priority, especially as more and more of this information becomes electronic, and maybe it gets easier therefore to eavesdrop in places that the patient would not allow had they known. So I think every possible effort ought to be made. I must say, I'm very gratified, after four or five years of bringing up these topics and not receiving much enthusiasm, now one sees in many areas on both sides of the aisle in both houses of the Congress, a good deal of interest in doing something about this. And in the case of Kassebaum-Kennedy, an actual piece of legislation has been passed and signed. Ms. DeLauro. Well, I think it's important to have your voice engaged in this discussion, because I think it's a very important road we're going down. Dr. Collins. I couldn't agree more. Ms. DeLauro. These are uncharted areas in a whole variety of these cases. And we truly do need to make sure we're going to continue with discovery part of it, and then how do we ensure, that we can protect the individual. Dr. Collins. The greatest tragedy would be if this project is scientifically successful but socially unacceptable. And you have this wonderfully powerful new brand of medicine which has promise to save many lives, but nobody wants to have anything to do with it, because they're fearful that the information will get used against them. What a terrible stillbirth that would be. Yet, we can prevent that if we act now. Ms. DeLauro. Thank you. Thank you, Mr. Chairman. Mr. Porter. Thank you, Ms. DeLauro. Mr. Hoyer. Mr. Hoyer. No questions, Mr. Chairman. Mr. Porter. Dr. Collins, thank you for the marvelous work that you do at your new institute, and for your always fascinating testimony. We very much appreciate that. I suspect that the subcommittee may want to ask you to come back, perhaps for another hour, sometime later in the year. Dr. Collins. I'd be delighted. Mr. Porter. If we do, I hope that you would be able to respond. We do respect your very, very busy schedule and Dr. Varmus'. Sometimes these hearings are just too short to get really deeply into this. I have pages of questions I haven't been able to ask and I really want to ask them. So again, we appreciate your testimony today, and hope you remain ready to come back. If we ask you, would you? Dr. Collins. I am most ready at your wish, by all means. Mr. Porter. Thank you very much. The subcommittee will stand in recess briefly. [The following questions were submitted to be answered for the record.] [Pages 523 - 581--The official Committee record contains additional material here.] Thursday, February 27, 1997. NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES WITNESSES ANTHONY S. FAUCI, M.D., DIRECTOR JOHN J. McGOWAN, M.D., ACTING DEPUTY DIRECTOR GEORGE W. COUNTS, M.D., DIRECTOR, ORMWH STEVEN J. BERKOWITZ, ACTING ASSOCIATE DIRECTOR FOR MANAGEMENT AND OPERATIONS THOMAS D. WILLIAMS, BUDGET OFFICER HAROLD VARMUS, M.D., DIRECTOR, NATIONAL INSTITUTES OF HEALTH DENNIS P. WILLIAMS, DEPUTY ASSISTANT SECRETARY, BUDGET, DEPARTMENT OF HEALTH AND HUMAN SERVICES Mr. Porter. The subcommittee will come to order. Dr. Fauci, we somehow scheduled both you and Dr. Collins in the same two-hour timeframe. I think it's insufficient for either one of you, and we will ask you also if you would consider coming back later in the year when we can spend a little more time. I just think this timeframe is simply too short. Dr. Fauci. I'd be delighted to do so. Mr. Porter. With that, I am going to ask you to introduce the people with you, and then proceed. We will see how expeditious we can be and perhaps we can save some time at this point in the proceedings. introduction of witnesses Dr. Fauci. Thank you very much, Mr. Chairman. Let me first introduce my colleagues at the table. This is Dr. George Counts on my far left, who is the Director of our Office on Research on Minority and Women's Health; Dr. John McGowan, who is the Deputy Director of the Institute; Mr. Steven Berkowitz, who is the Associate Director for Management and Operations; Mr. Thomas Williams, who is our Budget Officer; and you know Dr. Varmus and Mr. Dennis Williams. You have my written statement, Mr. Porter. What I would like to do is just take a few minutes and summarize some of the salient features of that, with some visual aids. Opening Statement The question that I often get asked relates to the cover of Newsweek magazine and other popular lay magazines that we've seen over the years; are we really approaching or at the cusp of the end of HIV/AIDS? And the answer is, although there have been substantial and dramatic advances over the past year, the answer to this question is no. [See figure 1.] [Page 585--The official Committee record contains additional material here.] Dr. Varmus appropriately spoke about culminations and inspirations. Certain aspects of AIDS research are almost but not quite yet culminations, and there are probably more inspirations than there are culminations. Since I have testified before this committee about the advances in AIDS several times over the past years, what I would like to do very briefly is summarize, in a temperate fashion, some of the things that I've actually told you in this committee regarding the evolution of treatment strategies for HIV/AIDS. You might recall that in 1987 when I came before the committee and told you about the use of AZT as a single drug monotherapy, let me put into perspective what this drug and other drugs have done, one, to the virus, and two, to the patient in question. [See figure 2.] [Page 587--The official Committee record contains additional material here.] This is a measurement of level of virus, and this is week of study or time upon the antiviral. When we had AZT alone in 1987, this is what we call a logarithmic scale, so that when you go down from 1 to 2, you are actually going down by 10--10 times the amount, not twice the amount. As you can see, there is a substantial drop in the level of virus, but that drop is transient, and comes back down with mutations that are resistant to the drug. So in the short run, AZT was good for people with advanced disease, but proved in people with early disease to not be sufficient to have a significant clinical impact. Then in 1994, just a couple of years ago, I came before the committee and told you about the double-drug combination which not only brought the virus down further, but it was more sustained, and for the first time it was actually a clinical benefit in early disease. What we are seeing now in 1997 with the combination of three drugs, including the protease inhibitor, is the virus going, in many cases--and sometimes the majority of cases, depending on the study--to below detectable level in the blood. But as we know from recent studies, the virus has not been eliminated from the body, because you can still isolate it. But in the blood it is below detectable level, and that is sustained. Just a couple of days ago we had a study which compared three drugs in late disease, including protease, with two drugs, and for the first time a clinical benefit with regard to death and adverse events in late disease was shown. What we don't know is if there is going to be a clinical benefit if given over a long period of time, and whether the cumulative toxicities and the emergence of resistance might outweigh some of the beneficial effects that everyone seems to be so excited about. I said this, actually, in an editorial last summer at the time of the Vancouver meeting, when I stated--which is really summarized right here--that there has been much accomplished in AIDS research, but still much to do. What I would like to spend the next couple of minutes on is talking to you about some of those things that Dr. Varmus referred to as ``inspiration.'' Again, going back historically, several years ago, more than just a few, I came before the committee and told you about the different targets of our antiviral drugs. Looking at the life cycle of HIV, very quickly, the virus binds to the cell; enters it; uses an enzyme to convert its genetic material--this is the target of AZT and ddI and ddC. It integrates into the nucleus, and then it has production of additional virions. This is the target of the protease inhibitors. But what we just discovered this year is very exciting because it's the example of the convergence of two areas of research, one that was directly AIDS. You've heard several of the members talk about the overlap between AIDS and non-AIDS. Investigators were looking at the physiology of a cell and the receptors that it uses, and investigators were looking at how you block the virus in a particular cell, and a co-receptor or a co-factor was found by investigators who were looking at why cells, when they get infected, fuse with each other. This co-receptor turned out to actually be a normal receptor for a protein that the body uses to mount an inflammatory response. [See figures 3, 4, and 5.] [Pages 589 - 591--The official Committee record contains additional material here.] So investigators have been working on this for years, having relatively little interest in AIDS. AIDS investigators were looking for the receptor for the virus. You put them together, and what you find out is that these natural proteins are very, very potent in blocking the ability of the virus to bind to the cell because they occupy the same receptor. So just on a fundamental basic science observation, we now have a brand new target, not only for the development of therapeutics, but perhaps for the development of a vaccine. This is a classic example of how something came out of basic research, and hopefully in future hearings I will be telling you about some of these clinical trials. We heard yesterday a bit about where we are in AIDS vaccine. You know that we have a renewed effort in AIDS vaccine. We have Dr. David Baltimore now who is heading our Advisory Committee. Rather than go into any detail about this, I would say that we have a balance of the fundamental basic research approach with an empiric approach of looking at candidates that are in various stages of development, and you'll be hearing more about this over the next year or so. [See figure 6.] [Page 593--The official Committee record contains additional material here.] Speaking of basic research, you might also remember one thing that hit the newspapers, which is that the Nobel Prize for 1996 in medicine was given to two immunologists, Dr. Peter Doherty and Rolf Zinkernagel, a current and a former grantee of NIAID. And more than 20 years ago, they made a fundamental observation that had nothing to do with any particular disease. They were able to very clearly demonstrate that when a T cell, which is the major guardian cell looking for disease in the body, encounters a virus-infected cell, that the molecules that form the fit of a lock-and-key account for both the specificity and the restriction of that response, opening up an entire new avenue of research to explain many immunological phenomena. They didn't even fully realize then, when they were dealing with an animal virus, that they would open up so many doors in immunology. [See figure 7.] [Page 595--The official Committee record contains additional material here.] One of the doors that they opened for us has to do with vaccines, because the vaccines of the future--again, this has been in the newspapers a lot over the last year--is the DNA vaccine. You actually take the gene that codes from a protein of a microbe, so that it's perfectly safe; you don't take the whole microbe. You inject it into the muscle of an individual, and that protein presents itself to the body in association with the right molecules that Doherty and Zinkernagel spoke about over 20 years ago, giving you a very potent immunological response of both antibody and cell-mediated response. [See figure 8.] [Page 597--The official Committee record contains additional material here.] We already have clinical trials looking at it in influenza. We've begun them in HIV, and it's going to open up new possibilities for diseases for which we don't have a vaccine: malaria. We can get an approved vaccine for measles, hopefully; but also, the other emerging microbes that I spoke to this committee about, that we haven't even identified yet. But once you identify them, once you use the genetic technology that we have available, you can go right into this type of vaccine work. This is another example of basic research leading to very important and potentially practical results. So let me close on this introduction by getting back to the thing that I started with, the fundamental area of basic research and how this is the source of the inspirations that Dr. Varmus spoke about yesterday. For our Institute, it's immunology and infectious disease. But this chart could just as well apply to virtually all of the Institutes that you're going to be hearing from over the next week or so. And in our case, the fundamental research leads to these types of advantage. [See figure 9.] [Page 599--The official Committee record contains additional material here.] We would, again, thank you very much for the support that you have given us--not only for the practical things, like for an identifiable disease, but for the basic research that is the source for the inspirations that lead us to those practical applications. I would be very happy to answer any questions. [The prepared statement follows:] [Pages 601 - 604--The official Committee record contains additional material here.] protease inhibitors Mr. Porter. Thank you, Dr. Fauci. You may have answered this in part, but let me ask it anyway. Viral load testing of the patient's blood is thought to be the most accurate measure of the severity of a patient's HIV infection. Some reports, however, indicate that even though viral load testing may indicate no evidence, which you indicated on the chart, of the virus, it may still be present in the lymph nodes. Dr. Fauci. Right. Mr. Porter. How can we be confident that we are correctly measuring the impact of the protease inhibitors? Dr. Fauci. It is very clear from a number of studies, Mr. Chairman, that the level of replication of the virus is reflected in the level of the virus in the blood that we measure by our sensitive techniques. Also of importance is that there have been good retrospective and prospective studies that indicate that the level of virus in a particular individual accurately predicts where that person is going with their disease. So that if you have a very high level, you know that the curve of disease is like that, and they will deteriorate more rapidly than someone who has a low level. That doesn't tell you that the virus is completely absent if this goes below detectable level. In fact, we know from experiments that it isn't. But what it does accurately tell you is that there is a correlation between the level of virus and the clinical course, so that it is better to bring down the virus to below detectable level, even if you haven't gotten rid of it. I tend to explain this to people by saying that this means there's good news; we've gotten the virus to below detectable level. How good that news is going to turn out to be over the long run, vis-a-vis how long we can keep it suppressed, remains to be determined by clinical trials. But just because you can't get rid of the virus doesn't mean that bringing the virus down is not a very good thing with regard to the clinical course of a patient. hiv multiple drug therapy Mr. Porter. How long have we been testing the multiple drug therapy? How long do we know that it keeps the level down? Dr. Fauci. Well, again, it depends--and this is a very interesting, complicated situation vis-a-vis the sometimes lack of appreciation of the scope of this throughout the country. If you look at a very well controlled population of individuals who are highly motivated in a clinical trial, with triple combinations of drugs, you could bring down the virus to below detectable level in about 80 to 85 percent of individuals and keep it there for anywhere from 40 to 52 weeks. After a while, a certain percentage of them will start to break through with resistant viruses. If you go into the trenches, as we call it, in people who have had a number of different types of antiviral drugs, the percentage of getting those people down is somewhere around 40 or 50 percent. So what we can say, in direct answer to your question, is that for at least a year we know that in the majority of people we can keep that virus down. But since we know that the virus can stay latent for a long period of time, it won't be until several years from now that we can say confidently that we've been able to keep it down. Mr. Porter. You talked about motivated patients. Who would be not a motivated patient? An IV drug user maybe? Who would fall in the class that aren't highly motivated? Mr. Fauci. I don't want to use the word ``motivated'' in a pejorative or a laudatory sense. What I'm talking about is that when someone is within the confines of a clinical trial and they have a clinic and a doctor that's very interested in them, encouraging them to stay on the trial despite the fact that there are toxic side effects to the drug, encouraging them to continue to take their medicine, that's an excellent environment. That is much different than a situation where someone may not have a doctor that readily follows them or a clinic that has an intensive interest in them, gives them some drugs, the person feels better, then after three weeks to a month they stop taking the drug. That's what I mean by motivated, not necessarily in a pejorative sense of someone is not motivated. It's accessibility of the kind of care and environment that allows someone to feel good about staying on this type of regimen. aids clinical trials Mr. Porter. It's been reported that three or four trials being supported by your AIDS Clinical Trial Group include potentially suboptimal treatments because they were designed before the new potent drug combinations were available. Dr. Fauci. Right. Mr. Porter. Do you plan to modify the design of these trials? Dr. Fauci. Definitely. And that's already underway right now. There are a few trials--when you say suboptimal, you have to look at both the laboratory and the clinical data. For example, literally just a couple of days ago, and I alluded to it briefly in my opening statement, a trial called ACTG-320, by the number of the trial, was looking at triple combination of drugs compared to two nucleoside analogues, either AZT and D4T or AZT and 3TC, compared to that same regime together with Indinovir or Crixivan, which is one of the several protease inhibitors. And before the study was over, as the data and safety monitoring board analyzed the data, it became clear that there was a distinct advantage to three drugs compared to two drugs in late disease, not early disease. So we go back now, when we look at all the protocols in which there are two drugs in late disease, and since we know that that's suboptimum, you must reconsider then adding the option of a third drug and a protease inhibitor. However, what is still an open question is two drugs versus three drugs in very early disease. That's something where, as I alluded to before, you have to balance the potential clinically beneficial effect with the possibility of cumulative toxicities and the emergence of resistance. The answer to your question is that they are being carefully looked at on a protocol-by-protocol basis. Mr. Porter. We've heard that as many as five new types of protease inhibitor drugs are in the pipeline. Do you expect them to overcome some of the difficulties with the current protease inhibitors? Dr. Fauci. The answer is yes, some, but not all. Each of these drugs are potent drugs and each of them will either have similar or different types of toxicity. One of the things we would like to see overcome, and we already have some indication that this is the case, is that the mutation that is induced by one might not lead to a virus that is cross-resistant to the other. In other words, you can measure little changes in the genetics that lead to amino acid changes in the proteins of the virus. Sometimes protease inhibitor No. 1 would lead to a mutation at this particular point. If protease inhibitor No. 2, even if it leads to mutations, if it's a different mutation, you could wind up putting them together and still having the virus be susceptible. So that's our hope for developing new protease inhibitors in the pipeline. Mr. Porter. Do you think it is realistic to ever expect the drug companies to invest resources in the development of an AIDS vaccine, since its market would be undeveloped countries in large part? Dr. Fauci. The answer is, I don't think it's going to be easy because it will follow the same pattern as we see with any vaccine. This is not a field where there are many, many pharmaceutical companies which are breaking the doors down to try and get into the field. However, as we have consulted closely with our colleagues in industry, the limiting factor is really the scientific opportunity. If we can get a concept that proves to be having at least a reasonable chance of working, I think you'll see a larger number of drug companies than you see currently involved in the field. As part of our renewed effort in vaccine at the NIH vis- a-vis HIV/AIDS, we are engaging our industrial colleagues in discussions and collaborative efforts. So it's not going to be a simple problem to overcome, but I don't think it is going to be prohibitive if we get a good scientific concept to prove. Mr. Porter. Does the need to halt clinical trials due to ethical considerations limit your ability to measure the emergence of resistance? Dr. Fauci. The answer is, from a purely technical standpoint, if you stop a trial before you show that there's a relationship between a resistant mutant and a clinically deleterious course, one can say yes. But that's just part of the turf of research. The most important thing that we understand and guide ourselves by is to ``do no harm'' to the patient. So if a situation arises where there is an ethical consideration, that's what we call a non-starter. That's the first thing that takes preference. It may take a little longer to get to the truth, but we have done it successfully. You might recall, in fact, I think we had somewhat of a similar conversation several years ago when we had AZT proved to be effective and we couldn't have a placebo. There were those who threw up their hands and said we'll never show again that another drug works if we can't do a placebo trial. And now I just showed you three examples of how we did it within the realm of having people on drugs that ultimately turned out to be not as good as the one we were testing, but we didn't know it at the time. So, in the real world, I don't think it is a serious negative impact on our ability to answer questions. Mr. Porter. Thank you, Dr. Fauci. Ms. Pelosi. hiv drugs and vaccines Ms. Pelosi. Thank you very much, Mr. Chairman. Welcome, Dr. Fauci. It's always an honor when you are here. We are indeed blessed to have Dr. Varmus, at the head of NIH, and you in your capacity. I just wanted to call to my colleagues' attention the fact that Dr. Fauci has over 850 scientific publications, and that of the one million scientists in the world who publish each year, Dr. Fauci is the second most quoted among those. I think that, again, the NIH and our country are indeed blessed with your contribution. In that spirit, I wanted to follow up on a question asked by our Chairman about the involvement of the private sector. My question had been what actions can NIH and Congress do to help harness pharmaceutical expertise to the challenge of HIV vaccine research. You have said scientific opportunity is the key. But is there anything else that we could be doing to smooth the way? Dr. Fauci. I think you made the point. You are in some respects inadvertently doing it by supporting us. But a specific question that comes up, and I don't think it's a major problem, but it does come up and should be considered, and that is the question of the concern that drug companies have about liability and concern that they have about interference with pricing. We've come to a good agreement in our CRADAs in discussions about fair pricing in the sense that we don't have strict regimented controls on that. That has opened up the doors to more easy negotiations with them. With regard to the liability, that's a very difficult issue. But if it can be discussed with them at least that there is an intention of working with them to make sure that we can draw people in without that sometimes unrealistic concern, but sometimes realistic concern, regarding liability, that might be helpful. hiv therapy Ms. Pelosi. I think that is a tremendous challenge, including that non-interference in the pricing. Although we want to be the free market, we also do not want an exploitation of the need of these people. That brings me to standards of care. It is my understanding that the NIH panel to define principles of therapy for HIV infection has a draft report under review. Dr. Fauci. Right. Ms. Pelosi. As a committee co-chair, you expect to issue a report on standards of care for HIV disease shortly. Could you outline your timeline for these two reports? Dr. Fauci. Yes. There are actually two committees that are working in synergy; one is the committee that is a fundamentally NIH-based committee that is looking at principles of care. The other is a departmental committee, of which I'm co-chair with Dr. John Bartlett from the Johns Hopkins University, and what we're doing in that group is that we're actually going to be making recommendations based on the principles that were established by the NIH committee. We actually have a meeting next week, March 6th, I believe. We will be looking at the hopefully next to final, if not final, draft of the two committee recommendations. We will then, after we fine tune it and get it in a presentable form, send it out for public comment. After that, we will publish it in the MMWR and hopefully in a standard medical journal. So the timeline we're talking about is, if you include a month or so period for public comment, would probably be sometime in the early spring. Ms. Pelosi. Early spring. Mr. Chairman, you have been so receptive to our having a full discussion of this issue, and even in your own questioning about what the penetration is among people with HIV having access to these new therapies, and I would hope that in your willingness to pursue more information we might have a hearing specifically geared toward the new therapies; how they are available, how they meet the standards of care. I know you've always been open on these subjects. Mr. Porter. If I could respond to the gentlelady. I am not sure you were here when I said that I felt that we were short- changing the subcommittee in the sense that we have too much scheduled in too narrow a timeframe, and I've already asked Dr. Collins and Dr. Fauci as well as Dr. Varmus if they will make themselves available later in the year when we might follow up with them. hiv vaccines Ms. Pelosi. Thank you, Mr. Chairman. I'm sorry, in my capacity as ranking member on another committee, I couldn't be in the room to hear that, but I am very encouraged by it. I would hope at that time we could have people with HIV as well as their health care providers and hear directly from HIV- infected people and their care providers at such a hearing. Some of the stories are absolutely, to use Dr. Varmus' word of yesterday, ``miraculous'' in that people who were looking for help to make out a will now need help getting a job; people who were going on disability are now being made partner in their law firms. The stories are quite remarkable. But everyone doesn't have access to these drugs and everyone doesn't respond to them. So I would think that hearing directly from people with HIV and their care providers, in addition to our very distinguished witnesses, would be useful. In terms of the vaccine, I had a very specific question, because Dr. Varmus addressed it yesterday, and certainly the President did in his State of the Union address. Concerns have been raised about at least two structural issues concerning the way NIH awards funding to researchers. First, the peer review process often rewards proposals that demonstrate innovative science at the cost of more practical and less ground-breaking research which may be needed in order to develop an HIV vaccine. Second, the absence of a study section for vaccines has sometimes meant that the vaccine research is underfunded. How can these concerns be addressed, and how can Congress be of assistance in making NIH the engine of discovery? Dr. Fauci. A very important point, Ms. Pelosi, and we're aware of that. One of the ways you can do that, and it is short of creating a study section, because we've done it in other areas, is to create a special emphasis panel of review where you make known, as we have already done with the reconstituted advisory committee, about certain areas that absolutely need to be addressed. In fact, we've even gone so far as to establish a new kind of grant mechanism that is very rapid in its implementation, called an IDEA Grant, that has to do with the basic questions that need to be asked and answered in HIV vaccine research. You bring up a very good point. It is a problem and we are addressing it. I don't think there's anything that Congress could do. I think it is a question of being aware that we must look at these applications and the questions that they're asking in somewhat of a different light than just throwing them in the hopper with everything else. Ms. Pelosi. Is that it? Mr. Porter. I don't know. No, you've got a couple more minutes. Ms. Pelosi. Would Mr. Hoyer be able to finish? Mr. Hoyer. Mr. Chairman, you're going to have Dr. Fauci come back, is that it? Mr. Porter. Later in the year, yes, if the subcommittee wishes to do so, and I think they will. Mr. Hoyer. We have no members here, but I want Dr. Fauci at some point in time either to come before the committee or for the record to supplement Dr. Varmus' response on what clearly is going to be part of the debate when we mark this bill up in terms of how we allocate the resources to various diseases or Institutes within NIH. I think it is very important for us to understand on this committee, first of all, the fungibility of the research, if that's an appropriate way to refer to it, and secondly, the rationale behind the allocation that has been proposed. That was the question I was going to ask. I know we have a vote now, and I want Ms. Pelosi, who, in my opinion, is probably the expert, along with yourself, on this issue, to pursue her questions. But at some point in time, I want that question addressed by Dr. Fauci. Mr. Porter. Fine. If the gentleman would yield, I think it is a question that seems to be on the minds of a number of members and I think it might be an appropriate subject for us to have a panel from NIH to address together for us. Mr. Hoyer. Fine. That's an excellent idea, Mr. Chairman. Mr. Porter. Perhaps that's the way we ought to pursue it. Mr. Hoyer. I yield back to Ms. Pelosi. new therapies Ms. Pelosi. If I could just make one comment in closing, and that is when we have Dr. Fauci back, I hope he would be prepared to tell us when we would have new therapies that are easier to tolerate for many people for whom there's hope of new drugs. Dr. Fauci. Yes. I would be happy to, Ms. Pelosi. Mr. Porter. I've asked Dr. Fauci to stay until 12:30. We do have a vote on. Are you going to be able to come back here, Ms. DeLauro? Ms. DeLauro. I cannot come back. Mr. Porter. That's what I was afraid of. Ms. DeLauro. I've got several questions but I can submit them for the record. There will be opportunity to ask them again at a later time. I think Mr. Hoyer has said it, and Ms. Pelosi has asked appropriate questions, and we have the kind of work that you have been doing that Ms. Pelosi has talked about. So I can submit my questions for the record. Mr. Porter. Well, we did not expect, at least I did not expect to have a vote that we're going to have to address. Mr. Dickey, have you voted? Mr. Dickey. That's a personal question. [Laughter.] Mr. Porter. Yes, I know. I'm going to ask you to take the Chair. Mr. Dickey. Oh, boy! [Laughter.] Mr. Hoyer. Mr. Chairman, I'm going to have to go vote with everybody else and will not be back. Obviously, these hearings are a little bit difficult for me. But I want to say to Dr. Fauci and his colleagues that I know how difficult it is when we confront disease. But Dr. Fauci, Dr. Varmus has been with us for a long time and I consider myself a good friend of his and totally subjective, as is Ms. Pelosi, when dealing with him. We have extraordinary people at the Institutes, at NIH. I particularly on the record want to say that I was not here for the Cancer Institute yesterday purposefully. I didn't think I could make that. But Dr. Rosenberg was incredibly supportive at a very difficult time for me, and I want to thank you. office of aids research Mr. Dickey [assuming chair]. Thanks for sharing that, Steny. We've all been thinking about you. Dr. Fauci, I don't know if you've answered this question, but I would like to ask it of you. It seems redundant to have an Office of AIDS Research, OAR, in addition to your Institute which spends half its resources on AIDS. Couldn't the functions of OAR be handled by NIAID? Dr. Fauci. The NIH has a number of components besides NIAID. True, the NIAID is the major component of the AIDS research effort at the NIH, but it really spans multiple Institutes. The OAR, as it is constituted now, has functioned very well in the coordination of the research among the Institutes. We've had a very good working relationship with the OAR. So, I'm sure at any given time you could change the configuration, but the OAR actually is performing their function of coordinating research among the NIH Institutes. Mr. Dickey. Is it wasting money in any fashion by having a duplication? Dr. Fauci. No, I don't think that it's a money situation at all. Mr. Dickey. Why is it not a duplication? Dr. Fauci. Because the NIAID is an individual Institute. Since there are substantial efforts in other Institutes, such as the Cancer Institute, the Child Health Institute, and on and on, virtually every Institute, an office that is apart from the Institute is functioning in a coordinating fashion. There was concern about having an individual Institute be coordinating efforts of a variety of other Institutes as opposed to having a body outside of any Institute to coordinate the work of the individual Institutes. Mr. Dickey. Did you want to add to that? Dr. Varmus. Just that there have been very appreciable gains in just the past couple of years that could be attributable to the planning and evaluation processes of the OAR. The OAR, as you know, does not support research directly-- all of the research is done through the Institutes--but the OAR carried out a review of the entire AIDS portfolio that does involve, as Dr. Fauci mentioned, every Institute of the NIH and came up with a number of important recommendations that I think are going to make our expenditures in the AIDS field get more productive. It did not ask for more money for AIDS; it asked for better use of the money. I believe that attitude is one that actually contributes to a savings. aids from other countries Mr. Dickey. Dr. Fauci, what are we doing as far as preventing AIDS from coming to us through other countries? Dr. Fauci. Well, that's not a question that I have any responsibility for. But I would not be concerned, as I mentioned before, about AIDS coming from other countries when you have about 800,000 people in this country already infected with HIV. So, if you were dealing with a disease that's transmitted by a respiratory route, then you would have a different kind of a situation. Mr. Dickey. I see. Dr. Fauci. Whereas, if you have a disease that's spread by a behavioral pattern, be that sexual behavior or intravenous drug use, since the pool of infected people in this country is substantial, I don't see any public health benefit in trying to keep out other people who are infected rather than educating the public on how they can avoid infection within this country. aids cure versus treatment Mr. Dickey. Are your expenditures divided so that you can answer the question, what percent of your expenditures is being spent in the AIDS area on research to find a cure, and what percent is being spent on trying to cure people who already have AIDS? Dr. Fauci. If you look at the way we have the breakdown of the budget, according to what we call the NIH AIDS Plan, within that plan are two major categories that you're referring to. One is therapeutics, the other is vaccine, and then there is another called behavior that in some respects has to do with prevention. With regard to the percent of the total, 35 percent of what we do is for the treatment, either the development of drugs or the clinical trials of individuals. In our Institute, 15.7 percent is on vaccines. For the NIH as a whole, it's going up each year but it is somewhat less than 10 percent, about 8.9 or 9 percent. But in the NIAID it is 15.7 percent. And in our Institute we have a relatively small amount on behavior research. But Institutes such as the Mental Health Institute and the Drug Abuse Institute have a substantial amount more on behavior. Mr. Dickey. I'm not getting enough numbers here. I wanted, and I don't mind it being divided three ways, behavioral, preventive---- Dr. Fauci. Behavioral, vaccine, and therapeutics. Mr. Dickey. Okay. And therapeutics is after you get it. Dr. Fauci. Therapeutics is drug development and clinical trials, and that's after you get it; correct. Mr. Dickey. Bring me to 100 percent on those. Dr. Fauci. Okay. The rest is 14.8 percent in what we call the epidemiology or natural history, where we follow cohorts of individuals who are infected and follow them and look at the transmissibility from mother to infant or among sexual partners. Mr. Dickey. Isn't that aimed toward curing it or finding a cure? Dr. Fauci. That overlaps with virtually every aspect, because they are cohorts of patients that we study that you can examine pathogenesis in them, you can initiate them into clinical trials, and even some cohorts of individuals who are not yet infected might be put in a vaccine trial. Mr. Dickey. Are we spending more money on taking care of the patients who have AIDS, or are we spending more money on trying to find a cure? Dr. Fauci. Right now, percentage-wise, there is more money in trying to find a therapy, as I discussed earlier, for the treatment of infected people as opposed to preventing it. But if you look at the trend of where we're going over the last couple of years, the vaccine trend is steadily increasing at a time that the therapy has stayed either flat or is coming down somewhat. The trends are going now much more towards prevention either with a vaccine or with behavior modifications. But if you look at the numbers, there's more money going to treatment. Dr. Varmus. One comment, Mr. Chairman. It is inherent in nature of clinical trials that they are expensive. Therefore, it is probably not fair to look at the effort solely in monetary terms. The number of answers you can get may be equally great with a smaller amount of money in the prevention area. You heard that there is hesitancy on the part of pharmaceutical industries to enter into the vaccine area because of a lack of fundamental ideas about how to approach vaccine development. So there may be a large number of small projects, any one of which might give the inspiring result that would then result in development of a vaccine; whereas, probably, simple ideas for testing the various combinations of drugs, which Dr. Fauci alluded to, is a very expensive process involving hundreds or thousands of patients and many different combinations of drugs. Mr. Dickey. Do you share talent in those two areas, therapeutic and vaccine? Dr. Fauci. Definitely. Mr. Dickey. You do? Dr. Fauci. Yes. Not only do we share it in those two distinct categories, but, as Dr. Varmus just alluded to, those categories are very heavily fed into by the basic researchers that are looking at the pathogenesis, either the viral or the immunological pathogenesis, and both of those areas feed directly into both therapeutics. In fact, we have trials of therapies that are called pathogenesis-based and all of pathogenesis, or understanding how the virus works, will ultimately feed into vaccine development. That's the reason why, as appropriately referred to by Dr. Varmus, it is sometimes misleading when you look at strict coding of how you spend money because of the overlap and spill-over from one to the other. Mr. Dickey. I understand that. Dr. Varmus. To give you one very straightforward example. You've heard a lot about viral mutants. That is a particular problem with viruses, especially viruses like HIV, that become resistant to therapies and are potentially resistant to protection by vaccines. Attempts to understand the source of genetic change in these viruses, to categorize the viruses by genetic makeup, is fundamental to all the areas you've heard about. People who are studying the genetic properties of HIV have to be in touch with all the areas you've mentioned. behavioral research Mr. Dickey. What are you doing in behavioral? Dr. Fauci. In my Institute, the behavioral research that we do at NIAID is linked very closely to two components. One is the vaccine effort where we are building up cohorts that might ultimately serve as the group that we would try a vaccine on. Inherently built into that is behavioral modification. Mr. Dickey. Does that include abstinence? Dr. Fauci. Oh, absolutely. Mr. Dickey. How are our Federal dollars encouraging abstinence in the AIDS area? Dr. Fauci. If you look at the instructions of when you put someone in a vaccine trial, there are discussions of doing whatever you possibly can to avoid infection, and that's both for the people who are going to receive the vaccine as well as for the people who are not going to receive the vaccine. It is very clear and right up front that the most surefire way of avoiding HIV infection is abstinence, number one, and number two, if you're going to have sex with a person whose HIV status you are not sure of, then you use a condom. That's very clear. That's now essentially in every public health discussion that you have about prevention. Dr. Varmus. In fairness to Dr. Fauci, a number of the studies that address the issue of abstinence, that you've raised with me before privately and are now raising with him, are under study in other Institutes--the Child Health Institute, and the Mental Health Institute. There are a number of---- Mr. Dickey. On AIDS? Dr. Varmus. Yes, absolutely. Many programs have incorporated a consideration of sexual avoidance or abstinence in relation to HIV transmission. Obviously, we understand that abstinence is very good protection. But how do you get there? One of the interesting things that we've learned is that in instructing children and young adults about the risks, it is very important to be explicit about sexual practices. There is early evidence from some of these attempts to understand the role of sex education and education about sexual habits that it is important to understand that if individuals don't learn about the means for protection, when they actually engage in sexual activity later that they put themselves at higher risk. There is some evidence already that individuals who have simply learned that abstinence is important without being similarly educated about the need for protection engage in much higher levels of risky behavior when they do become sexually active. Mr. Dickey. Mr. Miller, do you want to ask some questions? protease inhibitors Mr. Miller. Thank you, Mr. Chairman. It is always a pleasure to see you. It's always exciting to be going through this series of sessions because I learn so much. Let me start off with the issue of protease. I remember last year talking about the issue of whether there was a breakthrough. First of all, when were protease inhibitors made available commercially? Dr. Fauci. It became available within the last year. The initial trials were a year ago last fall. The first licensure for it came about six months after that, last spring. So they've been out now about a year commercially available. Mr. Miller. Just before we had our hearing last year. Dr. Fauci. Right. Exactly. Mr. Miller. The question was raised then, in our discussion, ``is this a breakthrough?'' I forget how you qualified it. How do you evaluate that now? And has anything else come up more significant than protease since that last time? Dr. Fauci. In answer to the question, as Dr. Varmus joked about yesterday, I rarely, if ever, call anything a breakthrough, but I would say that this has now turned out to be an extremely important therapeutic advance. No question about that. [Laughter.] Mr. Miller. ``Therapeutic advance.'' Dr. Fauci. Yes. The point that I made, I don't believe that you were there when I was presenting it in my formal presentation, is that there is some confusion about how good this will ultimately turn out to be. If it does nothing other than what we've already observed it can do--namely, profoundly bring down the level of virus in many cases to below detectable level, associated with a clear-cut clinical benefit in people with advanced disease, and, in my opinion, will likely also be shown, as the clinical trials come to fruition, to have a clinical benefit in people who get the combinations with protease even earlier in the course of the disease--that, we know, is a very important advance in and of itself. If you want to call that a breakthrough, you can call that a breakthrough. The questions that remain open, since we know this is an extraordinary illusive virus and these drugs are very potent and can have terrible toxic side effects and can be difficult to take over a long period of time, are two among several very important questions: one, will the cumulative toxicity over a period of two, three, four years lead to an imbalance or somewhat negating the beneficial effects; and number two, will the emergence of resistant mutants in those individuals who haven't had complete suppression of the virus' ability to replicate, will those mutants now come back with a vengeance, as it were, and be refractory to other drugs. That gets us to the thing that you alluded to in your second question, which is: has anything else come along. What has come along have been other protease inhibitors that are more than just complementary to the existing ones in that they induce a resistant mutant that's a little bit different than some of the originals. Which means that if you give them, and there are various trials that they are now undergoing, two protease inhibitors either alone or together with the AZT class of drug, we want to determine if that can actually give you even more benefit than having the triple combination with one protease inhibitor. The other answer to your second question is that we are constantly looking for new targets in the life cycle of the virus. I gave an example of one, which was serendipitous, as it were, with regard to AIDS research, the discovery of a particular receptor that the virus absolutely needs to get into the cell but which may not necessarily be absolutely essential for the survival of the person. So that if you block that receptor, you might be able to profoundly interfere with the ability of the virus to replicate. There's an intensive amount of activity going on in biotech firms, et cetera, to try to develop molecules that can be used to interfere with that binding side. So there are other things going on. We're constantly looking for new targets and/or new drugs for the same targets. media Mr. Miller. Yesterday, we had Doctor Klausner from the Cancer Institute. I saw him on ABC News earlier in the week and it was about a new idea, which you brought up here a few minutes ago. The question I asked him is regarding the treatment of the media to scientific breakthroughs. Kind of like the Newsweek phenomena. The implication is maybe that headline is not what you would have written. Dr. Fauci. No, definitely not. Mr. Miller. How much of a problem is that? I read it, and this was Newsweek, and I watch ABC News whenever I get a chance, or MacNeil-Lehrer, and Business Week is always interesting because they have that material a lot of times because of the financial interest. But it is always interesting how the media overplays certain areas. Dr. Fauci. Right. So how much of that is a problem for me? Mr. Miller. Yes. How much of a problem is that with you, and then maybe Dr. Varmus would make a comment, too. Dr. Fauci. Actually, to be honest with you, none as a scientist. The problem, if there is a problem, is trying to clarify, and we have to put in more time on that. I have spent a considerable amount of time trying to be the moderating force in this hype aspect of the drugs. Even though the drugs are quite good, I have found that the media has perhaps pushed it over in the eyes of the general public to be a little bit more than we know it actually is right now. But from a scientific standpoint, it doesn't really have any impact on what we do. And it involves several of us here in the room; it involves Dr. Varmus, who doesn't get impressed with that at all, and, in fact, has his areas of emphasis based on scientific opportunity, not what's in the newspaper. Quite frankly, I also applaud not only the administration for not responding to that, but also the appropriations subcommittee--Mr. Porter, yourself, and all the other members of the subcommittee--for allowing us to make scientific decisions based on the scientific opportunity and not what's in Newsweek. So I'll end my answer by saying thank you for not making it a problem for me. Mr. Miller. I remember reading about Dr. Ho, I believe, that won the Nobel Prize. He was very reluctant, at least in what I was reading, because why should one person be singled out? That is a very legitimate question when there is a wide range of people contributing to that. Do you have any comment, Dr. Varmus? Dr. Varmus. I think Tony has covered many of the important aspects. We appreciate the attention that's being paid to medical science in these articles. Sometimes they have an emphasis that we may not share, but the fact is that Time magazine devoted nearly an entire issue to research on AIDS. They did endow many of the properties in the field on a single individual, but it made the story better reading. Time magazine also recently ran a wonderful piece about early development of the nervous system, featured on the cover. And there's been a tremendous interest in genetics. All of this has had a very strong educational influence on the public and has had a role in attracting young people to the ferment that exists in biomedical research. hemophilia Mr. Miller. I guess the point is that it makes the American people feel good that there are some good things that government is doing, and this is obviously one of the good things. Let me switch my line of questioning to an area that I'm very interested in, which is hemophilia. The statistics have levelled off with respect to hemophiliacs. Their exposure was way back in the early 1980s or whenever and I assume blood is not now a major factor any more. Dr. Fauci. No. Mr. Miller. And most of it is either drug related or sexual transmission. I think the gay community has levelled off too, as I understand. Dr. Fauci. Yes. Mr. Miller. But specifically hemophilia, how does it relate to the effectiveness of treatment today versus others? Do drug users have a different reaction versus the gay community and all for the different protocols available? Dr. Fauci. No. We have as a component of our AIDS Clinical Trial Group, our ACTG that you hear me refer to frequently, the Hemophilia Foundation as a designated AIDS clinical trial unit with several subunits. So we have incorporated the treatment of hemophiliacs into our AIDS treatment agenda in a totally integrated manner. As we can tell thus far, they respond to the drugs in the same manner as individuals who have been infected from other routes. Mr. Miller. There's no difference then? Dr. Fauci. No. No. drug issues Mr. Miller. Okay, onto the drug issue. The drug companies-- is there any problem about the sharing of information with the drug companies between themselves, and the fact of the potential amount of money here is enough incentive for a lot of them getting into it. In cancer there is a much larger market dollar-wise from an investment standpoint. Dr. Fauci. Right. Mr. Miller. How does that play in this whole issue? Dr. Fauci. There are a couple of parts to your question. With regard to HIV therapeutics, there certainly is an extraordinary market for that. So there's not any constraints of companies getting involved because what they don't see as a profitable market margin for them. So that's not a question. With regard to sharing information, whenever you have proprietary rights to something there is always the question of companies sharing information. But I must say I was very gratified a year-and-a-half, two years ago when some of the major drug companies brought themselves together in a consortium whereby they shared their Phase I or earliest data with each other so that other companies wouldn't go down a track that is a non-fruitful track that one of the other companies already did. It is the first time to my knowledge that I've ever seen that. The reason they did it I think was twofold. One, I think there was a bit of altruism in it. But also it was good for the companies because it was a give-and- take, they could learn something from another company about what direction they went. As it turned out, that has turned out to be very, very fruitful. What we're also seeing now is more collaborations among companies in donating their drugs for a clinical trial to compare them head-to-head. A typical example was the Glaxowelcome/Merck collaboration on the study that I referred to just a little while ago where AZT and 3TC came from Glaxo and Merck gave us the Crixivan and Indinovir. So although you have competition, which is good, I think what we're seeing right now is a considerable amount of collaboration that you would not have predicted if you had thought that the market was very secretive. It isn't. Mr. Miller. Thank you. Thank you, Mr. Chairman. malaria Mr. Porter [resuming Chair]. Thank you, Mr. Miller. Dr. Fauci, there seems to be a resurgence of interest in the research community in malaria. The disease kills more than one million people a year. Efforts to develop a vaccine have been unsuccessful, and many anti-malarial drugs are becoming ineffective because of resistance. But early reports of a new vaccine candidate developed at Walter Reed are encouraging. A large malaria genome sequencing project is underway, and a major conference in Africa in January brought together scientists, including Harold Varmus, to kick off a new coordinated plan to attack malaria. With this encouraging news on several fronts, do you think it is likely that effective therapeutics and perhaps even a vaccine will be developed before we lose the battle against drug resistance? Dr. Fauci. The answer is that the battle against drug resistance is an ongoing battle. It is not a single battle that you win or lose. If you go to certain parts of developing countries, a substantial fraction of the malaria there will be drug resistant. What we're seeing now, and I feel very good about it, and there has really been a considerable amount of help from Dr. Varmus who has been very interested personally in this and has actually, as you mentioned, gone to Africa, is a resurgence of interest of combining the new technologies, for example, of being able to sequence the genome of microorganisms including the malaria microorganism, but also of getting the countries involved. We call them ``Host Countries,'' countries in which you do clinical trials, to get their scientists involved and utilize the resources of their country as well as our own country, and, in addition, to train them to really be partners with us. That's something that we've seen little bits of but never really in a full-blown effort, and we're starting to see that now. So, again, it is a convergence of the age of molecular technology, the ability to approach the question of resistance from that standpoint, as well as the idea of a vaccine. So I think things are going to be going in much more accelerated fashion with regard to malaria than they have been in the past. Mr. Porter. Dr. Varmus, do you want to comment on that? Dr. Varmus. Just briefly because Tony has covered many of the important points. One of the things that you learn when you go to Africa to see malaria in its native setting is that-- while there is tremendous need for new research opportunities that will come from the malarial genome project and from more emphasis on vaccines and drug development and better understanding of the life cycle of the organism--there is also the need for research at the local level that addresses epidemiology, treatment patterns, health services research. One of the things that you learn very quickly is that in certain parts of Africa drug resistance is not really the problem at all. Drug resistance is very sparse in these places, but the real problem is getting the right drugs to the right people at the right time, and having people be able to recognize disease in young children where it is frequently lethal in the cerebral malaria form. One of the things that I found very heartening was that in areas such as Mali--where NIH has established a research foothold, building a very excellent research team headed by African scientists--that the field stations that are used by those laboratories as sites for research on epidemiology and pathogenesis become treatment areas. In these places, the disease is controlled even though the infection rate is still extremely high from the tremendous number of Anopheles mosquitoes carrying the organism. But treatment is prompt, people don't die of the disease, and people learn about the disease. In many parts of Africa it is not understood that the mosquito is the transmitting agent, but it becomes very apparent when people are being recruited into the studies to capture mosquitoes that this is the way it is transmitted. That knowledge spreads to other communities, and other kinds of health benefits, like digging wells to prevent infantile diarrhea, follow from these initiatives on malaria. tuberculosis and cholera Mr. Porter. Do you think a similar concentration of effort is necessary in the worldwide fight against tuberculosis and cholera? What makes these conditions different from malaria? Dr. Fauci. The answer to the question is yes. Both of those could benefit. You may be aware that we have accelerated greatly our tuberculosis effort both on the national and international front. Just a few short years ago, the tuberculosis effort in the NIH was just a few million dollars. We now have it up in my Institute alone to $37 million and there is activity in other Institutes as well. Cholera. We're testing a new cholera vaccine which we feel has some hope in giving us some good results with regard to cholera. They're different because of the complexity. Cholera and tuberculosis are really spread from person-to-person. Both of them are bacteria. Malaria is a parasite, a larger organism that has an intermediate vector, the mosquito. The complexity of malaria compared to tuberculosis, which is a difficult enough problem, as is cholera, is related to the fact that you have the vector itself to deal with. So it is a mosquito problem, a vector borne disease. The other is essentially a person-to-person disease. With cholera, it is because of the contamination of water supply. With tuberculosis, it is generally respiratory borne. Dr. Varmus. But you shouldn't go away with the idea that we're spending tremendous amounts of money on malaria. We spend only about $20 million at NIH. The NIH is the largest funder worldwide of malaria research. So our spending in the area of malaria research, despite the new initiatives for collaboration, is still, in my view, very small in relation to the magnitude of the problem. Dr. Fauci. Yes, this falls under the category of something that I've said several times before the committee. That is the discordance between the scientific opportunity and the resources available. You could look at a disease like tuberculosis, cholera, malaria, or even several others, notwithstanding the extraordinary world burden of it, there are scientific opportunities that don't match the resources that are in them. I can say that very clearly without any holding back. There's no question the opportunities we have in all three diseases that you just referred to are far greater than the resources that are in them. hansen's disease Mr. Porter. Dr. Fauci, you've agreed to support in 1998 the Hansen's Disease research formerly funded by the Health Resources and Services Administration's Carville appropriation. What are your plans for continuing this effort in 1999? And will you open up Hansen's Disease research through competition to a potentially different set of researchers? Dr. Fauci. The answer to the question is yes. The way we have it now, we have had $3 million that has been put into our appropriation for the Hansen's Disease research that is going on now in Carville, in Louisiana, with the instructions that it should ultimately be turned over into a competitive grant line. In 1998, since it is difficult to so quickly do that, we're passing through the money back to them, and then in 1999 we're going to recompete and open up the granting process to anyone who wants to put in for a grant. So by the year 1999, it will be competed at the level that anyone either down in Louisiana or elsewhere could compete for that money. Mr. Porter. Dr. Fauci, thank you very much for your willingness to stay late. I have to say to both you and Dr. Varmus, you've seen from the questions today that there's a certain amount of concern on the subcommittee about the allocation of resources to different areas of health concern. I believe that what we probably ought to do, Dr. Varmus, is to bring back yourself and Dr. Fauci and the Institutes most concerned with cancer, heart, diabetes, and maybe some others and have a panel here where we can allow the subcommittee to raise these questions and get answers from everyone. Dr. Varmus. I think that would be extremely instructive. Mr. Porter. Wouldn't that be helpful? Dr. Varmus. Yes. Mr. Porter. And then we could perhaps raise other issues that we have not been able to cover in the abbreviated time we've had today. I would ask you to work with us on finding an appropriate time when everyone might be free. Perhaps setting it early, now, in other words, for sometime in April or May might serve everyone's interest best. We will be in touch with you about this and see if we can set aside maybe half a day or maybe even longer. Dr. Fauci. I would be happy to do that. Mr. Porter. Dr. Fauci, thank you for the absolutely wonderful job you do for humankind; not only for NIAID, and for health in general. You're one of our real treasures. Thank you so much. Dr. Fauci. Thank you very much. Mr. Porter. The subcommittee will stand in recess until 2:00 p.m. [The following questions were submitted to be answered for the record.] [Pages 622 - 710--The official Committee record contains additional material here.] Thursday, February 27, 1997. NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES WITNESSES KENNETH OLDEN, PH.D., DIRECTOR SAMUEL H. WILSON, M.D., DEPUTY DIRECTOR CHARLES E. LEASURE, JR., ASSOCIATE DIRECTOR FOR MANAGEMENT LAURIE JOHNSON, BUDGET OFFICER HAROLD VARMUS, M.D., DIRECTOR, NATIONAL INSTITUTES OF HEALTH BILL BELDON, [DIVISION DIRECTOR, OFFICE OF DEPUTY ASSISTANT SECRETARY] BUDGET, DEPARTMENT OF HEALTH AND HUMAN SERVICES Mr. Porter. The subcommittee will come to order. We're pleased to welcome Dr. Kenneth Olden, the Director of the National Institute of Environmental Health Sciences, for his testimony. Dr. Olden, would you introduce the people who are with you and then proceed. Introduction of Witnesses Dr. Olden. To my far left is Ms. Laurie Johnson. She's Director of the Budget Office. The Deputy Director, Dr. Sam Wilson; Mr. Charles Leasure, and you know Dr. Varmus, and Mr. Bill Beldon is on the end representing the Department. Opening Statement Mr. Chairman and members of the committee, I welcome the opportunity to appear before you today to discuss the important work of the National Institute of Environmental Health Sciences. The development of environmental regulatory policy is one of the most problematic areas of Congressional responsibility. This is a problem area, because there's too little scientifically sound information on which to base decisions. When there is too little information, there can be no satisfactory solution to the complex issues surrounding human exposure to environmental pollutants and health outcomes. In my testimony today, I want to outline a vision for environmental health science research that will transform environmental health decision making. A vision based on four critical areas of science. Areas where major information gaps exist, areas where reasonable research questions can be formulated, areas where technologies are available, and areas where understanding offers the potential to significantly improve public health and regulatory policy. First, research is urgently needed to determine the basis for the wide variation and individual responsiveness to exposures to environmental toxicants. To address this problem, NIEHS proposes to expand its molecular genetics research to identify susceptibility genes for environmentally induced diseases through a new Environmental Genome Project. This genome project will be a broad multi-center effort to obtain information about DNA sequence diversity for the U.S. population on all the environmental susceptibility genes identified to date. Second, there is an urgent need to develop new approaches for toxicological testing, to cut costs and to increase timeliness. If we are going to work our way through the thousands of chemicals to which humans are exposed, we must develop bold new screening strategies. Technologies are now available to develop new high through-put technologies to screen that are less costly and more relevant to predicting human health. And they should be more timely in terms of generating the information. Identification of carcinogens and other toxicants can be reduced from years to days. Third, investigation of the mechanism of the health effects of mixtures is another area where lack of scientific information is a problem. The current toxicologic data bases were developed using single chemicals in animal bioassays. As we all know, humans are exposed to a variety of chemicals in the form of mixtures. Depending on the assumptions made regarding the nature of the interaction between components of the mixture, risks may be either seriously over or under estimated with dire economic and public health consequences. NIEHS proposes to develop high through-put biologically based screening procedures to address this problem. And lastly, a major challenge is to strengthen the links between environmental science, toxicology, epidemiology and public health. To achieve this objective, NIEHS proposes to monitor human exposure to specific chemicals in our environment by measurements in body tissues such as blood and urine. Such real world exposure assessment would be far more useful than the estimation of exposure based on the EPA toxic release and production information as is currently done. Estimation of exposure based on toxic release and production information is at best only a reflection of the potential for human exposure. In conclusion, progress in the four areas of research emphasized offers real world answers to the quagmire of indecision and discontent as a consequence of having too little information. Our vision of a more science-based environmental health regulatory decision system is achievable, given today's technology. The President's budget request for NIEHS is $313,583,000. I would be happy to answer any questions that you might have. [The prepared statement follows:] [Pages 713 - 716--The official Committee record contains additional material here.] funding increase Mr. Porter. Dr. Olden, thank you for your excellent statement. I notice that the rate of increase for your institute is higher than the rate of increase for NIH generally. I assume you think that is a very good sign. Dr. Olden. I'm very pleased with that. Mr. Porter. My question is, does this reflect expenditures on the new screening procedures that you described in your testimony, or is this apart from that? Dr. Olden. Well, if I may go back a bit, it probably reflects a number of things. And certainly the resources that we are requesting will at least in part be used to address the new issues. And these are new issues for NIEHS. And we think they are extremely important. I think we've convinced Dr. Varmus that these are important new initiatives and I guess that's at least one of the explanations for why we are enjoying a good budget increase recommendation. But let me say, over the years, the Institute has not fared as well as some of the other institutes. So in fact, maybe it's at least in part a recognition on Dr. Varmus' part of the important public health problems that this Institute must address. Other institutes have important problems as well, but the point is, to deal with these issues I just mentioned. It creates problems for Congress in making decisions about what is the appropriate standard. I think we have to do the science in order to answer these questions to put risk assessment on a solid scientific foundation. Mr. Porter. Dr. Varmus, would you like to comment also? Dr. Varmus. Just briefly, since we've been talking about priority setting. The fact that one institute happens to be a half percent or a quarter percent or even 1 percent above some of the others, does not represent an evaluation of that institute or an attempt to remedy what may be perceived as past inequities. Because almost every institute feels it's been penalized at some point in the past. It represents a decision by me and my colleagues to place money on initiatives which are frequently trans-institute in nature. And what I try to avoid is getting into a discussion of the pecking order of institutes based on hundredths of a percentage point difference and instead, look to support new initiatives, of which the NIH has many good ones this year. And that may account for NIEHS being slightly above the others. Mr. Porter. Yes, sir. My question was, does this reflect the cost of the new screening procedures? I wasn't suggesting anything different at all. And I simply wanted to know whether that was included in this budget figure, which obviously is a high priority. Dr. Olden. Yes, absolutely. The Environmental Genome Project is a high priority. And we will make the investment with it in 1998. Mr. Porter. And you didn't skirt around Dr. Varmus and talk to the President directly to get this? Dr. Olden. No, we did not. [Laughter.] vitamin d and prostate cancer Mr. Porter. Last December, researchers at your Institute reported that men with a particular vitamin D receptor appeared to have only a third the risk of developing prostate cancer requiring surgery. How does vitamin D play a role in prostate cancer? Dr. Olden. Well, vitamin D is protective. And that's been known for some time. And what the investigator at NIEHS demonstrated was that, depending on the level of activity, whether the receptor was active or inactive, it increased the susceptibility to prostate cancer. In other words, if one had an inactive receptor, then the protective effect was not observed. Mr. Porter. No matter how much vitamin D you might absorb or take? Dr. Olden. Exactly. It could not be metabolized. So this is an example of the kind of research that I had in mind when I talked about looking at differences in susceptibility. And that's just one of them. mixtures Mr. Porter. In January, NIEHS scientists reported that three existing tests used in combination provide a rapid assessment of whether chemicals have estrogen-like qualities. This topic of environmental estrogens has been hotly debated in the past year. What can these new tests contribute to the debate that was unavailable previously? Dr. Olden. Well, that gets at the issue of mixtures. And I said, we don't know whether agents in mixtures--estrogens or otherwise--act additively, synergistically or even antagonistically. In the papers that were reported by scientists who used to work at NIEHS, but did not at the time we reported those studies, it was determined that estrogens, in the particular yeast assay systems that they used, acted synergistically. In other words, the response together was elevated by more than a thousand-fold. Potentially, that was very significant. Because of the threat that even low level exposures to a mixture of estrogens could be a significant health effect. Last year, I testified before this committee that my impression was that the low level exposures to synthetic or man-made chemicals would probably be dwarfed by exposures to natural estrogens, and that my opinion was that man-made chemicals probably did not represent a health threat. But if their observations were found to be correct, then that would be a very significant and important finding. However, I must point out that a number of other investigators, using different yeast systems, have been unable to repeat that observation in other systems. We are bringing all of the investigators together at our Institute in the near future to try to resolve the differences in the observations between the one laboratory and many others who were unable to get the same results. But admittedly, in different yeast systems. So I guess the answer is, we don't know what it means. Because that may be simply a unique or artifactual observation for that one system. endocrine disruptors Mr. Porter. The Environmental Protection Agency by statute is required to evaluate the risk of chemicals to the endocrine system. In addition, EPA is funding a two-year National Academy of Sciences study on the health impact of synthetic and natural substances that have estrogen-like effects. Has EPA taken the lead role in this area of science, and how does your research on endocrine disruptors mesh with their research portfolio? Dr. Olden. Well, EPA has not taken the lead role. We've been involved in this research area for over 20 years. What EPA is doing mainly is two things. Most of their estrogen-related research is directed towards ecology, for one. And the other is to develop risk assessment methodologies. Our research is coordinated at two levels, or at two official and formal levels. First is through the Environmental Health Policy Committee of the Department of Health and Human Services, which is chaired by the Assistant Secretary. In fact, we met on Tuesday of this week with the Assistant Secretary, EPA, to discuss the Government estrogen-related research. So it is coordinated through the Environmental Health Policy Committee. It is also coordinated through the CENR, which is the Committee for Environment and Natural Resources of OSTP. There is a subcommittee of CENR that deals specifically with estrogens. And we co-chair that subcommittee with EPA and the Department of Interior. And again, the purpose of the subcommittee is to coordinate estrogen research across the Federal Government. We've done an inventory of the research in the Federal Government, so it is closely coordinated formally through those two committees. Now, when EPA recently funded their estrogen grants, they consulted with us to make certain that they were not funding research that we were already funding. In some cases we agreed that we had not funded adequate research because of limitation of resources. And they are co-funding some projects with us as a consequence of that consultation. So the research is very closely coordinated, not to mention that the Health Effects Laboratory is right down the street from NIEHS in Research Triangle Park. And so there is also informal interaction to make certain that there is synergy between the two programs. congressional visit Mr. Porter. Speaking of Raleigh-Durham, we are attempting, as you are aware, Dr. Olden, to get our subcommittee, as many members as can do so, to come down and visit you. Because you're off there by yourself and we want to have a chance to see what you're doing. And if the other facilities are nearby, maybe that would work out very well. Dr. Olden. Thank you very much. We are looking forward to your visit. Mr. Porter. Both of us have to talk to Dr. Varmus about this. Dr. Olden. Dr. Varmus has been down recently, and we enjoyed having him. new testing methodologies Mr. Porter. Tell us more about your Beat the Mouse experiment in which researchers are testing alternative methods to predict whether 30 chemicals cause cancer before the results are available from a series of standard rodent tests. Has anyone crossed the finish line yet? Dr. Olden. No, but they will, the results will be reported out soon. In our November meeting of our advisory committee, the results will be revealed, and we'll see. We are anticipating that we will have at least 30 chemicals that have been tested through the traditional classical two-year rodent bioassay and have also been tested through our transgenic animal models in a period of six months at a reduced cost. And we are hopeful that the results will demonstrate that the transgenic animal models are just as effective in identifying carcinogens, both genotoxic and non-genotoxic, as the two-year rodent bioassay. Mr. Porter. Assuming that's true, how many increased chemicals can you test in, let's say, a year, with this faster procedure, if that's factual? Dr. Olden. Well, we haven't, I can't tell you what the costs for the transgenics are exactly. We are testing about 10 in the rodent bioassay now. We think with the same dollars, we could test about 40 new ones. Mr. Porter. Four times as many? Dr. Olden. That's what we think. Now, let me say that the tests that I just described in my testimony, the high through- put technologies, we are very excited about those. We've had discussions with people in pharmaceutical industries. The technologies are available so that we should be able to screen, if we make the investment into the technologies, we should be able to screen a hundred or more chemicals per year for the same dollars. So it's mind-boggling, what the potentials are. It is simply the fact that we've never made the commitment to develop these new tests. And we are excited about them. During my tenure as Director of the Institute, I am confident that I can come back here and report exciting results about these new tests. And we've consulted people in the scientific community, and they are eager and excited, and tell us that these things can be done. But for the first time, we will be asking them to do them. environmental genome project Mr. Porter. Before I call on Mrs. Lowey, I wonder if you would explain to us more about the environmental genome project that you mentioned in your testimony. Dr. Olden. I present it to you somewhat prematurely, let me say that. I have had brief preliminary discussions with Dr. Varmus. This is in a sense a trans-NIH effort. And what we are going to do, as a matter of fact, is we have a date I think some time in March, to meet with Dr. Varmus, Dr. Collins and Dr. Klausner, and some other staff to talk about this project. We are confident that it doesn't overlap activities going on in the Human Genome Project or in NCI. But we want to make certain of that. We think there is synergy between the two projects. The Human Genome Project is identifying disease genes, but not the ones that interact and are affected, influenced by, the environment. In our case, an individual could inherit an environmental susceptibility gene and not have a disease at all. In fact, the only way that that person would be at increased risk would be in a certain or specific environment, that is, when exposed to a specific environmental agent. For example, recently one of our investigators demonstrated that individuals who have either none or very low levels of a detoxifying enzyme called glutathionine-s-transferase, cannot detoxify certain toxic chemicals. Those individuals then are at increased risk. But they are only at increased risk if they are exposed to the chemicals that glutathionine-s-transferase detoxifies. We also reported that one of our grantees recently reported that individuals differ in their susceptibility to organophosphate. We were interested in it and reported it to you because it's a component of nerve gas, Sarin. It is also a component of a lot of pesticides. One of our grantees demonstrated that there is an enzyme that detoxifies the lethal form of the organophosphate pesticides. And individuals who have a defect in that enzyme are more susceptible to nerve gas, because the organophosphates nerve gases inhibit choline esterase. So they inhibit nerve transmission. So these are the kinds of genes, that we will go after. There's roughly 200 identified to date. What we will try to do is sequence those 200 or so genes and ask what is the variability in the population, and can that account for the differences in susceptibility. Now, when we have that kind of information in hand, then we can begin to protect people based on individual differences in susceptibility, not on the basis of an average person to an average exposure. The absence of that information really creates a problem for risk assessment. That information is being obtained now at a slower rate. We want to enhance the rate at which we do that. And make that a major initiative. I would say the four things that I've presented here, even though I've presented seven or eight in my written submission, the four things that I've presented here will revolutionize environmental health decision making. And those are the Institute's and my top priorities. And these are things that I would like to be the legacy for my tenure as Director of the Institute. Mr. Porter. Dr. Olden, I can see how you convinced Dr. Varmus. [Laughter.] Dr. Olden. Thank you. link between science and public health Mr. Porter. Mrs. Lowey. Mrs. Lowey. Thank you, Mr. Chairman. And I do apologize, Dr. Olden, as you know, with our schedules, it's hard to be in three places at the same time. But I want to assure you that I am extremely interested in the work of your Institute. And I think there is rising concern and rising interest in almost every area of the country about the impacts of the environment on health. And we're all struggling to gain additional knowledge about the impact of the environment on the health of women, children, families. I have had scientists come to me and express concern about the research that is being done involving human subjects versus research on animal subjects. Research in the lab versus beast research on actual populations. Could you discuss this with me and your view of this and the dollars that are being spent? Dr. Olden. In my opening statement---- Mrs. Lowey. And I do apologize if I missed it. Dr. Olden. I said there are four priorities. And one of those is creating the linkage between basic laboratory science, epidemiology, toxicology and public health. We're very much concerned that the science that we do is linked to public health. Now, at least three or maybe all four of the projects I talked about are population based studies. For example, I talked about exposure assessment. Now, we propose to do the exposure assessment with EPA and CDC. And we already have a pilot study going now with CDC. And what we really need to know is exactly, of all the chemicals in the universe, in the U.S., which ones should we really be worried about. And the way to make that determination is to decide exactly which ones are we taking up in our bodies. Which chemicals are humans actually exposed to. Not based on some potential. But really exposed to. And we can do this by taking samples of blood, of urine. And we can find and identify, either by biomarkers or chemical markers, and we can come back in a matter of years and say to the American people, these are the 40 or so chemicals out of the thousands or so that we really should be worried about. Because these are the ones that people are indeed being exposed to. That's a public health initiative. That's why we're involving CDC. We already are funding such studies. The money's been transferred to CDC to do this for us. Because they have the technologies. And we want to expand that effort. The Environmental Genome Project is population based. And we will sample maybe 10 different populations, maybe 100 individuals. And again, we will have information that's relevant to public health. So we are doing that. But in addition, we have some human studies. We have a study that I discussed here before, looking at developing a treatment for lead poisoning in the range of 20 to 45 micrograms per deciliter of blood, a project devoted to children. We also have a project that we're funding, that is being conducted in China, to look to see if we can use the biomarker of oltipraz as an agent that we've demonstrated from basic research that will prevent aflatoxin-induced liver cancer. Well, now we have a trial going on in China to see if we can indeed prevent the formation of an adduct between aflatoxin and albumen in the blood. And what we've demonstrated, at least preliminarily, is that if we treat individuals with oltipraz that indeed we prevent the formation of aflatoxin albumen adducts. And that's an intermediate bit of information to say that we can prevent aflatoxin-induced liver cancer. And that's the next phase of the study. So we are supporting human studies. But I think all of our, at least my four priority areas, are oriented toward public health. endocrine disruptors Mrs. Lowey. Thank you. And I also know that NIEHS has been a pioneer in conducting research on the health effects of endocrine disruptors. Dr. Olden. Yes. Mrs. Lowey. And I'd like to know how your agency is coordinating its research with other Federal agencies, particularly in light of these new directives, and what is your best estimate of how long it will be until we have definitive answers about the threat to public health posed by endocrine disruptors? Dr. Olden. Well, I am personally spending a lot of time talking with everybody who's concerned and has research programs dealing with environmental endocrine disruptors, not only estrogens, but other hormone mimics. We have collaborations with EPA, I mentioned earlier, we are co-funding projects with EPA. Every three months, we meet in the Department to talk about the research going on in the Federal Government, not just in the Department, because EPA, Agriculture and other departments participate, to make sure that we are indeed coordinating the research. It's coordinated also through the Committee for Environment and Natural Resources. I have also reached out to industry. I have met with chemical manufacturing industries that are responsible for making many of these estrogens. And we believe that we are going to be able to develop a partnership with the chemical manufacturing industry to pursue the research to make certain that we leverage our dollars which you provide us to have an impact that's much larger than the amount of money that we're devoting to this project. So we are in touch with and coordinating our research efforts with everybody, not only other Federal agencies, but with private industry, because private industry, the ones that make more than 95 percent of all the estrogenic-like chemicals in the United States, are represented through the chemical manufacturing industry. collaboration with industry Mrs. Lowey. I'm delighted you brought that up. Because recently, I attended a conference, and one of the participants was a representative from DuPont. And I'm aware of the fact that they've invested quite a bit of money and done a good deal of research, because they understand it's in their own interests. Dr. Olden. Right. And we had discussions with them about that at the outset. And they are part of the chemical manufacturing industry. Mrs. Lowey. Actually, if the Chairman would approve, I wonder if you can enlighten us as to cooperation from other corporations. I mean, they are spending enormous amounts of money, making enormous profits, and to what extent are they investing in this kind of research, as DuPont seems to be doing? Dr. Olden. Significantly. The project that I mentioned about developing the transgenic animal models, new alternative models that are faster and cheaper, well, that project is an industry-Government collaboration. There are 35 industry groups participating in the partnership. EPA is participating, and FDA and the NIH. So this is indeed a Government-industry partnership. Now, we got everybody to the table because when I first became Director, I went around and met with the industry, DuPont, Dow Chemical, Proctor and Gamble, and I discovered that they have exactly the same problems that we have in the National Toxicology Program. They need models that are faster and cheaper, because they have to provide information to EPA, FDA and regulatory agencies to get their products approved. So we then convinced them that it was in their best interests for all of us to pool our intellectual and economic resources to address these problems collectively. We have now had several meetings. We meet regularly in Research Triangle Park, around the table just like this, and we discuss these issues. We decided together what body of science was necessary to convince the American people that indeed, these new models are valid. In other words, will they identify a carcinogen? And that's what we're focusing on at the present time, just carcinogens. And they were eager to do this, because if these tests cost the Government $2 million to $6 million per chemical, it costs them the same amount of money. So they are interested in the same issues we are, saving money and saving time and getting products to the market sooner. So we have that partnership, and we are very proud of that. Mrs. Lowey. Well, thank you very much. In light of budget realities, I would encourage you to continue to encourage the private sector to continue to invest in these areas. Dr. Olden. We are. Mrs. Lowey. I thank you. Dr. Olden. Thank you very much. gulf war syndrome Mr. Porter. Thank you, Mrs. Lowey. Dr. Olden, has your Institute been involved in any of the ongoing evaluations of whether there is a true Gulf War Syndrome? We seem to be caught between the President's panel, which doubts its existence, and a series of studies published in January in the Journal of the American Medical Association, which assert that the syndrome is real. What's your personal assessment of the available evidence? Dr. Olden. Well, Mr. Porter, actually I had it in my opening statement, but it would have made it a bit too long, so I cut it out. I simply was going to say that the Gulf War veterans' illness is a prime example of what I said, of having too little information to make a decision. And that's the problem. It's a problem for you, it's a problem for the American people. And in this case, there's too little information about multiple chemical sensitivity, or chronic fatigue syndrome, or fibromyalgia, and those three at least probably have some similarities in terms of underlying mechanism. There's too little information about susceptibility. Again, from what I read in the newspapers, and it was just in the newspapers today, that some of the veterans were indeed exposed to Sarin. Sarin is a nerve gas. We know what the components are, organophosphates. We know that if you expose 10,000 people, there are going to be ranges of susceptibility. Some are going to be susceptible and others aren't. And we understand now why that is the case. So there's too little information about susceptibility, and there is also too little information about mixtures. Clearly, from what I read in the newspaper, indeed the veterans were exposed to mixtures. There were pesticides. And pesticides often contain as many as 100 different chemical components. There was possibly the nerve gas exposures also. So I would say, Mr. Porter, there's too little information about multiple chemical sensitivity. There is too little information about mixtures. And there's too little information about differences in susceptibility for us to ever figure out what happened. And what we need to do, and my recommendation has been, when we've had these discussions on one occasion in the Department, is that we do what I've asked be done here, and that is, let's focus on doing the science to answer the basic fundamental questions that we need to do intelligent human risk assessment, irrespective of whether there is a war here or there. Because the American people have the same kinds of exposure. They are exposed to mixtures. We don't know about differences in susceptibility. We have the same kinds of problems. If we had solved these problems for civilians, then we would not be in this quagmire about what to do about the Gulf War. So, I don't think we'll have a satisfactory solution, because there's inadequate science. Mr. Porter. It kind of indicates a problem, perhaps, also with our legal system. Because let's assume this was not a Government, but a private party, and the burden of proof would be on the plaintiff to prove that this was a cause and effect. And what you're telling me is, in a situation like this, it's probably impossible to prove. Dr. Olden. That's what I think. Mr. Porter. Yes. And that means that maybe we need some method apart from the traditional methods to compensate people who are injured, and not worry about the cause of the injury or even the causor of the injury. A total aside. Dr. Olden. Right. artificial sweeteners Mr. Porter. At the time of its initial approval concerns were expressed by some about the safety of the artificial sweetener, aspartame, and its possible links to brain cancers. In the intervening years, has your Institute or anyone else supported research providing further answers to this question? Dr. Olden. Aspartame has been nominated for testing on several occasions. We've discussed the nominations with FDA on each occasion, once during my tenure. And we will discuss them with FDA officials, tomorrow. I have a 10:00 o'clock meeting tomorrow to discuss aspartame again. And the reason that we keep coming back to aspartame is, first of all, and there are other sweeteners among these---- Mr. Porter. That's my next question. Dr. Olden. There is increased usage in terms of sweeteners in sodas, for example. We're very much concerned about increased exposure for children, in one example. Also, aspartame was tested in the early 1970s when test standards and methodologies were very different from what they are today. And although we've reviewed that data critically, we don't see anything flawed about it. But we have to admit if it was tested today, it may test differently, in other words, positive. But there is a problem, and I understand FDA's reluctance to go back and test any chemical that we tested 20 years ago. The reluctance is, once you open that can of worms, that's a slippery slope. Because there are a lot of chemical agents that are in the marketplace that were tested using 1970s technologies and standards. So why single out aspartame and other sweeteners? Are we going to get petitions to test all the others? We believe, the American people are very concerned about sweeteners, there is tremendous exposure and increased usage in sodas and other things that children are exposed to recently. So we are concerned about it. We are going to express our concerns to FDA tomorrow morning, as we have done in the past. And based on that discussion, we will decide whether we want to reevaluate aspartame in a two-year rodent bioassay. Mr. Porter. Being a major user of the product, I think you should do that. [Laughter.] Dr. Olden. Well, that's what we hear. NutraSweet, is the trade name, commercial name. Mr. Porter. A new artificial sweetener already used in Canada called Sunett is being considered for approval in this country for soft drinks, and again, safety concerns are being raised about possible links to tumors. Do you plan to conduct studies on this sweetener? Dr. Olden. It's included in the discussion tomorrow. There's two. And that's the other one. It's been nominated for testing and fits into the same category. Both were tested in the early 1970s. Same kind of test procedures, same problems. And we're going to discuss it with FDA tomorrow morning at 10:00 o'clock. nanofabrication Mr. Porter. Last year, we briefly discussed the technology of nanofabrication. Your justification indicates that this field has matured to the point of application in environmental health. Can you give us some examples of possible uses of nanofabrication in your Institute's work, and do you have any plans to support this technology? Dr. Olden. Well, I must say, thanks to you, I really gave it a lot of thought and looked into it. And it is a very rapidly developing technology. It developed as a consequence of the computer industry, and informatics industry, and it is important. And it is being used now for environmental monitoring and assessment, mainly in the defense industry. Right now, my prediction is that nanoscale tests will be developed some time in the future. Right now, the tests that I've talked about, the new tests, the fast through-put technologies, are going to be done on a microscale, not necessarily a whole animal. But we're talking about a microscale, much smaller. And I think with time, we will be doing tasks that are fast through-put on the nanoscale dimension. So yes, I am interested. The Institute is very interested in new technologies. And we have scheduled, in fact, to bring a few people in to talk about this technology and its potential for some of these fast through-put screening tests that we want to develop. But right now, as we perceive it, we will be working at the microscale level. But in a matter of years, we will be at the nanoscale level, and the technologies will be highly relevant. But they could also be very important for exposure assessment, individual exposure assessment. They are relevant, highly relevant, to what we do in NIEHS. And we are exploring. contract mechanism Mr. Porter. Your budget continues to emphasize the use of the contract mechanism, 22 percent of the total compared to an NIH average of 6 percent. You have testified in previous years that you were trying to increase the share of your budget allocated to research project grants. Does that continue to be an interest for you, or have you found that the nature of your work requires you to heavily use the more directed mechanism of contracts? Dr. Olden. Well, I'm clearly interested in getting more money into the grants mechanism, in part because I think we buy better science. So that's the motivation. During my tenure, we have dramatically decreased the amount of money that, dramatically may be an overstatement, sir, but we have decreased the amount of money that we spend via the contracts mechanism. For example, many of the NTP studies now we are doing on a grant mechanism. And I can just cite two. There was the National Academy report about two to three years ago about the health effects of pesticide exposures on children. And it turns out that we just had no studies any place to address any of those issues. Most pesticide exposure experiments are done with an adult animal. We are now doing studies involving in-utero exposure to pesticides and to estrogens. It seems that the critical time for exposures to estrogens at low levels may not be during adulthood, but may be during development. And there's lots of studies to suggest that is the case. And those studies are NTP studies that are being done via a grant mechanism, R01 grant mechanism. We advertised RFAs, we took the very best grant applications that we had and we funded those. So that is the trend, and we will continue to do that. But in the end, for some work that we do through the National Toxicology Program we simply have to use the contract mechanism. I mean, they are kind of routine kind of screening activities that we would not get a scientist to invest time and effort to do. And you don't need a university professor to do. I mean, these are just studies that are kind of assembly line things, same activity day after day after day for two or three years. So unfortunately, that's where we are. I can get it down, and I've gotten it down. But in the end, I won't be able to reach the NIH average. Mr. Porter. Thank you, Dr. Olden. Mrs. Lowey. asthma Mrs. Lowey. Thank you, Mr. Chairman. And I just have two follow-up questions. Dr. Olden, you talked about your focus on public health problems. In recent years, there has been an increased number of children being admitted to the emergency room as a result of asthma. Could you give us some insight as to the work you are doing in that regard? Especially in our cities. Dr. Olden. Yes. We created one new program, and it's called the Five Cities Study, to specifically address that problem. Then we collaborated with the National Institutes of Allergy and Infectious Diseases on another project called the Inner City Asthma Project that Dr. Fauci may have described to you this morning. The Inner City Asthma Project is an effort to look at indoor allergens, cockroach dust, and dust mites on asthma in inner city children. These are kids who are mostly minority and also economically disadvantaged. Since the Inner City Asthma Project focused on indoor air, and it is at the point now of being an intervention study, we created a new project this year called the Five Cities Study, to look at the effects of outdoor air pollution on asthma admission rates to emergency rooms. And so those are the two major projects that we initiated specifically to address those issues. But let me say, we go way back. We have 24 city studies, the 6 city studies, and in fact, the bulk if not all of the data that's being used to debate the new EPA-proposed air standards for ozone and particulate matter in the air, that data was generated through NIEHS grant mechanisms by Doug Dockery and collaborators at Harvard. So we've been in this business a long time. And I would say have made the major contribution to that area. retesting of chemicals Mrs. Lowey. Just one last follow-up question to the Chairman's question. If I heard correctly, you mentioned that you were concerned about retesting aspartame because there would be, I don't remember what you said, thousands, many petitions to retest other products. Dr. Olden. Right. Mrs. Lowey. Now, what immediately came to mind were the advance in science, with all the new information, how do you make determinations on which products, which additives you should retest? If something is passed 15 years ago, there's a good deal of new information since then. How do you set your priorities and how do you make those determinations? Dr. Olden. Well, that's going to be very difficult. Because even the test, the rodent bioassay that we're using today, I hope that that becomes obsolete. That's what we're working for. Everything that we're testing today will be obsolete in 20 years in terms of the test standards. And do you want to go back and test the things that we're testing today that we believe in? So that is what we're faced with. And obviously, I can't make that decision alone. I have to have a number of people who are more expert than I to give us advice on what we should do. And in the end, it's not only a scientific issue, it's a social issue. Do we want to make that kind of investment, because we've never tested about 80 percent of the agents--chemicals, man-made chemicals--that are in use commercially today. About 80 percent have never, ever been tested in a single assay. We've only tested about 20 percent of them. Now, do we want to spend our money retesting or do we want to go forward and test new things that may pose a health hazard. This is a dilemma. And that is FDA's position, or it has been, and we'll find out if it still is tomorrow. And I don't have a lot to combat that. We'll present it, we have advisory councils, and I will take the discussion tomorrow back to my advisory council, and it's made up of scientists, industry people, and lay people, and we'll present it and get their input. Mrs. Lowey. I'd be interested in hearing more from you in that area. It certainly seems to me roughly, well, I imagine there are thousands, of chemicals and additives that are part of foods and products. And right now, you're saying that if a product's been tested 15 years ago, it's safe, it's off the agenda, is that correct? Dr. Olden. I'm saying that that is a position. And do we want to go back and retest those? Because once you start that, there's an awful lot of things that we tested over the last 20 or 30 years. And the test standards and methodologies were different. The things we're testing today, we will have sophisticated, better tests 20 years from today. And so it's kind of a never-ending issue. So I guess what we'll do is present it to our Council and we'll get a feel for how comfortable people are with data that was generated 20 years ago. The artificial sweeteners are obviously of concern, because 60 Minutes featured them in a 20 minute segment one evening about a month ago. And I get a lot of letters, and FDA gets a lot of letters about it. And the public is very concerned, as Mr. Porter said. Well, all of my friends who saw 60 Minutes immediately the next morning came to us and asked us, what are you doing, can you assure us of safety. So these are the issues. And our council and board of advisors will have the same kind of reservation. Mrs. Lowey. Well, thank you. I frankly didn't watch the 60 Minutes, and I'm much more concerned today than I was yesterday as a result of your question. [Laughter.] Mrs. Lowey. So I certainly look forward to continuing this dialogue. Thank you. Thank you, Mr. Chairman. Mr. Porter. Thank you, Mrs. Lowey. I think there's a difference between those things that we voluntarily ingest and believe are okay and those that we might be exposed to involuntarily or unknowingly. And with the volume of use of artificial sweeteners like aspartame now in our society, it seems to me that looking at children, who would probably be at greatest risk on these things, it's probably a wise thing to do, if it otherwise seems to point in that direction. Dr. Olden. Yes. And that we can do. air quality standards Mr. Porter. Speaking of coordination between agencies, there is considerable discussion in Congress about whether EPA air quality standards are based on sound science. You know there are new regulations. Dr. Olden. Yes. Mr. Porter. Has your Institute provided any data to EPA to aid in this debate? Dr. Olden. Yes in part. In my answer to Congresswoman Lowey, I mentioned that the data that is being used to decide what the new standard is, and in fact, the reason it's being debated at all, was the result of the 24 city study that was done by Doug Dockery at Harvard. He found that particles, and he called them particle size ten, which are very small particles, he discovered and demonstrated in his epidemiologic study that the mortality rate was increased by something like 23 percent and that translates into a life expectancy decrease of 2 years. He found that that was true for the most polluted cities compared to the least polluted cities. It is exactly that data that EPA is now using to advance a new regulatory policy. And in fact, we've been in discussion with EPA and Congress, as a matter of fact, in the last week or two, about that data. So the data from these studies is being used for documentation. And the reason that there is a concern, even going way back to the Middle East oil crisis, has to do with work that the NIEHS supported. Mr. Porter. So you, I can conclude that you believe that the science on which EPA based their regulations is sound science? Dr. Olden. Well, I think, as I understand it out of the newspaper, both EPA and industry are not, people aren't refuting the science. The question is, EPA and industry both agree that more data is needed. I think where they disagree is, should you regulate, err on the side of safety now and put in place a regulation, or should you wait until the science is in. I think that's the debate. So it's not about the need for more science. I think EPA would like to see more science in place. Industry would like to see more science in place. So this again is an example of where there's inadequate information. And probably, no matter what decision is made, it's going to be problematic. People aren't going to be satisfied with the decision without the additional information which we do not have today. So the data that's been presented is fine, but there are gaps. And that's the problem, and that's what the debate is about, those gaps. EPA acknowledges those gaps. smoking Mr. Porter. Dr. Olden, I thought we had planned our time quite well, but Ms. DeLauro just arrived. Ms. DeLauro, would you like to ask questions of Dr. Olden? You can proceed if you want. Ms. DeLauro. One question, because I just came from the Agriculture subcommittee where we were talking about tobacco. I've been a strong advocate for trying to get at kids to stop smoking. We have something called the Kick Butts Connecticut campaign, where we're working with middle school kids. We've got this army of middle school kids, about 50 or 60 of them in the district, who are going to the elementary schools and talking to their peers about not smoking. It's a great effort. But what I wanted to ask about is your initiatives in terms of dealing with a link between cigarette smoking, disease and cancer. That effort in terms of what that body of research is, and getting that information out to deal with the issue of children and adolescent smoking. If you could just comment on that. Dr. Olden. Over the years, the National Cancer Institute and NIEHS, and I would say more even the years before I got there as Director, made long-term commitments and investment in basic, fundamental research, on the health effects of chemical agents in cigarette smoke. And it's that long-term commitment to the basic fundamental research that demonstrated the epidemiological association between cigarette smoking and cancer. And many of the chemicals were subsequently indentified, not only by NTP assays, but also by the bioassay program conducted by the National Cancer Institute. We played a major role in it, and we continue to look at some aspects of lung cancer. I did not say one of our other susceptibility gene discoveries in the past few years was one that enhances the susceptibility to lung cancer if exposed to 925 cigarette smoke carcinogens. So we continue to do research in that area. But so does the National Cancer Institute. And they are clearly much more active, I would say, than we are in the outreach component in terms of public education. Ms. DeLauro. They are more active on the outreach component than you? Dr. Olden. That's what I would guess. We do have an information service. But I would say we probably get no questions on that issue. And NCI has, as you know, an information service and community outreach that's focused on smoking cessation. So I would say that the bulk of that work is being sponsored and supported by the NCI, although we certainly have played a major role over the years and will continue to. Ms. DeLauro. Thank you, Mr. Chairman. Mr. Porter. Thank you, Ms. DeLauro. Dr. Olden, thank you very much for your good testimony, your forthright answers to our questions, and for the fine job that you're doing at NIEHS. And we look forward to coming down and visiting you and seeing things up close in April. Dr. Olden. Thank you. We look forward to your visit. autism Mr. Porter. Thank you. Now, as Dr. Snow comes to the table, I want to ask a question of Dr. Varmus. I want to keep you a little busy here, Dr. Varmus. Many of us on the subcommittee have been visited this past week by parents of autistic children who are concerned about the level of support that NIH research provides with respect to this disease. I wonder if you could tell us which institutes are involved, do you have an estimate of how much is being spent, has the money been constant or has it been rising or falling, and what are the prospects for research into autism in the years ahead? Dr. Varmus. Thank you for the question, Mr. Porter. As you may have read, the NIH is taking a dramatically increased interest in autism for a number of reasons that I'll come to. At the moment, there are roughly four institutes that do research in this area: NICHD, NINDS, NIMH and NIDCD, which is at the table with me now. The level of funding as of 1996 was approximately $14 million. I can give you the exact number if you like. And there was a very substantial increase for 1997 of about $4 million. And we expect to have that increased a little further in 1998. In addition, we as a result of my request for initiatives to support with my 1 percent transfer authority, we have decided to put together a package of $4 million that will go for the study of the genetics of autism, to be sponsored by the Institutes to my left, NIDCD, NIMH and NICHD. Now, let me say a word or two about autism. This is obviously a devastating illness for the child and for the family. And for many years, it was marginalized, in my view. But for a number of reasons, it's become more central and more accessible to research. And now it's positioned itself in the middle of the technological advances that are revolutionizing our view of neuroscience. It's approachable by neuroimaging, it's approachable by genetics, approachable by neurophysiology. It's become recognized as a disease that is likely developmental in origin, with subtle anatomical changes. It's been changed by the perception that it's not really one disease. It's a range of diseases, at least four, possibly five, discrete syndromes, that can be fairly well recognized. And that is changing our notion of how to go about approaching the disorder. There is already underway a fairly extensive attempt to understand the genetics of autism. In particular, the NIMH has assembled a large cohort of families. Recently published work suggests that it's possible to exclude a fair amount of the genome as the site of genetic lesions that contribute to autism. That's helpful to narrowing down this ever-engaging search for the loci involved. As you might appreciate, since there seem to be several syndromes that go under the general term of autism, it's important to have clear criteria for deciding what disorder you're looking at. And recently, the four institutes that are involved in the study of autism have gotten together and agreed to try to work out some common defining principles, so that the genetic information that we're assembling can be made more useful. In addition, there have been recent reports that suggest that it's possible to develop an animal model for at least one sub-form of the disease. And that's based on evidence from a small number of autopsy patients who seem to lack what are called the nuclei for some of our cranial nerves. What that suggests to developmental neurobiologists is that the developmental lesions in at least some cases of autism occur about the time of the closure of the neural tube during development. By using known developmental anomaly-inducing agents, one in particular called valproic acid, which happens to be a drug that's used in the treatment of epilepsy and schizophrenia, using that drug in a rat model, it's been possible to reproduce some of the anatomical defects that are seen in at least an occasional case of autism. So all those things combined, I don't want to go on longer, it's clear there are a lot of new things to do. I'm sure you're aware that about two years ago, we had an important workshop on the NIH campus. It was very widely attended, I was there myself to hear many of the talks. I think that had the effect that I like to see when we think about funding at increased levels in an area. That is, people were there from a number of fields that had not participated actively before. We were drawing new talent to a field instead of simply putting more money into the pockets of those who were already working on the problem. And the synergy among the neurobiologists, geneticists, and clinical and behavioral students of autism, was very obvious. One of the reasons that there was a lot of enthusiasm among my outside advisors for supporting the work on autism that was proposed for the 1 percent transfer authority was the fact that in response to the RFA that Dr. Snow and Dr. Alexander put together, applications of very high quality were received in excess of the ability of those institutes to support them. Mr. Porter. Thank you, Dr. Varmus. [The following questions were submitted to be answered for the record.] [Pages 734 - 803--The official Committee record contains additional material here.] Thursday, February 27, 1997 NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS WITNESSES JAMES B. SNOW, JR., M.D., DIRECTOR DONALD H. LUECKE, M.D. DEPUTY DIRECTOR W. DAVID KERR, EXECUTIVE OFFICER PATIENCE T. SPARKS, BUDGET OFFICER MARSHALL MOORE, INTERPRETER HAROLD VARMUS, M.D., DIRECTOR, NATIONAL INSTITUTES OF HEALTH BILL BELDON, DIVISION DIRECTOR, OFFICE OF DEPUTY ASSISTANT SECRETARY, BUDGET, DEPARTMENT OF HEALTH AND HUMAN SERVICES Mr. Porter. Now we'd like to welcome Dr. Snow, Director of the National Institute on Deafness and Other Communication Disorders. Dr. Snow, we're anxious to hear from you. And my first question will be to ask you whether you want to follow up on anything that Dr. Varmus had to say about autism. Why don't you proceed to introduce the people at the table and then your statement, and then if you'd like to address the autism question further, please feel free. Introduction of Witnesses Dr. Snow. Thank you very much, Mr. Chairman. It's my pleasure to introduce Dr. Donald H. Luecke, the Deputy Director of the NIDCD; Mr. David Kerr, the Executive Officer of the NIDCD; Ms. Pat Sparks, the Budget Officer of the NIDCD. Mr. Marshall Moore is the sign language interpreter. You, of course, know Dr. Varmus and Mr. Beldon. Opening Statement Mr. Chairman, members of the committee, I am grateful to have this opportunity to appear before you to report on the research progress of the National Institute on Deafness and Other Communication Disorders. That research benefits 46 million Americans who are challenged by diseases and disorders affecting hearing, balance, smell, taste, voice, speech and language. The NIDCD is seizing opportunities to accelerate discovery that will lead to elucidation of the biology of brain disorders such as aphasia, finding new approaches to the pathogenesis of diseases including laryngeal carcinoma and spasmodic dysphonia; new treatment strategies against immune-mediated inner ear hearing loss; and applying genetic medicine to hearing impairment and the velo-cardio facial syndrome, while developing new therapy for disorders of balance and the symptom of tinnitus that are critically important in improving the quality of life for those faced with communication disorders. Progress that we're experiencing within the portfolios of the NIDCD is due to careful planning and emerging opportunity. In the past several years, with the support of the NIDCD, a multitude of genes for syndromic and nonsyndromic forms of hearing impairment, including autosomal dominant and recessive, X-linked and mitochondrial modes of transmission have been located in specific regions of the human genome. And at least 12 different genes on 10 different chromosomes have been located for various forms of autosomal dominant nonsyndromic hearing impairment and at least 11 different genes on as many chromosomes have been identified for autosomal recessive nonsyndromic hearing impairment. Recent NIDCD-supported research will further our understanding of normative patterns of brain development in all children and provide a more detailed understanding of the acquisition of sign language in deaf children. The Institute has established two clinical trial cooperative groups to plan, implement, conduct, analyze and disseminate results of priority research in the efficacy of treatment of diseases and disorders affecting human communication. The Institute is improving technology for individuals with communication disorders. A unique collaborative effort is fostering partnerships among scientists, industry and Federal laboratories to carry out research needed for commercialization of promising hearing aid technology. There is progress in developing a new vaccine against otitis media in infants and small children. Plans are underway for a Stage I clinical trial in the NIH Clinical Center of a conjugate vaccine against the nontypeable hemophilus influenza. The chemical senses, smell and taste, greatly influence nutrition. Scientists are studying the role of the gustatory thalamus in food aversions and food-seeking behavior that will help in the effort to understand life-threatening eating disorders. NIDCD investigators are applying the newest tools and strategies to long-misunderstood and often misdiagnosed diseases and disorders of human communication. Mr. Chairman, the fiscal year 1998 budget request for NIDCD is $192,447,000. I will be pleased to try to answer any questions you might have. [The prepared statement follows:] [Pages 807 - 810--The official Committee record contains additional material here.] autism research Mr. Porter. Thank you, Dr. Snow. Would you like to add to what Dr. Varmus said about autistic children? Dr. Snow. I'd just like to add an experience that I had yesterday. The first meeting of the Autism Research Coordinating Committee was held. All of the directors of the institutes involved were present. Some of the staff of the Institute are meeting with the Cure Autism Now group, actually right at this time this afternoon in Bethesda. I think that the coordination is really enormously important and an agreement was made yesterday afternoon to try to work towards a common phenotyping clinical description of children in autism, so that all the various groups, the molecular geneticists supported by the National Institute of Mental Health, as well as those that will be supported by the NICHD and the NIDCD, will use a common basis for categorizing the patients. And that will greatly improve and hasten the work. Mr. Porter. Just one small question. Is it correct that the inability to properly hear sounds of human speech may contribute to the disorder of autism? Dr. Snow. Well, I don't think there has been any satisfactory demonstration of that as far as I know. Certainly autism is a disorder of human communication. It's a language disorder. It is of particular interest to us because it is at times associated with near-normal or even above normal intelligence, a situation where the language disorder occurs in the presence of normal cognition. And to approach the molecular genetics of that leads us directly to an understanding of the genetics of language. And that, of course, is an area that we have had great trouble breaking into. We have not had the success in that area that we have, let's say, in the hearing area, where we have literally a multitude of genes that have been discovered. So we're very interested in trying to get a handle on the molecular genetics of language. And we think this may be a very fine opportunity to do that. hair cell regeneration Mr. Porter. Dr. Snow, last October, researchers in Philadelphia found a method to generate the growth of hair cells in chickens. This finding was the first to suggest a possible method to regenerate hair cells which are often the cause of deafness when they die. Is the scientific community optimistic that this finding may also work for mammals? Dr. Snow. Yes, we are optimistic that it may also work for mammals. I believe that you're referring to the work of the principal investigator that's supported by the NIDCD, Dr. Oberholtzer. And his finding in the chick was that compounds that activated cyclic AMP, and that in turn activate the protein kinase A system, led to the development of new hair cells when there had been no injury present. All of the other research on the regeneration of hair cells had been in a situation where first the hair cells had been destroyed. So this is of enormous importance. This publication, which actually appeared in Nature in August, was brought to my attention immediately by Dr. James Battey, the Scientific Director of the Institute. And we agreed that this was an enormously important finding and indeed, in turn, acquainted Dr. Varmus with it. And indeed, that has become one of our areas of emphasis for 1998. And in the development of the budget, $500,000 was committed to pursuing research along that line. stochastic resonance Mr. Porter. Nature Medicine Magazine reported last August a finding that translates a principle of physics into a possible aid for the deaf. Stochastic resonance is a process in which the addition of the right amount of noise results in an improvement in response. Applied to the cochlear implant device, it is thought that hearing is improved when noise is added to the stimulus. Do you expect random noise to be added to commercial cochlear implants to improve hearing for the deaf? Dr. Snow. Yes, I think that may well be, that in time the principles of stochastic resonance may be added to the input to cochlear implants. Stochastic resonance is a phenomenon of non- linear statistical physics, which as you say, introduces noise or interference, and in this case, it is truly noise, into a system. And this increases the informational content of responses when you're dealing with a non-linear system, and the auditory system, as well as some other sensory systems, is a non-linear system. Actually, we benefit from stochastic resonance all the time in natural hearing. If we were presented with strictly pure tone rather than the ambient noise that exists all around us, both in a relatively quiet room like this, as well as in nature, it would be more difficult for us to understand and to appreciate certain phonemes, particularly those that are represented by the vowels. So not only is that helpful in normal hearing, but it would also be helpful in cochlear implantation. For several years, we've recognized that the opposite of a stochastic resonance stimulation is a deterministic stimulation. And that, when there is electrical stimulation of the remaining nerve fibers, they tend to all respond at the same time. You might think of it as a military organization marching all together, all in step. They are all synchronized. Although that tends to happen naturally in the normal auditory system, there's a certain amount of phase locking that brings that about which is beneficial. But when the system is being driven by electrical stimulation, that deterministic or phase locking becomes too severe. And as you rise in the auditory system from one waystation to another, that becomes more severe, and actually interferes with understanding. Dr. Terry Hambrecht, who is in charge of our cochlear implant program, where we issue requests for proposals for directed research through contracts, has been aware of this for several years, and has investigators trying to achieve stochastic resonance, rather than a deterministic form of stimulation. So we've been incorporating this kind of principle into our cochlear implant research and development work for the last several years. Mr. Porter. Thank you, Dr. Snow. Ms. DeLauro. consensus conference findings Ms. DeLauro. My understanding is that the NIDCD has engaged in a number of activities and initiatives regarding kids, particularly the consensus conference to evaluate research on hearing impairment in children. Were there some findings that you might be able to discuss with us and how they are being put to use in doctors' offices in this country? Dr. Snow. Yes. We've had two consensus development conferences that involved hearing impairment in children. The first was in 1993. And it dealt with the early identification of hearing impairment in infants. And a very important recommendation came out of that consensus development conference. For the first time, anywhere in the world, there was the recommendation that there should be universal screening for hearing impairment of all newborn infants. Now, that recommendation was made in 1993. And it has greatly influenced the field since then. Ms. DeLauro. Are we doing that? Are we screening them? Dr. Snow. We're making progress in it, but we have a long way to go. Maternal and Child Health has recently awarded a grant to the University of Colorado to implement as a demonstration project, to implement infant screening in 19 states. And we are currently in conversation with the CDC and Maternal and Child Health to extend that screening to a larger number of states through Maternal and Child Health. Hearing identification of infants is in the Secretary's initiatives for this year, under child care. And we're hopeful that we'll move forward in a major way this year. Ms. DeLauro. Are there any states that are currently doing it? Dr. Snow. Yes. States that have the very best and most complete systems are Colorado and the Hawaiian Islands. Next I would probably put Utah. The way in which this is developing, though, is to do it hospital by hospital. There are two good techniques for identifying hearing impairment in the newborn. The measurement of oto-acoustic emissions and the use of automated brain stem responses. Both are very effective, very efficacious in identifying hearing impairment. Once the infant is suspected of having hearing impairment on the basis of one or the other of these tests, then they are brought to a diagnostic evaluation, usually about six weeks later, to determine whether there is actually hearing loss that can be confirmed or not. Both of these techniques have a very high success rate, though, high specificity. And so both are good for that purpose. Ms. DeLauro. Has there been any evaluation in Colorado or the Hawaiian Islands or Utah? Are we able to affect any outcomes, finding something early enough to prevent it happening in the future? Do we have any results? Dr. Snow. Oh, yes. The average age of identification of hearing impairment in the United States is now at about two years. The latest information from CDC is that in their survey in the Atlanta area, it's down to two years. That's down from two and a half to two years over the last seven years. And then when we identify an infant that has a hearing impairment, we begin special education of that infant right away. And indeed, we'll put a hearing aid on the infant as early as six months of age. Then the family, of course, needs to begin to decide what form of education they wish to pursue, what form of rehabilitation in the way of special education, whether they follow the manual-visual approach through American Sign Language, or whether they follow an oral-auditory approach, which would make maximum use of any residual hearing, either with a hearing aid or with a cochlear implant. Ms. DeLauro. Would hospitals hesitate to incorporate something like this? You say we need to go hospital by hospital. But what would be the hospitals' resistance? I am not saying that there is any, but what would be the hospitals' resistance? Dr. Snow. They have to work out a form of reimbursement for it. If this is a service that has not been delivered in that community before, both the insurance companies or the health maintenance organizations don't know what to do with the bill when they get it the first time. So there has to be negotiation over how the reimbursement is to take place for these services. So that's the principal block. Ms. DeLauro. Is this an expensive procedure? Dr. Snow. No. As screening procedures go, it is not. It costs about $35 per child. About 1 in 1,000 infants are born with hearing impairment. And in order to test all 1,000 of those, it would cost about $35,000. What this says is that in order to identify a deaf child early, it costs about $35,000. That's $35,000 per deaf child, and $35 for each child screened. The other consensus development conference had to do with cochlear implantation, both in adults and children. The outcome of that as far as adults were concerned is that there was a recommendation that individuals who did not get more than 30 percent of sentences correct on sentence material with the best hearing aid arrangement probably would benefit from a cochlear implant. This is because it was found that individuals who had received a cochlear implant did much better than those individuals who got 30 percent or less of their words or the sentences correct. This was an enormous change in the field. There are 1 million people in the United States who fit this new classification. And so this increased the number of people that are now candidates for cochlear implants among adults increased by 1 million people. As you probably know, cochlear implantation was not done in the United States until two years of age. There have been some experimental trials at an earlier age in Europe. And one of the recommendations of the consensus panel was that more research should be done about earlier implantation of children with cochlear implants. And of course, more study needs to be done on what leads to a successful outcome and what does not. Ms. DeLauro. Thank you very much. Dr. Snow. Yes. Ms. DeLauro. Thank you, Mr. Chairman. sensory regeneration Mr. Porter. Thank you, Ms. DeLauro. Dr. Snow, your budget justification mentions research demonstrating that odor responsive neurons in the brain are capable of regenerating and reconnecting in adults, and that this regeneration occurs throughout life. Does this finding have promise for restoring the sense of smell lost through injury or age, and more broadly, does this suggest research leads in other fields like spinal cord injury and neurodegenerative disease? Dr. Snow. Yes, the interneurons in the olfactory system are continuously replaced, even if there is no injury. If the system is injured, then that activity greatly increases. If the first order neurons are injured, those that have connections within the nose and extend to the olfactory bulb, if they are injured, they are reconstituted, not regenerated from themselves, but from other cells in the area. They make central connections and the function is restored. And this ability throughout the olfactory system for neural regeneration or neurogenesis to occur suggests that this might be very helpful in bridging across a defect area, either in the brain or in the spinal cord. And we are supporting research through the grant mechanism that is studying the use of these interneurons in the repair of created neural lesion. And that could, if it proved to be successful, turn out to be of value in spinal cord injury. eating behavior and nutrition Mr. Porter. Dr. Snow, variations in eating behavior and nutrition among individuals have been linked to genetic variation in tasting ability. Is it far-fetched to think that genetic manipulation of tasting abilities would be a strategy for weight loss for the chronically obese? Or is consumption not likely to be altered by taste sensations? Dr. Snow. Well, there are many factors that enter into obesity. And the influence of smell and taste is only one. Characteristically, individuals who are tasters of PROP (propylthiouracil), particularly women who are tasters of it, tend to be thinner individuals. Some people are tasters of this compound, some people aren't; some have a mild reaction to the taste, others have a severe reaction to the bitter taste. Those that have the more severe reaction, among women, also experience more sweetness and more bitterness from the additives to food that provide those tastes. And as a group, they tend to be thinner, slimmer individuals. It is an important consideration, but of course not the only one. And there is the genetics that primarily determines obesity, for which major discoveries have recently been made. But assuming that the person does not have that sort of genetic predisposition to obesity, and is more governed by simply what the food intake is, this probably plays an important role in their body habitus. Mr. Porter. And maybe genetic manipulation could therefore be of help in those individuals? Dr. Snow. Well, what's been found is a good thing. You wouldn't want to change, I think, slim women. I don't know where the manipulation comes in. If we had a finding, which we don't, not one that comes to mind, where it led to the obverse situation of obesity, then yes. But no, this is a healthy phenomenon. Mr. Porter. This is far-fetched, I can tell. Dr. Snow. We'll just let it be. sense of smell Mr. Porter. Women are thought to have a keener sense of smell than men. Is it known why that is the case, and is it true with any other senses? Is it true with that sense? Dr. Snow. Yes, it is very true with the sense of smell, and it goes throughout the lifetime. Young girls have a keener sense of smell than young boys of the same age. And that goes throughout the life span. There is of course a dropping off of the acuity of the sense of smell starting at about age 60, and that goes on for the rest of one's life. And all through the years, women maintain their sense of smell better than men for each comparable age. In other sensory systems, I don't know. Of course, the same is true in hearing, in terms of the hearing level. Women hear better than men in advanced age. But young women don't hear better than young men and girls don't hear better than boys of a comparable age. And I don't think there is any difference in vision or the other sense that come to mind. Mr. Porter. Do we know why? Dr. Snow. No, I don't know why that is. balance disorders in the elderly Mr. Porter. Disorders of balance and vestibular function are common among the elderly. Do we have any idea what percentage of falls resulting in hip fractures, which often seem to be the first step toward assisted living, are attributable to balance disorders? Are any treatments or compensating rehabilitation techniques available for balance disorders? Dr. Snow. Yes. It is believed that 50 percent of the falls that result in hip fractures are due to a vestibular disturbance. The elderly tend to develop vestibular disturbances that lead to all sorts of uncertainties about their position in space and these can be improved. This inability or disability can be improved by physical therapy. There are techniques that the NIDCD has supported that lead to an improvement in an individual's ability to manage under relatively adverse circumstances, of shifting weight, getting in and out of a bathtub and other things in the way of daily living. And these individuals can be trained to cope with these situations and the actual exercise improves their ability to deal with them. loss of voice Mr. Porter. Your budget mentions that little research has been done in the field of voice loss. Is this condition thought to be a muscle disorder that may be amenable to therapy, or is it the result of cell death or some other degenerative condition? How prevalent is voice loss in the population? Dr. Snow. Mr. Chairman, I'm not sure what you're asking. Voice loss from what cause? Mr. Porter. All causes. Dr. Snow. Well, let me just say that 6 percent of our budget supports research on voice and voice disorders. There are a number of causes of voice loss. And we have a fairly extensive portfolio of research in that area. Mr. Porter. Does any of it relate to muscle disorder that's amenable to therapy, or does it relate to cell death? Dr. Snow. Yes, there is a lot that relates to muscle disorder, if you include both neuromuscular, both the neural supply as well as the muscle itself. For example, spasmodic dysphonia, a condition that I've discussed with the committee before, is an abnormal muscular activity, perhaps mediated through the central nervous system, but the end organ being the larynx. This is the condition, you know, that we have developed the treatment by injection of botulinum toxin into the muscles of the voice box. And that research continues, and actually we have engaged in that kind of research in the intramural program since 1989. Current, new research efforts are aimed at developing objective clinical procedures for the diagnosis of these disorders, generally spoken of as dystonias, which spasmodic dysphonia is one part of. And these are patients that have generally been misdiagnosed or incorrectly diagnosed. And now there is a greater recognition of the problem, and a better recognition of what to do about it. When it was recognized in the past, the recommendation was to cut one of the nerves to one of the vocal cords. And indeed, we practiced that for many years. And it was some help, but it tended to be a temporary one. Often the condition would return. And not only would the patient still have the spasmodic dysphonia, but would also have a vocal cord paralysis. The botulinum toxin injection, on the other hand, does wear off after several months, but gives several months of relief, and then the injection can be repeated. Mr. Porter. Are there any side effects from that injection? Dr. Snow. Well, sometimes, if it's overdone, it can lead to an incompetence of the larynx. There can be aspiration of food or fluid. This is usually a temporary matter. And there can be weakness of the voice if it is overdone. In each patient, there has to be a calibration or a titration as to how much should be used. We start with a small dose and then gradually work up until a satisfactory response is reached. Sometimes there is an overshoot of that and it results in one of these complications. Fortunately, they're temporary. They wear off, too. Mr. Porter. Since I am suffering some voice loss today, I am very interested in this subject. Did you tell us how prevalent voice loss is in the population in general, do you know? Dr. Snow. It's difficult to answer that question. We don't have good epidemiologic data on voice disorders. Voice disorders, of course, are very common. All of us may experience an episode of laryngitis in the course of a year, and have several days of hoarseness. We see many individuals who use their voice in their work, as of course we all do, but particularly in public speaking, who have chronic problems with their voice. And at the periods of time when the voice has to be used more than others, that hoarseness recurs. That's really a very common problem. But I really can't give you any data on the matter. government performance and results act Mr. Porter. Of all the people, I know two people who have voice loss, one is being treated with the injections, the other one is the result of voice loss from an injury, and apparently can't be treated. But those are the only two I'm aware of. Much of the research that NIH supports does not lend itself particularly well to measurement under the Government Performance and Results Act. It does seem, however, that GPRA standards could be appropriate for your research in the development of hearing aid technology. Have you considered performance goals and time frames for your contracts and grants in this area? Dr. Snow. No, we have not done that as yet. But we can certainly do that, as we develop the plan. clinical trials Mr. Porter. Last fall, you announced the creation of a clinical trials branch within your Institute. How many trials do you expect to have in operation at one time, and what are the major research topics you would like the clinical trials branch to focus on? Dr. Snow. We are in the process of awarding two clinical trial cooperative groups. These are two of the major professional organizations in the field, and within each of those cooperative groups, there are 15 to 20 clinical centers. In the case of one of these, the first protocol is on the treatment of immune-mediated inner ear hearing loss, either with corticosteroids, methotrexate or cytoxin. This problem of immune-mediated inner ear hearing loss is really a very serious problem. It often begins in mid-life, 35 to 45 years of age. And often goes on to bilateral deafness in an individual who had otherwise had healthy hearing. This is quite a dilemma for the clinicians to know what form of treatment is to be used. And of course there is treatment that will prevent the progression of the hearing loss to deafness. So we consider this a very major and important study to be undertaken. The other study that has undergone peer review and is ready to begin is the one on the aspiration of fluids in the elderly. And this clinical trial will compare two forms of therapy that are thought to be effective, one due to head positioning and the other due to changing the viscosity of the food and fluids that are ingested. This is particularly a problem in the elderly who are demented, either with Alzheimer's disease or some other form of dementia. We look forward to a series of clinical trials in each of these cooperative groups, probably not starting one each year, although that would be very desirable. Because each have four more proposals, important studies such as the use of diuretics in Meniere's disease, again a prevalent disease, and it's quite unclear as to what the efficacy of this form of therapy is. I'm very keen to see the carrying out of the next protocol in the other group, which will deal with the use of magnesium sulfate in the prevention of noise induced hearing loss. As you know, there are 10 million people in the United States that have noise induced hearing loss. And there are another 20 million that are exposed to hazardous noise in the work place. And so this is a problem of enormous magnitude. About three years ago, an Israeli study was done of Israeli army recruits who were given magnesium sulfate during the period of time that they were in basic training. And those that received the magnesium solution did not develop as much noise induced hearing loss as those who did not receive it. We are very anxious to replicate that study to see whether it can be corroborated or not. That, of course, involves impulse noise and we need to determine whether magnesium solutions can prevent noise induced hearing loss of the impulse type. And then the next step would be to move on into the industrial kind of noise where it is more continuous due to machinery. vaccine for otitis media Mr. Porter. Dr. Snow, we've heard for a number of years about a vaccine for otitis media. Are there multiple types of bacterial pathogens responsible for otitis media, each of which requires its own vaccine? Dr. Snow. Yes, there are. The three principal organisms are the pneumococcus, the non-typeable Haemophilus influenzae, and the Moraxella catarrhalis. More progress has been made in the pneumococcal vaccines. In order for these vaccines to be useful in otitis media, they have to produce the immune response during the first few months of life, just like with the hemophilus influenza type B vaccine, which is given to prevent meningitis, and is given during the first month of life, and then there are booster doses at three and subsequent months. We need the same sort of vaccines for otitis media. And in the case of the pneumococcus, the same strategy that was used in the Haemophilus influenzae type B vaccine, that is to conjugate the polysaccharide coating of the organism with a protein led to immunogenicity early in life, in the first month of life. We need to do the same thing. Well, the pneumococcal vaccines are now in a stage 2 trial. And so that's going very well. We now have the non-typeable Haemophilus influenzae vaccine which is ready for the stage 1 trial: if it is found to be safe in adults, then we will move on to a stage 2 trial that will very likely be conducted by a pharmaceutical company that manufactures vaccine. Our work will probably stop at that time, and we will turn it over to the appropriate vaccine manufacturer. We are just starting the same process with the M. catarrhalis and carrying out a similar strategy of conjugating the polysaccharide that is the endotoxin of the organism with a protein and then seeing if it produces immunogenicity. Mr. Porter. Assuming you are successful in that, will there ever be a vaccine that handles all three different types? Dr. Snow. Yes. Probably the three vaccines will be combined in a single injection, and so just as youngsters receive their immunization against Haemophilus influenzae type B meningitis, they will also receive their immunization against otitis media at that time. specific language impairment Mr. Porter. I was not familiar with the condition called specific language impairment, SLI, in which children have unexpected and unexplained difficulties learning and using spoken language. Is this thought to be a single condition or a family of disorders? Dr. Snow. I believe it is best looked at as a family of disorders. One of the early epidemiologic studies that we did through a contract was to determine the prevalence of specific language impairment in children. And we, as the whole scientific community, were shocked to learn that 8.36 percent of the population has this disorder. And these youngsters have difficulty, academic difficulty, difficulty reading, they often speak late, and develop speech relatively late in childhood. And this turns out to be a lifelong problem for these individuals. This encompasses all of those who are spoken of as having dyslexia, and yes, there are receptive forms of this, there is the motoric form of it, the expressive form of it. But there are commonalities among these children that make it reasonable to lump them together for certain purposes. And now that the incidence or prevalence of this is known, we are now pursuing the molecular genetics of this problem. Mr. Porter. And this could be severe enough to require them to be placed in special education classes? Dr. Snow. Yes. There is variation from mild learning disability to very severe learning disability. Mr. Porter. Dr. Snow, you've answered all of our questions very forthrightly and candidly. We thank you for the wonderful job you're doing at NIDCD and thank you for coming before us to testify today. Dr. Snow. Thank you very much, sir. Mr. Porter. Thank you, Dr. Varmus. We stand in recess until next Tuesday at 10:00 a.m. [The following questions were submitted to be answered for the record.] [Pages 821 - 863--The official Committee record contains additional material here.] Tuesday, March 4, 1997. NATIONAL HEART, LUNG AND BLOOD INSTITUTE WITNESSES DR. CLAUDE LENFANT, DIRECTOR, NATIONAL HEART, LUNG AND BLOOD INSTITUTE DR. CARL ROTH, ASSOCIATE DIRECTOR FOR SCIENTIFIC PROGRAM OPERATIONS JAMES WEHLING, FINANCIAL MANAGEMENT OFFICER SHEILA MERRITT, EXECUTIVE OFFICER DR. HAROLD VARMUS, DIRECTOR, NATIONAL INSTITUTES OF HEALTH DENNIS P. WILLIAMS, DEPUTY ASSISTANT SECRETARY, BUDGET, DEPARTMENT OF HEALTH AND HUMAN SERVICES Introduction of Witnesses Mr. Porter. The subcommittee will come to order. This morning we will hear from the National Heart, Lung, and Blood Institute. We're very pleased to welcome the Director, Dr. Claude Lenfant. And if you would introduce the people who are with you, Dr. Lenfant, and proceed with your statement, please. Dr. Lenfant. Thank you, Mr. Chairman. On my far left is Sheila Merritt, who is the Executive Officer of the Institute; Mr. Wehling, with the Budget Office of the Institute. On my right is Dr. Roth, the Associate Director for Scientific Programs of the Institute; and of course, Dr. Varmus. Opening Statement And I'm very, very pleased to be here today, Mr. Chairman, to present the 1998 budget of the Institute. It's especially meaningful to us because 1998 will be the year that the Institute will celebrate its 50 anniversary. As we look back on what has been accomplished during the last 50 years, we see considerable progress. For example, when the Institute was created in 1948 under the name of the National Heart Institute, the country was experiencing an epidemic of heart disease, of which heart attack, coronary heart disease was the most common. If we adjust for the aging of the American population, the death rates that existed at that time have been reduced by more than half during that period of time. A very recent study has shown that the decline in the death rate can be accounted for 25 percent from primary prevention, that is preventing people from developing heart disease, and 75 percent from improved treatment. The net result of all that is that coronary heart disease which was50 years ago a very acute condition, from which most people would die very quickly, has become a rather chronic condition which today affects between 12 and 14 million Americans. The good news of all that is that we clearly have added years to the life of the American people. As we look at the years which are ahead of us, we see many researchers with new ideas, new directions which, if successful, will continue to improve the life of patients, and new treatments will certainly be developed. imaging technology One of the questions that is most important is: Can we prevent further this coronary heart disease? And last week, Dr. Varmus mentioned to you the advance of new technology, new imaging technology, and in the next few minutes I would like to tell you how these technologies are going to help us to, in effect, help to prevent more of these diseases. On your right side, what you see here is the conventional angiogram, which is an invasive procedure that requires cutting up the skin, opening up a blood vessel, introducing a catheter up to the heart, injecting dye and exposing the patient to x- ray. On your left side, you see a magnetic resonance imaging angiogram, which is non-invasive. Basically, it takes the patient into a magnet and that's what you get. [See figure]. [Page 867--The official Committee record contains additional material here.] Let me spend a minute to show you what we see here. Those two circles are the aortic valve, which keeps the blood from returning into the heart after it has been ejected by the heart into the aorta. On both sides, you see coronary arteries, this one here which originates from the aorta, and this one, which is the one that is most often obstructed in the case of coronary heart disease. The point I would like to make is that this very small vessel that you see here has a diameter which is approximately half a millimeter, and so that you visualize what half a millimeter is, I would like you to see the piece of pencil lead that I have attached to the picture in front of you. That is what half a millimeter is. And that is what you can see with this technique. The beauty of course is that if, through this process, using this technology, we can see abnormalities inside the arteries, then we can act upon them and basically do something before the development of overt disease. The advantage of such technology is that it can be repeated without any danger as many times as one would want. One thing that I should tell you is that conventional angiogram is a procedure that costs approximately between $6,000 and $8,000. This one here is in the order of less than $1,000, and that's what it costs today. I would expect the devices would be further developed and the technique itself would be further developed, it would cost much less than that. So basically, I think that we have amazing opportunities to help in the prevention of this disease by basically detecting abnormalities in the arteries before the development of symptoms and clinical problems. And the opportunity therefore to do something about them. lung and blood diseases So far I have talked exclusively about heart disease. But in the late 1960s or early 1970s, the Institute changed from the Heart Institute to the Heart, Lung and Blood Institute. I would be remiss not to underscore that the research programs of the Institute in lung diseases, such as for example asthma, or the pulmonary complications of cystic fibrosis and research on blood diseases, have been just as successful. For example, 20 years ago, most patients with cystic fibrosis died from the pulmonary complications that developed. They would die in their teens or early 20s. Today, the same patients live to their 40s and 50s. They have jobs, they have families and although they have to take care of themselves on a daily basis, they can really enjoy life. With regard to asthma, let me remind you that three of the gold winners that we had at the Olympics last year were asthmatic patients. Twenty years ago, it is not certain that their condition would have been properly diagnosed. In addition, if it had been diagnosed, the treatments that are available today were not available then. Regarding blood diseases, I would like to mention that 25 years ago, the Congress enacted the Sickle Cell Disease Control Act. Then, many patients with sickle cell disease died in their second or so decade of life, after a life of suffering. Today, these patients live later with much less suffering. So to conclude my remarks, I would like to say that as we reach 50 years of age, and after 50 years of investment by the American people, you can point to remarkable public health benefits with regard to heart, lung, and blood diseases. And I should say, in the future, maybe the next 50 years, I believe the potential of the research that we're undertaking will bring about results which I believe will eclipse the accomplishments of the past. I will be pleased to answer questions, Mr. Chairman. [The prepared statement follows:] [Pages 870 - 872--The official Committee record contains additional material here.] imaging technology Mr. Porter. Dr. Lenfant, thank you very much for your statement. We very definitely congratulate you on 50 years of great progress. We want, obviously, that progress to continue. Is 2.4 percent for the next fiscal year going to allow that progress to continue? Dr. Lenfant. Well, it will allow some to continue. Maybe not as much as one could do with more, but we will be able to undertake very significant, useful and important projects. Mr. Porter. You're a good soldier. Let me say preliminarily that when we looked at the schedule of hearings for the Institutes, I decided that we had them much too compacted and wanted to provide a little extra time. This morning, since there are no recorded votes scheduled for the floor of the House, our members are not probably in town, with the exception of Mr. Bonilla and Mr. Miller. Mr. Miller we expect later on, but if he does not arrive in time, I have received from him some questions that he wants me to ask you. And I will ask those as well. Let me also apologize for the condition of my voice, which is the result of having a very bad cold. And let me ask about MRI as opposed to a conventional angiogram. Can you use MRI to tell the degree of clogging of arteries just as well as you can use an angiogram? Dr. Lenfant. Yes, indeed. The picture that I showed you here is from a normal person. But as you can see, if you look at the smaller vessels at the bottom of the yellow rectangle, or even much higher, you could detect irregularity on the line that separates, if you want, the vessels from what is next to it. And that would be an indication of the development of abnormalities in the arteries. That can be seen, and there are also some examples which I didn't bring where you can see very clearly the beginning of an obstructive process of these arteries. Mr. Porter. And would a physician go directly from an MRI angiogram that showed clogging to an operation, a heart bypass, let's say, or would they perform a conventional angiogram following up on it? Dr. Lenfant. One thing I would like to say, Mr. Chairman, is that the conventional angiogram, the invasive procedure, is a diagnostic tool. The other one, the MRI, assumes that you have patients, somebody who is part of a family where there is a history of heart attack, where you know that this person has elevated blood cholesterol, but yet does not do anything, because an elevated blood cholesterol is a little bit too abstract. A physician might say, well, let me see if there are some abnormalities which are developing in your arteries, and that is before the occurrence of symptoms. And that is the beauty of it, to find the abnormalities in these arteries. And to show a picture to the patient would be much more convincing than just the result of a blood cholesterol test. And we believe, and there is some evidence, actually, that people would respond to that. Because that's something that they see inside themselves. One thing I should underscore is that these little arteries that you see there, the smallest ones, are basically three or four inches below your skin. So it's quite remarkable what we see there. Mr. Porter. So it could tell you that you don't have clogged arteries, and you would end your investigation of that as a problem. But if it told you that you did have clogged arteries, you might then go to see the extent of how they're clogged? Dr. Lenfant. No, I don't think you would go. You would initiate a medical treatment for this patient, telling this patient to check their blood pressure, if that's the case, if this patient has an increased blood cholesterol, it would be a much more convincing argument for that patient to do something about that elevated cholesterol than just if you see a number on a piece of paper. Mr. Porter. I guess my real question is, is MRI imaging going to replace conventional angiograms completely? Dr. Lenfant. It might. It might also become a diagnostic tool, that is correct. And in this case, it would be much cheaper. But again, the conventional angiogram today is used exclusively as a diagnostic tool. You have a patient who comes to you and says, I have chest pain, I have this, I have that, and the physical examination reveals that this person is a likely candidate for coronary heart disease, and you want to confirm it, to set up a treatment which is a very serious treatment, such as, for example, angioplasty or coronary bypass. And that's what you would do. The other one, we see that as a tool of the future to basically try to detect abnormalities before the occurrence of clinical symptoms. And if that works, and we do believe that it will work, basically what you can say is that the development of an overt disease is no longer inevitable. You can do something before it becomes overt. in utero bone marrow transplantation Mr. Porter. Last December, the New England Journal of Medicine reported what sounded like an extraordinary finding, that a bone marrow transplant had been done in utero to successfully treat severe immunodeficiency disease. Does this research present the possibility of a new form of treatment for other diseases, like Cooley's anemia? Dr. Lenfant. The answer is yes. Yes, it offers that opportunity. I think there is much more work that needs to be done before it is done. But the potential exists. In fact, almost any, or many genetic diseases could be corrected that way. Mr. Porter. Does this in utero transplant bypass some of the difficulties that have been encountered in transplants after birth? Dr. Lenfant. Yes, yes. In fact, the paper that you refer to, was a story of a woman who had two children. The first one died with that inherited immunodeficiency which is, I should say, very rare. And the first child received a bone marrow transplantation after birth. But that was not successful, and eventually the child died. And the new pregnancy was a child with the same disease, that was diagnosed in utero, and that's what led to the treatment, the in utero transplantation. The reason is that during fetal life, the immune system is not developed or not as developed, and therefore you know, you do not have the problem that you would have after birth dealing with immune reaction to bone marrow if you don't have a perfect match. gene therapy Mr. Porter. Last August, a Tufts University research team reported the successful treatment of gangrene through gene therapy. A gene that codes for vascular growth was coated onto an angioplasty balloon, which was inserted into an artery to stimulate the growth of new blood vessels and restore blood flow. Could this type of procedure some day be a less invasive alternative to heart bypass surgery? Dr. Lenfant. Yes. In fact, in our laboratories on the campus of the National Institutes of Health, we do have a protocol which is studying this very question. That is, to insert this growth factor in the coronary arteries and see if we can elicit the sprouting of new blood vessels. The case that you report is quite interesting. And not all of its aspects would be applicable to what you could do in the coronary arteries, owing in great part to the size of the arteries, and things of that sort. But eventually, you can conceive that it would become possible. Mr. Porter. Are there other examples of successful gene therapy? Dr. Lenfant. To my knowledge, I think that is the only case which is successful. I think one of the reasons for it is the following, that this gene, the naked DNA, if you want, can go directly into the smooth muscle cells which surround the arteries. These particles of DNA, the naked DNA, go directly into the smooth muscle cells. And that has greatly facilitated the issue of the transplant insertion of that gene into the cells. In other areas, the issue of vector is one which is often hampering the gene therapy. cell death Mr. Porter. Your research on congestive heart failure is targeted to stopping cell death and generating cell growth. This seems similar in many ways to the strategies being pursued in other diseases, like neurological disorders, spinal cord injury and stroke. Is it likely that lessons learned with heart tissue would be transferrable to these other disorders or vice versa? Dr. Lenfant. I think it's going to work both ways. Apoptosis, which is the cell death process, we learned about it relatively recently. The process and what triggers it is being investigated in many cell systems. I think that what we learn from the heart would be applicable to the other systems and conversely. In the old days, we saw cell death being caused by necrosis, that is, the matter that was around the cells would be altered for some reason. And that would lead to the cell death. The deaths occurred from alteration, from the nucleus, for example, inside the cells. But it's an entirely different process. And there is a lot of work which is going on to try to understand the differences which lead to it. asthma Mr. Porter. Your statement mentioned the findings reported in Science magazine in January that asthma prevalence may be increasing because of the lack of exposure to respiratory infections. Children in Eastern Bloc countries are much more likely than children in the West to contract these infections, and paradoxically, seem to be protected against asthma. How can these findings be used to develop asthma treatments for children who have not grown up with the disadvantage of frequent respiratory infections? Dr. Lenfant. This is a very interesting issue which has really become apparent during the last few years. Because a few publications have occurred in various journals, showing that indeed, an infection in the early age of individuals modifies or alters the immune system in such a way that later in life it would offer prevention against exposure to allergens. And the mechanism is really not fully understood. And actually our Institute, at this very moment, is preparing the initiation of a program to explore these mechanisms so that we can understand it. You are making a reference to the East European countries. In fact, this argument can be taken to other parts of the world. There are many developing countries such as New Guinea, for example, where they have very high prevalence of acute respiratory infection in the early months of life. And in fact, it's responsible for the deaths of many of these children. But there, although there is considerable exposure to pollutants, since they are living in huts and so forth, the prevalence of asthma is very low. And for years, epidemiologists, as well as asthma experts were wondering, how could that be, with the same level of exposure in the United States or developed countries, we would have a very high prevalence of asthma, but not there. And these publications, which have occurred, and these studies which have been reported during the last few months, shed an explanation which needs to be pursued quite actively. sleep disorders and melatonin Mr. Porter. Dr. Lenfant, melatonin seems to be widely extolled in the popular press as a therapy for sleep disorders. Yet the National Sleep Foundation commissioned a paper which concluded that the use of melatonin cannot be justified for any sleep disorder at this time, since neither the therapeutic nor potential toxic effects of prolonged use have been documented. Do you agree with this assessment of the current scientific data? Do you think melatonin should be categorized as a drug rather than a food supplement and regulated by the FDA? Dr. Lenfant. The question is difficult for me to answer at this time. All I can say is that there is no question that the use of melatonin, based on public consumption, raises hopes that it will do wonders without too much evidence. If used for pharmacological purposes, if that becomes the case, I would think so. We are beginning to believe that it suppresses the perception of light, meaning that when melatonin increases in our system, then weunderstand that it's time to sleep, and vice versa. Now, if the melatonin is used pharmacologically and taken freely, I think that it may certainly have some adverse effects which in this case could be controlled by way of calling melatonin a medication. Mr. Porter. Is the Sleep Disorder Center within your Institute supporting any research on melatonin? Dr. Lenfant. Not at this time. But we are in the process of supporting a very significant program on the molecular biology of circadian rhythms. And in effect, melatonin is very closely tied to a study on this, and I think it's become incorporated to this line of work. Mr. Porter. Thank you, Dr. Lenfant. Mr. Bonilla. stroke research Mr. Bonilla. It is nice to see you again, Dr. Lenfant. I'd like to start out by asking you something about a study that was just released in the last 30 days about dealing with strokes and the ability to pump blood in reverse to the brain through the veins. I suppose this technique is to quickly reverse the negative impact and paralyzation or the after effects. It seems to be a profound way of dealing with stroke. And I'm wondering if this is going to be more widely used or what is the status? Dr. Lenfant. I don't know if it's going to be widely used. What I would like to say before commenting on your question on that issue is that this approach is something that has been taken from cardiology. Years ago, when a patient had a heart attack, in some centers, these heart attacks were treated by what we call retrograde perfusion, that is, a catheter was put into the venous side and blood or liquid with anticoagulant was forced against the normal current, if you want, into these vessels, in order to push back whatever the obstruction was. In the heart, it has been found to be not, or it has been found to be a fairly complex procedure. In the brain, when you have stroke, I don't know if it will be developed in such a way that it could be used everywhere. In specialized centers, yes. Having said that, the usefulness of this approach cannot be denied. Any way that a physician has to take to the clot, if you want, an anticoagulant or something which is going to destroy the clot, would be of tremendous benefit to these patients. The advantage of doing it this way is that not only are you putting in a drug which is going to eliminate the clot, the blood clot, but also you can push it out which you could not do if you were doing the same thing on the artery side. Because the clot would have to go through very, very small vessels and it wouldn't be possible to push it out that way. Mr. Bonilla. I heard that the recovery is remarkable in these cases where they actually pump the blood in reverse back into the brain. And if it's done within a short period of time, it's almost as though nothing had happened. In the past, these patients were oftentimes never able to use the left side of their body, or speak, or whatever the side effects would be. Dr. Lenfant. The great issue with stroke, Mr. Bonilla, is that there is a diagnosis that needs to be done before you start the treatment. There are two types of stroke, one which is an obstructive stroke, like what we are talking about, and another one which is due to a vessel being ruptured and the blood leaking out into the brain and causing the same kind of damage as if the blood does not go through. And of course, in the latter case, knowing what we are talking about would considerably worsen the condition of the patient instead of improving it. And that brings me back to the MRI. One of the best ways that we have today to diagnose between an obstructive and an hemorrhagic stroke, is to do magnetic resonance imaging of the skull, of the brain. genetic predisposition Mr. Bonilla. And don't forget, Dr. Varmus, I remember, no imaging institute. I remember that. Moving to a different area now, Dr. Lenfant, it's just something we discussed before---- Dr. Lenfant. I was here, I remember the question. [Laughter.] Mr. Bonilla. I understand that the NHLBI has found the approximate location of three stroke related genes. I know the Chairman touched on genetic research a moment ago. Would you tell the subcommittee about this progress and what it means for stroke detection, prevention and rehabilitation? Dr. Lenfant. Well, I think, if I understand your question, there are two approaches which are under study now. The first one is to identify the genes which are determinant factors for high blood pressure, which is the number one cause of stroke. The second is that we do know today, and that has been found through genetic studies, we do know today that individuals susceptible to complications of high blood pressure, whereas other people can have high blood pressure for many years and not develop any of the complications. And indeed, this genetic susceptibility to one of the complications such as stroke has been found in animals, not yet in human beings. And that is an avenue of research which is extraordinarily exciting, actually. Because it's true for stroke, it's true for congestive heart failure. It's true for kidney failure, which are all three being consequences of high blood pressure. And I should say, the same thing is true for cancer. It's true for chronic lung disease. You have people who smoke all their life, for 50 years, 60 years, and never develop any disease. But somebody else does, very quickly. And that is in fact caused by this genetic susceptibility, which we are talking about here. Mr. Bonilla. Someone just used the example last week about Deng Zao Peng, and how he had a cigarette in his hand all his life, and seemed to live a pretty full and prosperous life. I think he was 92 when he died. So we can see how your genes affect--how you're predisposed to a great degree. If someone is predisposed, though, for example, to have a stroke, and you could determine that through genetic research, how much can good diet, exercise and doing all the right things change that? Is there a figure you could put on it, like if you're predisposed to have a stroke and your chances are, let's say, 40 percent, can you cut that back to 20 percent? Dr. Lenfant. Well, before you came in, I was telling the Chairman that the death rate from coronary heart disease and heart attack has been reduced by more than 50 percent during the last 50 years, actually, since the Institute has been created. And that it has been reported out from various studies just recently that 25 percent, a quarter of this decline in death rate, is due to prevention of the development of coronary heart disease, and 75 percent is dueto better treatment. Now, that 25 percent, that's what we are talking about, you see, it's better lifestyles, it's not smoking, it's keeping the cholesterol low and appropriate diet and so forth. latino outreach program Mr. Bonilla. Let me ask now about your Latino community outreach program, Dr. Lenfant, because as you know, heart conditions are prevalent in every ethnic group, but because of the diabetic factor among Hispanics, it's an additional increase in risk that they suffer. Can you tell me about the program to reach out to the Latino community and how that's working? Dr. Lenfant. Yes. We, first of all, our Institute and of course our sister Institute for Diabetes and Digestive Diseases, are supporting very substantial research on diabetes, which is indeed a risk factor of heart disease. Diabetes, for a reason which is not clearly or fully understood, is more prevalent in the Hispanic Americans than people from other ethnicity. The way we address that, besides the research, is to have community outreach and to be able to communicate to the communities what needs to be done to minimize the risk of diabetes developing and coronary and heart disease. We have a model program here in Washington, actually, which we are pursuing with the Hispanic community that involves community leaders as well as church leaders and so far, it has been fairly effective. One of the biggest problems that we have with this community outreach is really, there are two problems. The first one is, what message do you give, and second, who gives the message. And it is true for Hispanics, it is true for African- Americans. The message must be culturally sensitive to the needs of that community. It must not be, you know, turn your life upside down. We have to adapt what we want to say and communicate to the way of life of the community in question. And the second thing is that it is very important to have a member of the community to go and deliver the message. That's why we are working with the community leaders here in Washington and in Texas where we have several activities, to communicate these messages. Mr. Bonilla. Just a comment on that subject, because I think in minority communities, churches are often the most influential entities within the community. If you could somehow channel those programs through those organizations, I think they somehow are more effective and listened to more carefully by people in those communities. Thank you, Dr. Lenfant. sickle cell disease advances Mr. Porter. Thank you, Mr. Bonilla. Mr. Stokes, as a ranking member on another subcommittee, has requested that he be taken out of order so that he can return to his other assignment. And the Chair recognizes Mr. Stokes. Mr. Stokes. Thank you very much, Mr. Chairman. Thank you, Ms. DeLauro. Appreciate it also from you. Dr. Lenfant, it's always a pleasure to welcome you back before our subcommittee. Dr. Lenfant, as you know, this year marks the 25th anniversary of the National Sickle Cell Disease Control Act. What has been the most significant progress the Institute has made in sickle cell research and treatment over this quarter of a century? Dr. Lenfant. Well, there is more than one, Mr. Stokes. As I hear your question, I am reminded that I have appeared before you some 15 times. And each year, you say, well, what have you done since last year. And when I give you an answer, you say, but you already told me that last year. If you ask me over a span of 25 years, I think there are lots of very important things which can be said. The first one, as I mentioned in my opening comments, is that 25 years ago, patients with sickle cells disease, many patients with sickle cell disease, were dying in their teens. Today the same patients live to their fourth or fifth decade or even later. When they were dying in their teens, they were dying after years of suffering. For many of these patients, that suffering has been alleviated, so that in effect they can have an active life and participate in the community. Now, the most significant achievements have been, number one, to realize that the treatment of patients with sickle cell disease must not be fragmented, must not be when somebody has a crisis, but it must be a continuous treatment. And that is the result of the Comprehensive Sickle Disease Centers that we have had. The second thing that has been established during this period is the development of the prenatal diagnosis of the disease. Now, the prenatal diagnosis of the disease has led subsequently to the prophylactic treatment of many of these infants who, as you know, develop pulmonary infection and in fact, approximately 30 years, 25 years ago, the newborn infant with sickle cell disease could die from that pulmonary complication. That is no longer the case. Now we know how to treat this, and they survive. And we know that we can stop the treatment when they are five or six years of age. In addition, because of that, the legislature I believe for 42 or 43 states has passed legislation requiring that prenatal diagnosis of sickle cell disease. Another advance, which I reported to you some years ago, is that the hydroxyurea, which is basically the first effective treatment of pain crisis in these patients with sickle cell disease, and that has been controlled quite effectively. And then the last thing that I would like to mention, which is work which is now ongoing, is treating these patients with bone marrow transplantation, and of course the prospect that successful gene therapy will have in the years to come. So I think a lot has been accomplished on sickle cell disease. Mr. Stokes. I appreciate very much the type of improvement and progress that has been made, as you have referenced here this morning. But ultimately, we must be talking, hopefully, about a cure. How far, Doctor, are we from being able to arrive at a cure? Dr. Lenfant. Well, there is one cure for which we have great hope. But not all sickle cell patients will be eligible. And that is bone marrow transplantation. Bone marrow transplantation has been used relatively rarely in children with sickle cell disease. I believe that today, only 30 or maybe 40 children have received a bone marrow transplantation. What is remarkable about it is that 92 percent of these children, basically 35 or so, are now cured of their sickle cell disease and have had no difficulties. And in the others, the treatment has not been successful. But when it is successful, it seems to result in long-term treatment. The second treatment that is being investigated by ourprojects is that of gene therapy. And there is very significant work which is ongoing on two avenues. The first one is to, if you want, modify the abnormal mutations that exists in the gene. And the second is to find vectors which would permit the implant of normal genes in these patients. cardiovascular disease in minorities Mr. Stokes. Thank you. Doctor, let me ask you this. I happen, here in the Congress, to be a co-chairman of the Congressional Heart and Stroke Coalition, a coalition between members of the House and the Senate. And this coalition is very concerned about the impact of cardiovascular disease on families across the Nation. I understand that cardiovascular diseases cause a death every 33 seconds in the United States. And so it's rather shattering to think that in the span of the time I pose a question to you and the time that you respond to that question, more than three people could conceivably die from cardiovascular disease. According to the World Health Organization, heart disease is projected to replace pneumonia as the leading disease cause of premature death and disability worldwide by the year 2020. Let me zero in on an area already touched upon by Mr. Bonilla, who articulated some concerns in this same area. And I have some similar concerns. What is the extent, Doctor, of cardiovascular diseases among African-Americans, Hispanics and other minorities, and is the onset of the disease earlier than that of the general population? Dr. Lenfant. In African-Americans, the prevalence of heart disease is a little bit higher than in Americans of European descent. Among Hispanics, however, although it is high, it is a little bit lower. And the risk factors are very different between the two populations. Among Hispanics, it is predominantly diabetes that is the most important risk factor. In African-Americans, the risk factor, the dominant risk factor is high blood pressure and also elevated cholesterol. In the Institute and elsewhere, there is considerable work which is done to determine these risk factors, as I mentioned, when I talked about Hispanics. With African-Americans, the same kind of program is being developed. But there I have to say that we are a little bit ahead of what we do with Hispanic Americans, because we have been working on that for a longer period of time. One thing that we have, and which I will say we are very, very proud, we have developed a physician network. Basically it's working with the National Medical Association and with the Association of Black Cardiologists to enroll them in this effort of prevention and treatment in the community. And we hope that it will give us the opportunity to make very significant headway. Mr. Stokes. Thank you. Thank you, Mr. Chairman. Mr. Porter. Thank you, Mr. Stokes. Ms. DeLauro. cooley's anemia Ms. DeLauro. Thank you, Mr. Chairman. Dr. Lenfant, pleasure to see you here today. And I'm glad to see you after my hiatus. It's good to be here. Let me ask several questions. First, last September, the Institute convened a special emphasis panel that looked at new therapies for Cooley's anemia. Let me just, from my point of view, Cooley's anemia disproportionately affects individuals of Mediterranean heritage, particularly Italian-Americans, so I was happy to see the Institute express an interest in the disease. The panel recommended that the NHLBI establish a network of collaborative clinical centers to address interventions, clinical interventions to the illness. I know that the Institute has had success in establishing these centers in the areas of heart disease, asthma, and other diseases. The recommendation of the panel to address Cooley's anemia, how has that been implemented at the Institute? Dr. Lenfant. Well, the recommendations of the group, to be very honest, were a little bit of a surprise to us. Let me explain why. You mentioned clinical networks and centers, a network of centers for asthma or sickle cell disease, for example. It is difficult to do that. Because asthma, for example, there are 12 million people with asthma in this country. So any center somewhere in the country has a large group of such patients. For Cooley's anemia, there are only 1,000 or 1,200 patients in the United States. And they are scattered all over the country. There is admittedly a prevalence, a high prevalence in New York. But they are really scattered all over the place. And for that reason, it makes it difficult, not to say impossible, to develop a network. So what can we do instead? We are prepared to work with the institutions and the medical centers where they have a substantial population, so that within that population studies can be conducted. And we have done that in the past, very successfully, looking at the iron chelator, for example, which has been and is still one of the most significant treatments for the disease. So we are still, this group met about two or three months ago, and we are still looking at what they have recommended. Whether it will be possible to implement it or not, I cannot tell at this time. Ms. DeLauro. So what you're going to take a look at are population centers where this is more common? Dr. Lenfant. Yes. Ms. DeLauro. Is there any sense of a time frame? For instance, is there something that can be done, and I would rely on you for the information, in the northeast for example, the tri-state region of New York, New Jersey. You've got the statistics. Are there places where the networks can be established in these particular places, rather than your point about asthma, which is where there's 12 million people. Dr. Lenfant. There is in the tri-state, which I assume is New York, Connecticut and New Jersey, a high prevalence of patients with Cooley's anemia. Our intention is to work with the people there who are doing this research and see what needs to be done. One thing, though, that I should point out, is that at the present time, unfortunately, there is no new treatment which is being developed. And therefore, you would want to have a network of centers to test something, try out the new procedures or what have you, if the procedure or new treatment exists, but at the present time, these patients are still treated with blood transfusion, iron chelators and that's where we are at this time. There are some, you may have heard that there is some discussion and some ideas which are emerging that perhapshormonal treatment may be of some value in these patients. At the present time, we really don't have enough with that to go ahead with the implementation of a network, which is what was recommended in this report. Ms. DeLauro. That doesn't give me a sense of real hope here for at least the immediate future, Dr. Lenfant, of pursuing this. And I don't mean that in a disparaging way. It just seems that it's a small population, and there's no new work or information about potential treatment. And I understand it's a small population, but these are---- Dr. Lenfant. Well, I don't want my comments to be perceived that because it's a small population, it is being ignored or neglected, not by a long shot. In fact, I would say that proportionately, we have a very significant program of research on this disease. What I am really saying is that to create a center, a network of centers, we want to maximize use because it costs lots of money, where there is a network like this one. And unless we have something that we can feed to this network to do, there is really no point at this time for the network. Ms. DeLauro. I understand. I would just comment that if there is a way to, as I said, not as expansive as what may have been recommended in terms of a network, but some way in which a network can be tailored to what the size of the population is, that some thought with regard to that area, to begin to scale, if you will, the recommendation to the need. Dr. Lenfant. I can tell you, and you have a commitment on my part, any recommendation which can be implemented, we will do it. There is no question about that. Here I am basically, well, the question is how to do it, not whether we are going to do it. Ms. DeLauro. I understand that as well, and how in terms of a timely fashion to be moving. I know you have lots of other priorities. Dr. Lenfant. That one is very important, basically for two reasons. First of all is that, while it is a small population, it is one that we are very concerned about. Also, we know that what we can learn from the disease will be applicable to many other conditions. And vice versa. smoking among youth Ms. DeLauro. I understand that recently the Institute supported a lung health study that examined effects that stopping smoking has on lungs. As I've said on this committee before, I'm a strong advocate of people stopping smoking, particularly our young people. I have instituted a program in my district called the Kick Butts Connecticut campaign to get youngsters in middle school to have an impact on their younger peers in terms of not starting to smoke at all. Did your study examine the effects of smoke on youth and their lungs, and if so, what kind of results did you obtain? If not, are you doing anything in regard to this area that targets youth and smoking? Dr. Lenfant. Yes. The answer is yes to both questions. The population that was looked at for this particular study, which incidentally I should say, to my knowledge is the largest epidemiological study on the effects of smoking and smoking cessation in the United States, in men, women, African- Americans and Caucasians. It has been a huge study. And in fact, it's being continued now through research grants. And the results which we found are really applicable to everybody, irrespective of age or job. That is, the benefits of smoking cessation and the goal of the study is for us not only to look at the benefits of the smoking cessation but also to have a program whereby the cessation would last. The big problem with smoking cessation is that people return to smoking very quickly. In this particular study, which is now, I think it started close to eight or nine years ago, the number of, well, it's-- the second phase started in 1993. So therefore, I would assume that the first phase probably started in 1989 or 1988, close to nine years ago. The number of individuals that stopped smoking is still very high, something like 85 percent. And that is not a modest success. Now, because of that, actually, the Institute now is moving into a new activity, which is a lung health educational program, in order to disseminate to a larger group or community what we have learned from that study. And many investigators in the country are getting together to develop this program. And hopefully, working with the American Lung Association and all kinds of professional groups we will be able to disseminate the results from this lung health study. Mr. Porter. Thank you, Ms. DeLauro. I would remind members that we will have time for a second round. Mr. Wicker. preventing heart disease Mr. Wicker. Thank you very much, Mr. Chairman. And Dr. Lenfant, it's a pleasure to have you before the subcommittee. You discussed in your prepared testimony fixing the failing heart. And we've had several rounds of questions already concerning heart disease. Let me just say that I appreciate the work that you're doing. This is an area of vital concern to the Nation, but particularly to me. Because I represent the State of Mississippi, which leads the Nation in the rate of death from heart disease. And I want to ask you if you have any idea why that might be. In 1994, according to the CDC, and this is a fantastic figure to me, cardiovascular disease contributed to 46 percent of the deaths in my State, according to CDC. And 33 percent of the deaths under the age of 65. So I'm very, very much concerned about doing something about this. And that leads to my question concerning prevention versus treatment. In that regard, I want to bring to your attention a study that you're probably already familiar with from the Harvard School of Public Health. It appeared in the Journal of the American Medical Association recently. I cite an article from the Boston Globe in February of this year which says that, for all the talk about exercise and low fat diets, a new analysis finds that the most recent progress against heart disease has come from better management of existing disease rather than from prevention. And the figures given are that adopting healthier lifestyles accounted for only about 25 percent of our progress. Treatment, such as clot busting drugs for heart attacks and coronary bypass accounted for about 43 percent, and another 29 percent was saved by drugs to lower blood pressure or cholesterol. The article goes on to say that the study suggests that efforts to prevent cardiovascular disease need to be redoubled. But points out that many authorities worry that our biggest gains in the area of prevention have already been won. So with all of that information, I wonder if you could comment on these two different approaches to heart disease. Dr. Lenfant. Well, I'm very familiar with the study that you just mentioned. But I would like to disagree on the conclusion which is the statement that all that could be gained from prevention is now behind us. In fact, I think the prospects for more effective preventions are enormous. And that's what I was discussing at the beginning of this hearing. At the risk of being redundant, I may go through that again. What we have today is an approach to recognize that in people who have no symptoms, no other disease, no nothing, that they may have some alterations in their cardiovascular system which are not visible when you look at them, and they don't complain about anything. But problems are there. And if you can identify people that, you've got a problem and here it is, I can show it to you, then we have here a tool to change the approach of people to their own behavior and their own well being. Having said that, I would like to comment on what you have there, on this poster. On your right side, you have what we call the conventional angiogram, which is a diagnostic tool to really look at the heart arteries of people when they come to the physician complaining about chest pain and whatever. And so if the physician, after the physical examinations and having spoken to the patient, says, aha, that must be somebody who is developing heart disease, an angiogram will be done. Now, what you see on your right side, that is the conventional way to do it, which is an invasive way to do it. You have to cut the skin, open a vessel, push a catheter into the heart and all those things, which of course you cannot do very often. Now, what you have on the left side is a non- invasive angiogram. That is, basically all you do is to take a picture of the patient, like taking an x-ray if you want, you're putting, it's not behind a screen like an x-ray, but inside a magnet, that's what it is. And you can do that as many times as you want. There is no invasion, no skin cutting, no vessel opening, no putting dye into the patient. Therefore, it can be done as often as you want. And the idea here is that if you have somebody who has, say, a high blood cholesterol or a high blood pressure and you want to know if these indices have already caused some alterations in the arteries, you can do what you have here, a non-invasive angiogram, and see whether inside the small vessels, the smallest vessels, which are here, you see, at the bottom, have some alterations and may be the precursors of overt disease. And you can determine that and prevent the development of physically overt conditions. For that reason, I believe that this kind of technology is opening the door to further preventive interventions which in effect will be much more successful than looking at blood pressure or taking a blood cholesterol. Because most people, you tell them, well, you have elevated blood cholesterol or high blood pressure, they may be concerned, but they won't pay too much attention to it, because they don't feel it. However, if you take them inside their body, as we do here, and show them some alteration, they will pay attention to it. I mean, that's the way people are. Therefore, I think that the option, the opportunities for further prevention, not in everybody, not all the people in this country, but in selected cases, are really quite remarkable. Mr. Wicker. Well, getting back to that poster, what is the difference in the cost of both of these procedures? Dr. Lenfant. That is the thing. The invasive one is $6,000 to $8,000, it depends where you have it done. But that's what we are talking about. The non-invasive one that you have on your left here is in the order, is less than $1,000 today. But with the developments which are taking place in the kinds of instruments that are needed to do that, I would expect that in the future, the devices will be much cheaper than what they are today, and therefore, the examination will also be much cheaper. One thing that I would like to point out, again, the smallest vessels that you see here have a diameter which is half a millimeter, and half a millimeter, few people recognize what it is. On the poster which is in front of you, you can see a pencil lead which is stuck there with a piece of tape. And that lead is half a millimeter. So as you see, it is really seeing what is going on inside the individuals with a high level of sensitivity. cardiovascular disease in mississippi Mr. Wicker. Just a follow-up, you heard my statistics about my State. Dr. Lenfant. Yes. Mr. Wicker. Would you speculate? I realize it would probably lead to speculation, but what is it that would cause us to lead the Nation? Dr. Lenfant. We know in part what's going on in your State. Your State is part of what we call the stroke belt. There are nine States which are in the southeast of the United States, beginning with Virginia, Maryland, and going south and a little bit to the west where you are, where we know that the prevalence of coronary heart disease and stroke is highest in the country. And that's why, actually, we began a few years ago a program which is called the stroke belt, because there's a high prevalence of stroke there, in order to work with the local communities, civic leaders and religious leaders, to basically send a message to the communities of what needs to be done to reduce this risk. And I should tell you that if you are concerned with the numbers that you see today, and I don't know from what year are the numbers that you quoted--1994. But I can tell you that 10 years before that, they were much higher than what they are now. I can tell you that we have been very successful in reducing the death rate from stroke and heart disease in these States. Mr. Porter. Thank you, Mr. Wicker. Ms. Northup. black lung research Ms. Northup. Dr. Lenfant, let me direct this question to you. The Office of Workers Compensation Program has prepared new regulations that refer to black lung, and whether or not somebody qualifies for workers compensation. Apparently, it intended to make a lot more people qualify for black lung benefits or workers compensation benefits. This is at the Federal level. I believe I'm right that these definitions were tried in the 1970s and so many States and the Federal Government were swamped, everybody that had ever been in a mine, practically, qualified for these benefits. They were starting to sink the systems, and the Federal Government reduced them, every single State except Kentucky reduced them. Finally, Kentucky reduced its in December in an emergency special session. It's not just the benefits and the cost of the program. It's also the fact that we have a whole sectionof Kentucky of people that are on these benefits and can't go to work. They lose the benefits if they work, even though they're perfectly capable of working. We thought that when we changed this, this was actually a new governor, a governor that was from the mining area and had the support of the mine community. I guess I'm wondering if you have any research that would support these mining regulations, or do they just have political support? Dr. Lenfant. Most of the research on black lung is supported by the National Institute of Occupational Safety and Health, which is under the CDC. And I have to admit that I cannot comment on the basis of that regulation. I'm aware of them, but I am not aware of the reasons why these regulations were reactivated, so to speak, after a period of interruption. Ms. Northup. Can you go back and look, or do you know off hand, why NIH hasn't done any additional research in the last, recent years? Dr. Lenfant. No, and our Institute certainly does not do any research in this area. The other Institute which could possibly look at that would be the National Institute of Environmental Health Sciences. I would surmise that, it has got to be looked at, but I would surmise they probably do very little, because you have an Institute under the CDC whose responsibility is to do that. Ms. Northup. Okay. So you're sure that there's nothing that NIH has done? Dr. Lenfant. I'm sure for our Institute. Ms. Northup. Okay. That's all, Mr. Chairman. Mr. Porter. Thank you, Ms. Northup. Mr. Hoyer. allocating funds by formula Mr. Hoyer. Thank you, Mr. Chairman. Dr. Lenfant, I apologize for missing the bulk of your presentation. I'm the ranking member, as so many people on this committee are, on another subcommittee. It's very tough to make them both, obviously. But I wanted to come by, mainly to say hello and to congratulate you on the continuing excellence of the work that you do, and your leadership. Dr. Varmus, Dr. Lenfant has been, as you know, with us a long time. And I'm always intrigued by his presentations. I'm sorry I wasn't here earlier to learn about the diagnostic capabilities and the savings that are being effected. Doctor, one of the reasons I wanted to be here is that you head up the agency where, if you look to Medicare, I suppose, it's pretty close to the top in terms of consequential costs incurred. Therefore, if we use sort of formula based funding, relative to incidence, not just of old people, although I increasingly believe that old people now is a relative term starting at about 80. I have an 83 year old mother-in-law who wouldn't say that she's old at all, Mr. Chairman. But, in any event, your Institute would presumably be one of the beneficiaries of such a formula based funding. And because of your expertise both in terms of your particular discipline, but also in terms of your expertise in dealing with the internal discussions. I, of course, would not call it politics related to NIH, but the internal discussions at NIH relative to the allocation of resources. I would like your comment for the record now on the issue of the appropriateness of funding by incidence of or cost consequences of Medicare or some other yardstick of particular diseases as it relates to NIH. Dr. Lenfant. Let me answer that in a generic way, by saying that I suppose all of us are coming into this committee and all of us would say, we think any amount of money you can give us, go ahead and do it. The issue as I understand it, is whether this committee thinks we should get more than this one and so forth, irrespective of what the incidence and prevalence of the disease might be. And as I hear there are several ways to---- Mr. Hoyer. Doctor, as I understand the question, it is more pointed than that. You sort of stated the obverse. It's the reverse, I think, which is to say, it ought to be funded based upon the incidence as it writes the cost consequence to Medicare in the particular discussion. But I presume because Medicare deals with 65 and over, presumably you'd have a broader spectrum of dealing with children, and young adults, and middle aged, etc., so that you would take as a formula, a yardstick for funding, the incidence of the disease. As opposed, for instance, to AIDS, where the incidence of disease as it relates to heart is relatively minor in the United States, notwithstanding its consequences internationally. And the epidemic nature of it, I would use those two as examples; there are others, diabetes being one, that's focused on as well. Dr. Lenfant. I think that the incidence and prevalence of diseases are one factor, but they cannot be the only one. Because it also depends on whether you can do it, and I would say that at any one time, there may be opportunities which exist in one field, and you have to support these opportunities so that this field moves ahead. Because it can do it. In another area, your opportunities are different, or even the needs, the importance of the public health issues. Relative to our Institute, as I'm sure you know, the most important component of our Institute is that concerned with cardiovascular disease. It's approximately 60 percent or so of the Institute. And then we have 20 for the lung and 20 for the blood. To look at that 60 percent and say, why shouldn't it be 80, or why shouldn't it be 60 but in twice as big of an envelope, I consider that deceptive. Because in effect, there is research which is supported throughout the NIH. Earlier we were talking about diabetes, well, now that the Director of the diabetes institute is not here, but I would submit that whatever that Institute is spending on diabetes is in effect working for the cardiovascular diseases. Because of the close relationship between this condition and our diseases. And so the way I look at it, you see, is that to look just at the budget of our Institute and not see what is being done with regard to the entire establishment relative to cardiovascular diseases may lead to an erroneous interpretation. You may be interested to know that we consider that, of the whole budget of the Institute, our Institute, approximately $800 million is cardiovascular. But the fact of the matter is that if you look at the Diabetes Institute, the Aging Institute, neurology and what have you, NIH is spending approximately $1.2 billion on cardiovascular. Basically, there is 50 percent of the monies that are allocated to this disease category that do not come from our Institute. So if you look at that in relation to the incidence, look at my $800 million, you say, well, you know that is maybe not as much as it should be. But I think that we should look at the $1.2 billion. And that is significantly different. So, that's a very difficult question, which during the last two or three years has come up regularly during these hearings. My answer to that is that we, sure, everybody could use more money. But I don't think that that money must necessarily be allocated based on either of the incidence or the prevalence or the number of people who die from that condition. I think there are many other factors. And again, returning to how the diseases work. You know, as you heard, the decline that we have in death rates are due to, a quarter of the decline is due to primary prevention. And so we could say, well, we've got to increase primary prevention. And we all agree with that. But you see, primary prevention is not an activity where we have as many opportunities as we may have in another area. And so you know, to me it would be important to allocate money where more opportunities exist and more progress can be made. benefits from research Mr. Hoyer. Thank you, Doctor. With respect to your particular Institute, Doctor, remind me, when did you start as the Director of the Institute? Dr. Lenfant. I am in my 15th year. Mr. Hoyer. So you and I are on a parallel track; I think I started in this committee about 15 years ago. As it relates to when you started, you may have had a chart, and didn't repeat the information. Maybe we have it, but one of the things that, frankly, I'm a little better able, I think, this week to deal with is, my wife's illness; I thought of all the billions of dollars we had spent on cancer since the war on cancer started in the 1970s under President Nixon, and how, notwithstanding those incredible sums of money, it was still impossible, except in the very late stages, to diagnose. She had an MRI. In fact, the interesting thing is, she had a stint put in, because she became jaundiced on December 17th, and on December 19th, which was her birthday, they put a permanent stint in. I believe it was the MRI, but it may have been the CAT scan operator came back in preparation for that incident, and told Dr. Yo, the surgeon, ``I can't find the cancer''. Her stomach was replete with cancer at that time, and she died, of course, some 45 days later from the cancer. But one of the things you think about, and the Dental Institute always talks about, is that they get a relatively small sum of money and a big payoff in terms of the very sharp decrease in dental disease, particularly long-term, as you grow older. But also cavities and fluorides and obviously all those things. If you presented it, I'll just look at it. But for instance, we've spent so much money but that $1 invested has had a $10, or $20, or $40 payoff because of the decreased incidence, decreased loss of work, decreased loss of family support, and all those sorts of things that result from either very serious or terminal outcomes? Dr. Lenfant. Yes. I don't have this data here, but we could produce this kind of data. But you could also look at it the other way, you see. Earlier this morning I explained, and reported to the Chairman that in 1998, we are going to be 50 years old, the Institute. And it's an interesting time to reflect to see what we have done during that period of time, after all, lots of money has come from the American people. So I feel strongly that after 50 years, it's time to give a report. Well, today we know that about half of the people, well, the death rate, if you want, of coronary heart disease, let's take that simple disease, which is not so simple, actually, but everybody knows what that is. But the death rate from that is half today what it was 50 years ago. Now, admittedly, there are problems with that, in a way, because you have many more people today who are running around with coronary heart disease than there were 50 years ago, because they didn't die. But they have the disease. We are not as successful to prevent it from occurring as we are to fix it. So the net result of that is that you increase the number of people with the disease. But the fact of the matter is that these people are walking, they are producing, they are very income producing citizens for many years. So you could say, sure enough, the fact that today we have many more people with that disease, it's costing the country. But I would like to submit to you that in effect, many of these people are paying their way, because they can work and before they didn't produce, they were not contributing to society. So these are very complex issues. And that's why I think that, you know, I don't want to put words in Dr. Varmus' mouth, but I think what he advocates is that the best way for us to make progress is to go where we have the opportunity, scientific opportunities. And I think the second part of this is that today, because of the very nature of the science that we are doing, the opportunity which is good for this disease is also important for that disease and for the third one. And so there is a great deal of overlap among the disease categories. And so you know, the net result of all that is to focus on the opportunity, what can be done, where we see a payoff is a good way to do it. Now, that does not mean that, coming back to cardiovascular disease, there are no opportunities. In fact, we are full of opportunities. But I think that the opportunities that we have now are being met with the way the judgements are made. In fact, for 1998, with the discussions that took place at the NIH, an allocation was made, a special allocation was made to this Institute in order to meet an emerging opportunity where we think that we can do something and we can do well Mr. Hoyer. Thank you, Doctor. I think it would be a ballpark hypothesis, because as you point out, if you live longer, you sustain more medical costs with a disease. On the other hand, if you died, your productivity, your support of family, your payment of taxes, etc., would be lost to this society. But what I think we all believe is that there is a great plus, both in terms of dollars and in terms of society as a whole. But that might be an interesting thing. As we debate this, the Chairman has been extraordinarily supportive, as you know, of funding for NIH. His predecessor used to always say, the budget for NIH is x billions of dollars. If it were $3 billion or $4 billion more, it would not be too much. His premise being that whatever resources we could apply was in fact paying off both in a dollar sense and in a societal sense. And I'm pleased to serve with a Chairman who shares that view, because we're advocates of investing in what we think is a very significant payoff for all our taxpayers in our country, and indeed, because we're the leader in the world. Thank you, Mr. Chairman, for giving me the time. human cloning research Mr. Porter. Thank you, Mr. Hoyer. Dr. Lenfant, we're going to give you a rest for just a minute, so I can ask Dr. Varmus several questions. Dr.Varmus, we understand you've been to the White House this morning discussing the human cloning issue. And today's radio reports indicate that the President intends to issue an executive order prohibiting human cloning in Federal research programs, and requesting a voluntary moratorium on private experimentation. Are the news reports correct? Dr. Varmus. Yes, he actually has signed that order. Mr. Porter. Is the executive order thought to be necessary because the human embryo research ban in our bill does not cover the entire Government? Or did the White House lawyers disagree with the NIH position that the provision in our bill covers human cloning? Dr. Varmus. My understanding is that the former provides the bulk of the motivation, not all of it. The bill covers HHS and there's concern about, we want to make it perfectly clear that no Federal dollars in any agency can be used, regardless of the intent of the manipulation, if they're intended for research or for reproductive purposes, solely. Mr. Porter. The President's 1998 budget proposes to lift the human embryo research ban in our bill. And you cautioned last week against quick legislative action on cloning before ethical and scientific factors could be fully considered. Is this executive order inconsistent with these views? Dr. Varmus. No. The intention is to have that order in place to reassure the public until the National Bioethics Advisory Commission, headed by Harold Shapiro, who was also in attendance this morning at the signing and discussion, can fulfill its responsibility to return an evaluation of the potential of performing human cloning and the ethical considerations around it. Mr. Porter. And does the White House, has the White House indicated whether the rest of the ban on human embryo research should be lifted, the portion that does not deal with cloning in our bill? Dr. Varmus. I think the position remains the same with respect to---- Mr. Porter. Regarding the rest of it? Dr. Varmus. Correct. laser surgery for the heart Mr. Porter. Thank you, Dr. Varmus. Dr. Lenfant, last September, the Journal of NIH Research reported on a laser technique called TMLR for patients with end stage heart disease. The laser essentially burns a series of small holes through the heart to allow the blood and oxygen to seep through and into the heart muscle. Early results are promising in terms of increased blood flow and patient endurance, and the procedure is currently being tested in a clinical trial. But scientists readily acknowledge that they don't understand why TMLR works. Is it troubling to you that the FDA could approve a procedure drilling holes into the heart simply if it shown to be safe and efficacious, even if the reasons for its benefit are unknown? Dr. Lenfant. Well, I think the procedure is being used in Europe. There is quite an extensive experience in Europe. I do not think that the FDA has anything to do with the procedure itself, but rather the approval of the device to drill the holes inside the myocardium. That's what they are going to be concerned with. To my knowledge, the FDA is not getting involved with surgical procedure. In fact, that's a problem, that emerging surgical procedures which have doubtful validity, but there is nobody to regulate that, unless the HCFA gets into it because there is a reimbursement issue. I think that we need to have the results of that clinical trial, which is going on. I have to say that we know very little about who is doing this clinical trial. We know it's sponsored by the company that makes the laser device. But I really don't know anything about the exclusion or the inclusion of the subject criteria that they have. We don't know for sure what the end points are. I think that for something like that, I would hope that the end point would not be after six months, but rather after maybe two or three years. I think the verdict is still out on that one. sleep center Mr. Porter. Last year, we discussed a problem being encountered by the Sleep Disorders Center in the low number of research applications it was receiving. Has that situation improved over the last year? Dr. Lenfant. Yes, yes, indeed. And I would say, it's to the tribute of the Director of that center, who is extraordinarily active, working with all the Institutes at NIH and developing all kinds of programs and things. For example, the research on melatonin that we were mentioning earlier, the bottom line is that we are indeed increasing the number of research grants and support. Last year, in 1995, the support at NIH was about $73 million. It was $76 million last year. This year, it's anticipated to be over $81 million. So we keep on increasing, and I think the center is doing quite well. I don't know if Dr. Varmus would agree with that, but that's my opinion. funding for public education prgrams Mr. Porter. Dr. Lenfant, as you know, this subcommittee has been concerned about administrative costs and has taken steps to limit these expenditures. But we want to be careful that we are not inadvertently limiting program activities. Your Institute's public education programs are included in the admin costs line. How much is your public education budget? Dr. Lenfant. Well, the public education budget is made of three components: paying the employees who work in there, and I would say that the number of employees has been reduced over the last few years. At one time we had 39 employees, we are down to 34. The second component is the support of the contract program, which manages the development of brochures and things of that sort. And the third thing are direct costs within the Institute. The total in 1995, taking that as a base, of these three components, was $10.5 million. This year it is going to be $8 million, is our projection. However, what you should know, is that the direct costs which were $3 million in 1995, are going to be less than $800,000 or $900,000 this year. And I have to say that that is reaching a very, very critical point, especially at a time when there is increased pressure on the Institute to further develop some of its educational activities, not least from the sleep community. We have been mandated to develop a sleep disorder educational program. And basically, it is very difficult, if not impossible, to do. Mr. Porter. Have you considered displaying the public education activity separately in your budget so it is not artificially constrained when administrative costs are frozen? Dr. Lenfant. We have considered that in other years a number of times. And I have to say that we really vacillate,sometimes for, sometimes against. And the reason is the following, that it is a relatively small amount of money. And it is going to be, you know, we are talking about, the whole thing is in the order of, well, in the happy days it was about $13 million, $15 million. Now it's down to half that. And if you see that from a total of almost $1.4 billion, I think nobody's going to understand what that $10 million does by itself there. And that is the reason that sometimes we think we should do it, and some other time we say, well, no, we should not do it, we should leave it where it is. It is a very difficult thing. But the bottom line is that we are exceedingly concerned to see the reduction of our flexibility and therefore the loss of opportunity for further development of our educational program. Mr. Porter. Dr. Varmus, from a centralized NIH perspective, would you have any problem separately identifying public education activities in the mechanism table? Dr. Varmus. No, I wouldn't. In fact, I think I'd prefer it in the long run. One of the outcomes of the administrative review that we're undertaking in response to your suggestion, I hope will be a more uniform way to account for expenditures across the Institutes. service centers Mr. Porter. Dr. Lenfant, you've established three service centers which provide services to other Institutes in the area of procurement, committee management and technology transfer. How many Institute and center customers do you have for your three centers, and is there any other Institute competing with you to offer these same services? Dr. Lenfant. Well, the first part of your question, in the procurement, we have three Institutes. In the technology transfer, we have four Institutes. In the committee management, we have four Institutes. And they are all different. And I can say that we have a few of other Institutes, not least the Office of the Director, who utilize our services for some of their functions. It is very labor intensive, and we are having discussions with Dr. Varmus' office to see how we can better set that up. My reaction is that it has been very successful for the Institutes which are being served. And I have to assume that they agree with that statement, because if not, we would not have other Institutes coming and asking to be part of our service network, especially the Office of the Director. government performance and results act Mr. Porter. Dr. Lenfant, you have the reputation of being a skilled Institute manager. How are you contemplating applying the analysis of the Government Performance and Results Act to your Institute's activities? Is it possible, for example, to link mortality and morbidity measures to the performance of your programs? Dr. Lenfant. Well, first of all, that's an activity which is emerging at NIH, and we are working to set up these measures of performance. The thing that I have to say, which I find interesting, is that we have done that to a point for many, many years. For example, you are familiar with our educational programs. And every so often, we do surveys to establish whether we have met our goals, which is to increase the number of people who are aware of their blood pressure, who keep it under control, or the number of people who do something about lowering of cholesterol, and so forth. In addition, we also have done it to some of our clinical trials to assess whether the practicing community has actually implemented some of the recommendations or outcomes coming from these clinical trials. Whether the death rate would be an appropriate measure, in all honesty, I would have to think about that. I don't know. But I think the whole thing is positive, but difficult. And we have to be very careful. Because research is not as predictable as building bridges or roads, or planting trees along the water. lung volume reduction surgery Mr. Porter. Last year, we found ourselves in the middle of the dispute about HCFA's refusal to reimburse lung reduction surgery. We had hoped the controversy would be settled by a clinical trial of the procedure, which your Institute and HCFA have jointly agreed to support. Instead, the outside groups seem to think that the trial you are developing is too narrow, and won't test the full range of procedures being used in the field. Can you review for us the status of this trial and how you are responding to criticisms of its design? Dr. Lenfant. Let me answer the second question first, which procedures are being used. Today, there are three approaches to excising, if you want, a part of the lung, so that the rest can expand and work better. One is a sternotomy, that you open the chest in the middle and do what you want to do. The second one is video assisted. And the third one is a laser excision. The clinical study that we have designed includes the two first approaches, that is the sternotomy and the video assisted, but not the laser. Why not the laser? Well, there are several questions, several reasons. The first one is that to do a serious study, you have to be able to compare this procedure with that procedure, otherwise, you cannot determine what is best. But the problem is that the surgeons, while doing the laser excision, do not do any of the two other procedures. And therefore, if you were to include it, you would never know whether it's better or worse, because of the surgeon or because of the procedure. Do you follow me? Mr. Porter. Yes. Dr. Lenfant. The second reason is that to have a clinical trial with the three procedures would be extraordinarily expensive. In fact, it would cost about three times what is underway. And the third reason, which is probably the most forbidding one, is that we know of two centers where they have a fairly large experience with laser excision. One of them has given up because of the number of complications. And they decided not to use it any more. And the second has not given up, but they have published a report to show that the number of complications is much higher than the two procedures which we are using. So the study is done to answer specifically two simple questions. The first one, is excising a piece of the lung beneficial to the patient. And second, which patients would benefit. As we went out designing the study, we thought that it would make no sense to include a procedure which at the outside was already so controversial. Of course, the people who do it don't think it's controversial. But the community at large does. Now, the other question, which is, are we too rigid in our approach to clinical trials, we now have 18 centers which are involved with it throughout the country. And their job now is to develop the protocol which will be implemented in acouple of months. Some of the participants say, but we have the answer, we have the data, we don't think we have to go through the protocol. The response of the Institute has been, fine, bring your data, we will have it independently assessed and reviewed, and if the independent review says, yes, these data should lead to excluding these kinds of patients, or making this change or that change, we will comply. But so far, that hasn't taken place. The position of the Institute, Mr. Chairman, has been very clear. If new data becomes available as we proceed, we are prepared to modify what we are doing. But so far, we haven't seen any of that data. Mr. Porter. So the criticism that the clinical trial, which is expected to take seven years, is too long a time to be useful for HCFA's reimbursement decisions, if I understand what you're saying, you're saying you're going to review whatever data comes along in the meantime, and even if new procedures come along in the meantime, if there's data to support their efficacy, that would be included in your study. Dr. Lenfant. That is correct. And I can tell you, that if we had included the laser excision in the design instead of taking 7 years, we were going for 10 or 12 years. hemophilia Mr. Porter. I was hopeful that Mr. Miller would arrive. He's at a budget hearing where Alan Greenspan is testifying, and that's the reason he's unable to be here. These are questions that Mr. Miller of Florida would have liked to have asked had he been here, and I want to ask them and have you answer them for me. What are the latest developments by your Institute in the area of hemophilia? Dr. Lenfant. Well, this year has been kind of a golden year, actually, in the sense that there have been some very significant advances. The first one, which is really novel and did not exist before, is that the recombinant DNA factor IX has been produced. The deficiency in two clotting factors, if you want, which are responsible for hemophilia, are factor VIII and factor IX. We have had a substitute for factor VIII for quite a few years, and I'm going to come back to that. The one for factor IX, we didn't have. But now we have it. And it is my understanding that it's being reviewed now by the FDA to decide whether they can approve it or not. Now, the second thing that has happened is that factor VIII, which I said we have had for quite a few years, was still including some human albumin in it in order to stabilize the product. And that in fact was responsible for some immune reaction when it was given to patients. Now what is being developed, and is almost developed, is a new factor VIII which does not include any human albumin, and therefore would be much safer for the patient. And then the third thing is that a new animal model has been developed. We have had hemophilic dogs, now we have hemophilic mice. And the advantage of having these two species is that it's going to enhance the capability for gene therapy development and assessing the effectiveness of gene therapy a great deal. Mr. Porter. Representative Miller's son is a hemophiliac. And he would also like to ask, are there any new developments on hemophilia from any biotech companies that you may have heard about? Dr. Lenfant. Yes, as a matter of fact, the recombinant DNA factor IX that I just mentioned is developed by a biotech company. As is often the case, the commercial outfits are picking up the result of the research which is conducted by the Institute. I have to say I don't know which company that is. But I could find out. Mr. Porter. Dr. Lenfant, thank you for your good testimony this morning, for your very candid answers and direct answers to our questions, and for the wonderful job that you're doing there at the Institute. And 50 years is a great milestone for the Institute. You've been its director for almost a third of its existence, and we appreciate the fine work that you're doing. Dr. Lenfant. Thank you, Mr. Chairman. Mr. Porter. The subcommittee will stand in recess until 1:30. [The following questions were submitted to be answered for the record.] [Pages 898 - 982--The official Committee record contains additional material here.] Tuesday, March 4, 1997. NATIONAL INSTITUTE ON DRUG ABUSE WITNESSES ALAN I. LESHNER, M.D., DIRECTOR, NATIONAL INSTITUTE ON DRUG ABUSE RICHARD A. MILLSTEIN, DEPUTY DIRECTOR DONNA M. JONES, BUDGET OFFICER LAURA ROSENTHAL, EXECUTIVE OFFICER DR. HAROLD VARMUS, M.D., DIRECTOR, NIH DENNIS P. WILLIAMS, DEPUTY ASSISTANT SECRETARY, BUDGET, DEPARTMENT OF HEALTH AND HUMAN SERVICES Mr. Porter. The subcommittee will come to order. We're pleased to welcome Dr. Alan Leshner, the Director of the National Institute on Drug Abuse. I apologize for being late. I was stuck on a phone call that I couldn't get off of. Dr. Leshner, why don't you proceed with your statement right away? Introduction of Witnesses Dr. Leshner. Thank you, Mr. Porter. Let me just introduce the people I brought with me. Donna Jones, NIDA's Budget Officer; Laura Rosenthal, our Executive Officer; Richard Millstein, our Deputy Director; you know Dr. Varmus and Mr. Williams from the Department. Opening Statement I'm very pleased to tell you that we've had another outstanding year in drug abuse research and its application. As you know, NIDA supports over 85 percent of the world's research on the health aspects of drug abuse and addiction. And we do that through a very comprehensive and broad ranging research portfolio. Because NIDA plays such a dominant role in drug abuse research, we've come to understand that doing great science by itself is not enough. And we know that if our scientific findings are not both useful and used, we're not fulfilling our mission. And that's why NIDA and its staff are continuously holding discussions not only with the scientific and professional communities, but also with policy makers and the general public. We do that both to share the results of NIDA-supported research, and to get input from the users of our findings about the information that they need to do their jobs. Our ongoing series of town meetings across the Nation exemplifies NIDA's commitment that our research both be useful and used. As just one example, we recently brought together community leaders and leading scientists at a town meeting in San Francisco to help confront the emerging drug problem of methamphetamine. And as one result of that town meeting, NIDA has launched a major methamphetamine research initiative to increase our knowledge about this drug's effects and what to do about them. I'd like to share with you just one of the very important new findings described at that meeting. Last year, I showed you brain images showing your brain on drugs, and then I showed some brain scans of persistent effects of chronic cocaine use on general brain metabolism that last at least four months after the addict has stopped using cocaine. Well, research published this year demonstrates just how pervasive, how devastating and how long-lasting other brain changes can be after chronic heavy drug use. And they're adding important specificity to the kinds of more general effects that we discussed last year. I'm going to use the case of methamphetamine. We know well that acute use of both methamphetamine and amphetamine produces very dramatic changes in brain function, particularly through the release of the neurochemical dopamine, and that spike in dopamine release is how the amphetamines produce their psychoactive effect. Well, we now also know that long-term amphetamine use produces dramatic changes in dopamine activity that persist long after the individual stops using the drug. And the effects are not limited to the toxic effects of amphetamines, since those effects in fact recover over time. This poster to my left shows the effects of 10-day exposure to heavy doses of amphetamines on the brain's ability to synthesize, to produce this substance dopamine. These are positron emission tomography ``PET'' scans, of verdant monkey brains. [The information follows:] [Page 985--The official Committee record contains additional material here.] And the top row shows you in white and red normal levels of compound fluoro-dopa, or fluoro-dopa activity, an index of the ability to synthesize dopamine. Red, yellow, and white are more activity, blue is less activity there. The second and the subsequent rows show a dramatic decrease in dopamine synthesis capacity that lasts at least a year after amphetamine dosing was stopped. So what you see there is the pre-amphetamine on the top row, amphetamine for 10 days, and then after you stop giving amphetamine, four weeks, six months, by a year it's coming back. The important point is it will recover by two years. And that bottom line is basically similar to the top line. Mr. Porter. Excuse me, it's just 10 days of the use of amphetamines? Dr. Leshner. That's right, it's 2 injections a day for 10 days. Mr. Porter. And that has an effect for at least a year? Dr. Leshner. Yes, sir. What's important about this is that these persistent brain changes are accompanied both by severe amphetamine addiction and by dramatic changes in social and emotional behavior processes that also persist for a very long period of time. And of course, it's not surprising that there are these behavioral effects, since we know dopamine is critically involved in social and emotional behavior processes, including particularly the regulation of human mood states. Turning to a very different domain, we've also been working very hard to try to improve the prevention of initial drug use, particularly among young people, which I know you know is a major problem in this country. In September we held the first national conference on drug abuse prevention research, bringing together over 500 researchers and community practitioners. And as a result of that meeting, in the next few days, we will be releasing the first ever science-based guide to drug abuse prevention. We'll be sending this guide to thousands of practitioners, community anti-drug coalitions and other lay leaders all over the country. This user-friendly booklet articulates the principles that we've learned from prevention research, and it gives practical guidance on how communities can apply these principles to address local drug problems.It even includes science-based checklists of criteria against which communities can evaluate local programs. NIDA is also working to continue to improve drug treatment approaches. We've mounted a new Institute treatment initiative this year that, among other things, is taking behavioral and pharmacologic therapies that our studies have shown to be effective in small-scale laboratory studies and evaluating them in real life, large, multi-site clinical trials. Behavioral approaches such as cognitive behavioral therapy and contingency management therapy that have been studied in academic settings but have not been applied very broadly in the real world will be further evaluated. We will also continue to develop new medications to restore a degree of normalcy to brain function and behavior, so that other therapies and rehabilitative measures, such as counseling and psychotherapy, can be more effective than they are now. Although behavioral and pharmacologic treatments can be extremely useful when employed alone, NIDA-supported research has taught us that integrating both types of treatment is the most effective approach. In fact, these integrated approaches are typically essential to restoring an addicted individual to normal functioning. We've also made tremendous progress in one of NIDA's top priority areas, the development of an anti-cocaine medication. One of the most promising and consistent basic science findings of the last year or so is that stimulating one of the brain's dopamine receptors, called the D-1 dopamine receptor, seems to suppress cocaine craving and cocaine seeking behavior. We're now in discussions with chemists from academia, from other NIH institutes and from industry to develop and acquire dopamine D-1 stimulating compounds that we can examine as potential medication. In addition, to expedite the path from these types of basic science findings, to actual changes in clinical practice, NIDA has just funded the first three grants of its Strategic Program for Innovative Research on Cocaine Addicts--SPIRCAP--program, which is that program I mentioned last year that we were inaugurating, to force the collaboration between basic scientists and clinical scientists to do the kind of translational research that I know many institutes have been talking with you about. These are just a few of the past year's findings in NIDA's new initiatives. Some others are spelled out in my full statement. I hope that they make clear that NIDA-supported research is providing us with a solid scientific foundation to better ensure that our Nation is equipped to respond not only to the problems of today, but to the challenges of tomorrow. To paraphrase a recent report by the Institute of Medicine of the National Academy of Sciences, the success of our national investment in addiction research will be measured in lives saved and reclaimed and the development of our youth into productive and healthy adults, and in the restoration of families and the security of communities. This same Institute of Medicine report applauded NIDA's past successes and stated the Institute of Medicine's belief that we're working in the right direction and are well on our way to meeting these important societal goals. To meet the challenges and opportunities now presented to us, NIDA requests $358,475,000 for fiscal year 1998. A hallmark of this request is the $30 million increase proposed by the Administration. This is a part of the Administration's cross- cutting efforts to combat drug abuse, which has been increasing in some populations. I would be pleased to answer any questions. [The prepared statement follows:] [Pages 988 - 991--The official Committee record contains additional material here.] relationship with ondcp Mr. Porter. Thank you, Dr. Leshner. Mr. Hoyer has another subcommittee that he has to attend, and I'd like to recognize him first. Mr. Hoyer. Mr. Hoyer. Thank you very much, Mr. Chairman. That's very thoughtful of you. Doctor, thank you for the report and it is indeed, as you said at the outset, a hopeful report. I think all of us are very hopeful that we will sort of get a magic formula by which we can suppress the desire that you speak to in your larger statement; the craving for drugs, particularly for those who have been on and are off. Obviously recidivism is a major, major problem for the medical side of the question, as well as for the law enforcement side of the question. Just a couple of questions. First of all, in my other subcommittee, the Treasury, Postal Subcommittee, General McCaffrey's Office of National Drug Control Policy, is budgeted there. Would you tell me what interface you have with ONDCP and General McCaffrey? Dr. Leshner. I will. We have been very fortunate, I think, to develop a fairly close relationship with ONDCP and with Director McCaffrey in particular. He has the unique characteristic of being very interested in science, and therefore, he has been known to track me down on vacation and ask literal scientific questions. He's met with Dr. Varmus and has been very interested in much of what we're doing. Our relationship is informational, primarily, that is, we brief him probably every few weeks on whatever issue is in front of him at the moment. Our staff went down recently, for example, to talk about the science of prevention, in particular, and they've been very interested in our medication development program. vaccine development Mr. Hoyer. I'm glad to hear that. Of course, one of the things I was struck with in my first meeting with General McCaffrey before he'd been confirmed but after he'd been named by the President, was his emphasis on prevention and rehabilitation. This is a four-star general, the most decorated soldier in America right now who is living, and he does not like to refer to the war on drugs. He sees prevention and rehabilitation as a major, major component, as you know. Toward that end, in your statement you refer to both identifying genetic markers for proclivity to use, as well as suppression of further desire. How far away do you think we are to, I know you referred to this, but to perhaps, I guess, an inoculation? What am I looking for? The word? Dr. Leshner. A medication? A vaccine? Mr. Hoyer. Vaccine. In effect, is that conceptually what we're looking toward? Dr. Leshner. Well, let me give you a slightly longeranswer than you might want, but I'll try to keep it brief. Actually, the problem of developing appropriate medications, and I need to say, I don't think we'll ever have a magic bullet, so anyone who's waiting for that, I apologize. The cycle of addiction is from a clinical perspective complex, obviously. There's an issue of initial drug use, there's an issue of once an individual becomes addicted, which I believe is a different, and qualitatively different state. Then there's the issue of how do you keep someone off drugs once they're off. I believe that we may actually need different pharmacological approaches for each of those stages, and worse, more stages. There has been a lot of interest, and NIDA has made a number of grants, actually, in three different places, to look at the potential for developing some kind of a vaccine based approach. We actually have a company called Immunologics that just got a very large grant from us in order to further the development of a potential vaccine. I don't think we're at a point yet where we really understand the complexity of how that might be used. That is, that it might be that for some individuals you would want to give them this vaccine which has been preliminarily developed, in animals, of course. That might help control their initial drug use. It's much more complex. An even more complex ethical issue is what you do for the long term with vaccinating somebody. Technologically, I would say that we're beginning to get close. That is, we have in fact in rodents developed a model where antibodies have been produced to block cocaine, and they do in fact block cocaine's entry into the brain. They do in fact block cocaine's initial psychomotor effect, that is, they block the stimulant effect of cocaine. What we don't know is if they would also block craving for someone already addicted, for later drug seeking. So at most, I think, a vaccine approach will be an initial stage. I think we'll need other kinds of medications, particularly to deal with the craving, which is the most difficult and the most complex aspect for an addict. alcohol and substance abuse Mr. Hoyer. Doctor, the last question, and I again apologize for having to leave to be on the other subcommittee, but we're going to hear from the National Institute of Alcoholism and Alcohol Abuse. Clearly, very closely related. I was interested to see in the paper today that although parents and teenagers or young people differed on a lot of things, in terms of drug use and what parents are telling students or their kids and what kids were hearing, they agreed on one thing overwhelmingly, that alcohol abuse was the major problem that confronted young people. Clearly, without getting into the political definition of alcohol and tobacco versus cocaine and heroin and making an analogy there, which I'm not making at this point in time, but clearly there is an analogy; presumably all these substances have a similar effect and are driven by similar drives which lead to addiction or overuse. Am I correct on that? And if that's correct, I presume there's a great deal of cooperative effort between the two Institutes. Dr. Leshner. Well, there are both similarities and differences among individual drugs. It's true that many, many abusable substances have common effects, particularly on the dopamine system in the brain. We do work very closely with the National Institute on Alcoholism and Alcohol Abuse. And we have a lot of programs that we do together and things that we study together. At the same time, there are separate sets of issues that pervade it. But the questions of adolescent substance use are very broad and cut across issues of value as well as issues of science. And they are pervasive, as you suggest. To answer your question, there are similarities and there are things that are different, including the nature of the metabolic effects that are going on with the use of different substances. nicotine addiction Mr. Hoyer. I said that was going to be my last question, but one thing occurs to me, Mr. Chairman. Alcohol is obviously a legal substance. What do we do, and this is going to be a controversial question, what do we do with respect to nicotine? We don't have a National Institute for Nicotine Addiction. Dr. Leshner. We actually study nicotine addiction. We coordinate, of course, with other institutes, the National Cancer Institute, the National Heart, Lung, and Blood Institute who study other aspects of nicotine and smoking. We actually are responsible for the primary research on the addictive properties of nicotine. Mr. Hoyer. Mr. Chairman, you've been generous to me in time, and I appreciate that very much, and for recognizing me first. Thank you. Thank you, Doctor. Dr. Leshner. Thank you, sir. drug abuse budget increase Mr. Porter. Thank you, Mr. Hoyer. Dr. Varmus, I think I want to begin with a question to you. And this is not a hostile question, but merely one to determine how you reach conclusions. The NIH budget specifically identifies, as Dr. Leshner has said, a $30 million or 9 percent increase for non-AIDS drug abuse research. In general, you've tried to avoid disease-specific increases and have instead constructed your budget on the basis of six areas of emphasis. But only $17 million of the $30 million non-AIDS increase for NIDA is associated with these six areas. Do you see any inconsistency in the way your budget provides such a large proportionate increase to drug abuse? Dr. Varmus. The extra money for the Drug Abuse Institute represents an Administration decision that there ought to be more emphasis placed in that area of research. The Drug Abuse Institute was slated for substantial monies, which you've seen represented in the areas of prevention and neuroscience. The increase is more than it might have been had there not been a coordinated decision by us, in collaboration with the Department and the White House, to make a special push this year to try to advance medications development and other topics that Dr. Leshner will discuss. Mr. Porter. Do I understand then that this was not in your original proposals sent to the Department? Dr. Varmus. That's correct. Mr. Porter. And came from the White House instead? Dr. Varmus. It was a coordinated decision to go ahead and do this. alaska needle exchange Mr. Porter. Thank you. Dr. Leshner, there's been a great deal of publicity recently about research on needle exchange programs, and in particular, a study NIDA is supporting in Alaska. First of all, can you summarize what we know and what we do not know on the basis of existing studies about the effectiveness of needle exchange programs in preventing the transmission of AIDS? Dr. Leshner. Well, I think if you look at the converging evidence as summarized now by a large number of reports, pretty much whatever measures we use are indicating that in the context of a broad set of prevention activities, needle exchange can be an effective vehicle for reducing the spread of blood-borne infections, including HIV, hepatitis virus and other kinds of blood-borne infections. The question that's more difficult to demonstrate, of course, is the question of how it affects drug use. And I should say that there is no evidence that it increases drug use. It is a very effective strategy for bringing people into treatment. Somewhere, in our various studies, somewhere between 15 and 25 percent of the people who come to those programs in fact enter into treatment. Mr. Porter. Now, can you describe the needle exchange study you were sponsoring in Alaska and the reasons it has been opposed by Public Citizen? Dr. Leshner. I'll try. The needle exchange grant at the University of Alaska is actually a, what we might think of as a second generation project. That is to say, it's comparing the efficacy of two different approaches to providing sterile needles. I should make clear that in any studies of this kind, and in any of the studies of needle exchange that we are doing, we recognize, and the protocols are created in such a way that the first attempt by all investigators is to get people into treatment and to get people to stop using drugs. The best prevention strategy, of course, for the spread of blood-borne infections, is for people to stop injecting drugs. However, we know that we're nowhere near as successful as we might be, and therefore, these are public health approaches that are being studied in a way to deal with this public health problem that goes beyond just an individual's drug use. Having said that, a question that needs to be asked is not really whether or not using sterile equipment is a good idea. There's no question that the use of sterile equipment prevents the use of blood-borne infections. The question here is, what is the best way for making sterile equipment used; that is, how to do that. Each of the studies NIDA supports in this domain includes a formalized protocol of outreach, education, counseling on drug use, counseling on treatment, and then after that doesn't work, then the study starts. This particular study, is a randomized trial, comparing the efficacy of a needle exchange program, supported locally. We don't provide the needles. It compares the efficacy of that approach to the approach of having people buy needles in a pharmacy, which in Anchorage, Alaska, are quite available. The questions that have been raised about the study had to do with whether in fact one needed to demonstrate that using clean needles works. We never thought the investigator was demonstrating that. What we thought the investigator was demonstrating is which is the most effective technique for it. And as you know, Dr. Varmus asked a group to look at that. And they came to a similar conclusion. Other than that, there was some discussion about the provision of hepatitis B vaccine. And we have made provisions to ensure that every individual in the study has access and is encouraged to get vaccinated against hepatitis B. Mr. Porter. And Dr. Varmus recommended you proceed with the study after making a change in its design? Dr. Leshner. A subset of the subjects in the study would receive free vaccine from the Indian Health Service or from other local service providers. A subset would not have had access to free vaccine. Dr. Varmus recommended, and we concurred fully, that we should provide vouchers for those individuals who would not get free vaccine, to make sure that everybody would be as encouraged as possible, if that's the correct phrasing, to get that vaccination. disease specific budgets Mr. Porter. Dr. Varmus, regarding my first question to you, I wonder if you would submit for the record a list of all those areas in the budgets of NIH that were suggested, either by the Secretary or by the White House that weren't contained in your original budget that are disease-specific? Would you do that for us? Dr. Varmus. I should perhaps point out that these are areas that were in the budget, not as an expansion, that we initially intended to ask for. Mr. Porter. And quantify them for us, too. Dr. Varmus. Sure. [The information follows:] National Institutes of Health Disease-Specific Budgets The following information is provided in response to Mr. Porter's request that NIH identify and quantify areas in the NIH budget that were suggested either by the Secretary, DHHS, or by the White House. It is important to note that these areas had already been identified by NIH and that the increases resulted from a coordinated decision by NIH, in conjunction with the DHHS Secretary, and OMB. NIAID's FY 1998 budget for Non-AIDS research included an increase of $3,000,000 for the support of Hansen's disease research at the Hansen's Disease Center, to be funded through a reimbursable agreement with the Health Resources and Services Administration. In the FY 1998 budget, NIDA received a total of $30,000,000 for Non-AIDS drug abuse research. Of this amount, $17,000,000 was for NIH special areas of emphasis as follows: Biology of Brain Disorders, $5,000,000; Preventive Strategies, $5,000,000; Therapeutics/Drug Development, $5,000,000, and Advanced Instrumentation, $2,000,000. In addition, an amount of $13,000,000 was included in NIDA's FY 1998 budget for research on drug activity. The FY 1998 passback level includes $15,000,000 for third party payments to the Clinical Center in addition to appropriated funds. The collection of third party payments is consistent with initiatives currently underway at NIH to encourage public and private insurance support of costs of patients who participate in NIH-sponsored clinical research. needle exchange Mr. Porter. Thank you. The Secretary of Health and Human Services has recently submitted a report to Congress on needle exchange programs. Can you describe her major conclusions? Dr. Leshner. Secretary Shalala's conclusions were basically similar to the conclusions that I just mentioned, which is that on the basis of the studies done to date, on the basis of the report of the Institute of Medicine and the recent NIH consensus conference, we were to pull together all of those data. The best models of this came from Yale. But the best models indicate that needle exchange programs can reduce the spread of blood-borne infections by as much as 33 percent. Secondly, the Secretary's report acknowledged that needle exchange programs are an effective vehicle for getting people into treatment. She did not draw a firm conclusion on the issue of whether or not needle exchange could reduce drug use, although she recognized that there are not data suggesting that it increases drug use. I believe that's accurate. medical use of marijuana Mr. Porter. Dr. Leshner, the medical use of marijuana and the Federal Government's position on it have generated considerable controversy. The National Drug Policy Director has ordered that an 18 month review of the science be conducted by the Institute of Medicine. And NIDA has recently convened a two-day workshop on the issue. At the moment, is scientific opinion truly divided on the medical benefits of marijuana for particular conditions? Dr. Leshner. Let me just clarify. First, the workshop that we just held, which I helped organize as an NIH-wide event, actually was not a NIDA-specific event, because of course, any research that would be conducted likely would come from another NIH Institute. NIDA would only provide support in the form of providing the marijuana itself. If the research were for a particular medical indication, the appropriate Institute would do that. This workshop, in fact, represented the joint efforts of 10 NIH Institutes, centers and divisions. Certainly in my experience, second to some of our neuroscience efforts, it was the most collaborative thing we've done. I would say that a reasonable conclusion, and again, all of this has to be seen in the context of the broad public health discussion that's going on at the moment, is that the existing data base is relatively thin for smoked marijuana. That is, there is not a large body of data suggesting smoked marijuana is a viable medication for any particular indication. There are a lot of anecdotes, and we can come back to that if you'd like. However, there are indications for which THC, tetra- hydrocannabinol, the main psychoactive ingredient, have been approved, such as AIDS-wasting, and nausea associated with cancer chemotherapy. Therefore, given the extensive nature of the discussion going on, I think it would be a reasonable question whether additional research should be done. That was in part a reason that NIH held this workshop and the workshop hasn't submitted its report to us yet. But what we did was to have experts in each of those areas summarize the literature, and give us advice, particularly about clinical trial issues. You can imagine how complex it is to do research on a medical indication for a smoked preparation that has psychoactive properties to it. Mr. Porter. And you have a marijuana farm in Mississippi that provides your research marijuana supply? Dr. Leshner. We do. On contract to the University of Mississippi, NIDA maintains a farm that grows research-grade smokable marijuana. The majority of it is used either for those remaining compassionate use IND patients who receive smokable marijuana from the Government through the FDA, and for research purposes in our research grants. We do have, as you would imagine, a large number or fairly large number of grants looking at the pharmacokinetics of smoked marijuana. Mr. Porter. How many grants is that? Dr. Leshner. We probably have five to seven grants using smoked marijuana. Let me just give you one example of the kind of research I'm talking about. This is on the top of my head, last week I was at our own intramural research program, where an investigator was looking at individual differences in blood levels of marijuana after smoking, and after a very controlled smoking experience, virtually an identical by all external measures, the blood levels were phenomenally different among all individuals, and that has to do with the smoking which affects the absorption through the lungs. So that's the kinds of studies that we do, and of course the abuse potential. Mr. Porter. Thank you. Mr. Miller. methadone treatment Mr. Miller. Thank you. Just a couple questions. Understanding the idea of where we're going five or ten years in time, methadone has been the treatment for heroin, right? Dr. Leshner. It's one of the medications for heroin, yes. Mr. Miller. Is that the most commonly used one? Dr. Leshner. It is, yes. Mr. Miller. It's been around a long time, has it? Dr. Leshner. Actually, methadone was first developed in the early 1970s. Mr. Miller. But is it fairly common? I know in my community, at least there was a place that heroin addicts---- Dr. Leshner. One hundred and twenty thousand people are on methadone. Mr. Miller. Is there a waiting list to get on? Dr. Leshner. Yes, sir, in some places, not everywhere. Mr. Miller. How is that funded normally? Dr. Leshner. Methadone treatment is typically funded through the State, not through the Federal Government. Some of it comes through the block grant to the States that is administered by the Substance Abuse and Mental Health Services Administration. But every State has to decide for itself whether or not it will in fact use methadone. And not every State does. And of course, not every country does. There's a lot of ideology out there about methadone as a compound, and a fair amount of misunderstanding. But it is a rather effective medication for, again, a subset of individuals. And typically, when combined with psychotherapy of some kind. cocaine medication Mr. Miller. Would the goal be with cocaine to do something similar? Dr. Leshner. Actually, my hope is not to have a substitute medication. Methadone is a substitute medication, it does not produce the same level of euphoria that heroin does, in contrast to popular misunderstanding about it. And what it does do is occupy the same receptors. So it is a similar compound in the sense that it is working on the MU opiate receptor in the brain. And it does have some abuse potential, that is, if you could get it out on the street and inject it, you could get a high from it, not the same high as from heroin, because it's absorbed less readily. In any event, we are hoping that we can develop a compound that will actually work on the craving end rather than on the literal substance specific addiction. But I can't promise you that yet. I can tell you that we do have compounds that fit different categories for cocaine, some that would compete, as does methadone, for the same receptor. Some that might knock cocaine off its receptor, so it's just working in a different way. And some that might actually work on a craving itself, as opposed to the specific compound. Mr. Miller. So is that true for other types of addiction? Your goal, five or ten years, if you could choose what you could accomplish five years from today. Dr. Leshner. If I could decide what to walk out of the National Institute on Drug Abuse's having done, it would have been finding an anti-cocaine medication, sir. I think that's the biggest single need in this country's fight against addiction. We have nothing for overdose, we have nothing to get people to stop using the drug, and we have nothing to keep them not using the drug. And it's why we have put so much effort into this particular issue, since crack cocaine is in fact one of the most serious problems. Mr. Miller. Do you have any clinical trials right now? Dr. Leshner. We have 26 compounds in advanced clinical trials, and we have about another 8 or 10 compounds sort of lined up waiting to go into clinical trials. That's a part of, by the way, expanding on Dr. Varmus' answer, that's a part of what this initiative is, is to try to accelerate the rate of medication development. For example, we're screening the libraries of pharmaceutical companies. We have about 12 strategies, I promise not to give you all of them. But we're trying to use converging strategies here. successor drugs of abuse Mr. Miller. What are other drugs that are going to be successor drugs to crack cocaine? Dr. Leshner. Well, we worry about it. We're very worried about methamphetamine. That's why we went and had that town meeting in San Francisco. It was an interesting experience for me that here on the east coast, you almost never hear about methamphetamine. But methamphetamine has now replaced cocaine in San Diego as the drug most likely to draw people into treatment. That's a little statistic most people don't know. It's a regional problem. We were astounded, I was astounded, not everyone was, Ms. Pelosi was there, she was not astounded. Actually, we had representatives from five state authorities who came to find out about methamphetamine and what to do. We have the same problem, we have no medication for methamphetamine, although we've made a lot of progress in understanding its neurobiology. And that will help us. Mr. Miller. Well, all this research has a lot of personal benefit but also economic benefit. Dr. Leshner. Yes, sir. Mr. Miller. Crime issues, as you mentioned, AIDS issues and all that. So I find it interesting and obviously very supportive, as does everybody on this committee. So thank you, sir. Dr. Leshner. Thank you. Thank you for saying so. Mr. Porter. Thank you, Mr. Miller. Mrs. Northup. nicotine addiction Mrs. Northup. Dr. Leshner. I'm sorry, Mr. Chairman, I was a few minutes late, so if this is repetitive. Does tobacco fall under the category of addictions? Dr. Leshner. Nicotine does. We do study nicotine addiction. Mrs. Northup. Do you study the relationship between people that start using nicotine at an early age, and then become drug addicted to something else later on? Do you recognize that as a gateway drug? Does it increase the chances of that happening? Dr. Leshner. It's a very important question. I'm a scientist, and so I feel that I should be very precise when I speak about the relationship of one drug to another drug. The term gateway, as used by some people, not by all people, implies direct causation. The data that we have are correlational. What they show are unequivocally that the odds on someone who uses tobacco or alcohol at an early age becoming addicted are incredibly higher than someone who does not use those drugs. That is between 65 times higher, and 85 times higher. However, that's a correlation, that's not a literal cause. That does not mean that if you smoke cigarettes, you will become an addict. It just means that the risk of it is substantially higher. The obverse is also true, that is to say, if you don't use alcohol, tobacco or marijuana by the age of 21, the odds on you ever becoming addicted to a substance is almost zero. It is not zero, but it's almost zero. However, again, that is not literal causation. It's sort of a funnel, if that makes sense. There's a funnel of all people who smoke, and the odds are very high, are much higher if you smoke than if you don't smoke. essence of addiction Mrs. Northup. How much research have you done into the pathological reasons for that and the habitual user? In other words, do you have a rebellious child, or do you have any sort of evidence that the pathological, you were talking about here increases in dopamine that are created by the addiction. Does that then sort of draw a person, pathologically, to fulfilling a craving and the drugs seem to do that, then they get hooked in there even faster? I know that's a real novice way of explaining it. Dr. Leshner. It's absolutely not a novice way, it's actually very sophisticated. Almost every abusable substance, nicotine, marijuana, cocaine, heroin, causes an increase in dopamine secretion and a spike not dissimilar from the one, sadly you missed last year that I showed. We have come to believe, and I need to be cautious about this, because I think this is early in our understanding, but there appears to be some commonality to the brain mechanisms of addiction. At a minimum, there are certainly these similarities. What I don't know is whether in fact having one addiction makes you predisposed to have another addiction, literally. All I can tell you is there is some cross sensitization, across drugs. If you are addicted to heroin and then you go off, cocaine can prime you back to craving heroin. Then the reverse, of course, is amphetamines and cocaine. So there is some commonality, but I think we should be very careful about it. Mrs. Northup. So are you saying that there is at least some indication of it creating a pathological interest or a possibility towards other addictions? Dr. Leshner. I think, being careful, I need to say I don't know. But I myself believe from my reading of the literature that we are beginning, and we're in an early stage, to understand, and behaviorally of course, that there ought to be some kind of commonality, some common essence to the phenomenon of addiction. Mrs. Northup. Do you have any pathological studies as to why a 13 year old that picks up a cigarette is going to become addicted compared to a 21 year old? Does it happen that that's pathological, that your incidence of creating these dopamine trails are more inclined to occur with earlier cells, earlier in life, than later in life? Or is it that if you have the tendency towards that, that you just tend to gravitate towards tobacco earlier? Dr. Leshner. We don't know, is the answer. People have sadly not studied developmental changes in those particular brain systems. But we have actually, as an Institute, been posing this question recently. Mrs. Northup. Are you doing those things? They're so important to me. Dr. Leshner. We have a lot of studies going on, not only on the psychosocial risk factors, but the biological vulnerabilities and the biological risk factors for not only the abuse of a specific drug, but for drugs generically. And again, I don't want to be promissory, but there are some data to suggest that there are genetic components to the vulnerability to becoming addicted. We haven't made a lot ofprogress, in our case, in identifying any of those genes, of course. But there are familial differences and suggestions that there are individual differences and age differences. Mrs. Northup. The statistics show, I think, 85 percent of smokers become addicted, is that right? Fifteen percent of alcohol users become addicted. So there would have to be some genetic or physiological reasons---- Dr. Leshner. There's no question in my mind---- Mrs. Northup [continuing]. Why you're inclined to become addicted. Dr. Leshner. I actually believe that most people are ultimately susceptible to being addicted. That doesn't mean everyone will be. It just means that given enough drugs for a long enough period of time, I believe people can in fact be made addicted. That's, again, not totally clear. Mrs. Northup. That's all at this time. Mr. Porter. Thank you, Mrs. Northup. Mr. Stokes. aids and drug abuse Mr. Stokes. Thank you, Mr. Chairman. Dr. Leshner, always a pleasure to see you. Dr. Leshner. How are you, sir. Mr. Stokes. Dr. Leshner, AIDS continues to take a devastating toll on people worldwide. In the United States today, it's the leading cause of death among people in the 25 to 44 year old age group. These individuals are probably in the most productive period of their lives. Tell us what portion of the AIDS-HIV toll is attributable to drug abuse. Dr. Leshner. Actually, I think we have just reached the point where intravenous drug use, directly or indirectly, is over 50 percent of the cause of new cases of AIDS. In fact, these two pandemics are totally intertwined. Our research program reflects the connection between the two of them, I hope. It's our intention that it reflect that. A very large percentage of women who are infected with AIDS, I think the latest number is 55 percent, and 64 percent of children infected with AIDS are drug-related. There's no question that these are totally intertwined pandemics. Mr. Stokes. Can you tell us what major research initiatives you now have underway and what you are planning for fiscal year 1998? Dr. Leshner. We have just about a third of our Institute's total budget, $116 million, that is devoted to HIV-AIDS. Our program runs the gamut from treatment approaches to using AIDS prevention as a part of treatment, so that we affect the public health aspect of AIDS, not just the individual's aspects of AIDS, of course. So treatment is one. Outreach to active drug users is another. As I said earlier, not everyone who uses drugs is willing to enter into treatment. We have to change the risk behaviors of those out of treatment individuals. We have a variety of studies looking at the medical consequences of the intersection between the two. We have some studies on the epidemiology of the intersection. We have a pretty broad program that spans almost everything from the molecule to managed care. And much of it is focused towards outreach to active drug users in order to reduce the public health problem as well as the problem for the individual. Mr. Stokes. How much of your Institute's budget is invested in AIDS-HIV drug abuse research? Dr. Leshner. I would say that a third of our budget is attributed to HIV-AIDS, and comes through that route. However, because of the intertwined nature of the two epidemics, it's difficult to give you a more accurate description. Much of the treatment research that we support is of course of great significance, because drug treatment is the best prevention for the spread of HIV-AIDS. Mr. Stokes. It would seem to me that this is probably an area in which there ought to be significant outreach. Is this the case? Dr. Leshner. Well, there has been. NIDA and CDC, have very extensive outreach programs. We have had a number of multi-site studies looking at the most effective AIDS outreach techniques. And I'm pleased to say that they've been extremely successful in reducing AIDS risk behavior, even in active drug users, by 35 to 50 percent. And that's very significant. That's not only sharing needles. That's using bleach, that's re-using needles. And again, the implication of that goes beyond just the individual. comparing united states drug abuse Mr. Stokes. In terms of understanding the nature and the extent of the drug abuse problem in the United States, how do we compare with other nations throughout the world? Dr. Leshner. Well, at the moment, we have probably as a percentage as high an overall drug abuse problem as most countries. I'm sorry to report, most countries are trying to catch up. We are at great risk. NIDA has done some international work, trying to come to understand emerging drug problems and see how we can help other countries prevent their drug problems, such as China and countries in southeast Asia and Russia, and countries within Eastern Europe. But at the moment, particularly because of the crack epidemic, we have very high levels of relative drug use in this country. Most other countries have predominantly heroin problems. demographics of addicts Mr. Stokes. What is the extent of the problem in the United States across racial and ethnic populations? Dr. Leshner. The distribution across racial and ethnic groups, if you just take large groups, is about equal, the percentage of addicts who are Caucasian, who are African- American, or Hispanic. However, as adults, minority group individuals are heavily over-represented in the population of addicted individuals. It's been informative that in younger people, actually, minority individuals begin using drugs later than Caucasian individuals. That may be tied to socioeconomic status, obviously. That's probably the most likely cause. But there are substantial differences in the demographics. minority related research Mr. Stokes. Doctor, can you bring the Committee up to date on targeted research and research training that is currently underway to further advance knowledge across racial and ethnic populations? Dr. Leshner. Well, we, as you would imagine, maintain a very large program that's geared towards understanding the particular problems of various cultural and ethnic groups. We spend about $67 million a year focused on specific, particularly minority populations. One of the things that's been most important, and I won't take very long with it, is that we've come to understand the need for culturally appropriate prevention and treatment programs. It's obvious once said. However, it's unfortunately not frequently done. The places where we've learned this, for example, are in traditional therapeutic communities. Those ethnic groups that don't like confrontation don't do very well in some of those, and they've had to be modified. This is a result ofthe kind of research that we support that's looking at a focus on the specific needs and the specific problems of different ethnic groups. It's a large part of our portfolio. Mr. Stokes. Can you tell us, what is the plan for fiscal year 1998, and how much is included in your fiscal year 1998 budget request for this activity? Dr. Leshner. Our total best estimate of minority-related research is about $76 million for fiscal year 1998. Some of that is devoted to our focused efforts to increase the number of minority investigators that NIDA supports. We believe it's very important for a variety of reasons to have a larger number of minority investigators. As far as we can tell, we've been quite successful at recruiting additional minority investigators in the last few years. So we spend, actually, probably on the order of $3 million or $4 million a year just on targeted recruitment activity to bring minority investigators into the pool of researchers. Mr. Stokes. Thank you, Doctor. I suppose I'm at the end of my time, Mr. Chairman. Mr. Porter. You actually have two more minutes if you'd like. Mr. Stokes. Maybe we can get in another question here. Dr. Leshner. Sure. needle exchange programs Mr. Stokes. Earlier on, as I came in, you were about to talk a little bit about needle exchange. And of course, my concern is, to what extent are there needle exchange programs in the United States, and whether or not the Institute has any major research underway in this area. Dr. Leshner. We have about 15 grants at the moment on the efficacy of needle exchange, and on various aspects of the use of needle exchange as a device to prevent the spread of blood- borne infections. There are many needle exchanges operating, either legally or illegally, in this country. Those are of course not supported by the Federal Government and are not supported by our Institute as part of the Government. The decision whether or not to have needle exchanges and to fund them is done at the State and local level. Mr. Stokes. Thank you, Doctor. Thank you, Mr. Chairman. Mr. Porter. I have about three or four more questions. Do other members have additional questions they would like to ask? Mr. Stokes. I have a few more. cocaine medication development Mr. Porter. Let's see how fast we can talk. Finding an effective treatment for cocaine abuse, which you referred to earlier, Dr. Leshner, has been a Federal priority since at least 1988. And now, almost 10 years later, although some promising research leads have been identified, there still is no medication to treat cocaine abuse. Do you find that record disappointingly slow, or is it unreasonable to assume that we're going to be able to find something, say in 10 years? Dr. Leshner. Well, NIDA's medication development program actually came into being in 1992. And so our focused effort has really only ramped up then. I think the truth is that it's only been in the last two to four years that we've had the fundamental neuroscience to give us the molecular targets at which to approach medication development. As I hope I've made clear, we've had unbelievable advances in understanding the ways in which drugs of abuse affect the brain and produce addiction. But that's really come in the last three to five years. Those targets are why we're so optimistic now that we have an opportunity to come up with these medications, and we're doing what we call strategic medication development, that is, focusing in on real biological targets, rather than screening thousands of drugs and hoping. So, we are optimistic. I would like the drug yesterday. prevention programs Mr. Porter. With reports of increasing drug abuse among teens, it's especially important to have good information about which prevention programs are effective. Your Institute supported research which indicated that, contrary to popular perception, the DARE program is not effective. What types of prevention programs do work, according to your research? Dr. Leshner. Let me just make clear, we believe the DARE program is an evolving program. So any study done of a particular program as a snapshot in time ought to be viewed carefully. And I will tell you that we have been working with DARE to help them evolve their approaches according to the scientifically based principles we have been talking about. I think that there are again a number of principles one could delineate. But one of the most important ones, which will sound obvious, is persistence, that is, if you begin a program early in middle school, you need to have another program later and another one later. It needs to involve not only one mode, like media, or basketball games or whatever, it has to be a much more comprehensive kind of a program. As I mentioned earlier, we have our new guide that we're sending out to only 100,000 of our closest friends, which will delineate the kinds of principles we were talking about, based again on the scientific research we've supported. bupropion Mr. Porter. Your budget justification mentions pending FDA approval of a drug, Bupropion, as the first non-nicotine prescription drug. Is this drug thought to be more effective than the transdermal nicotine patches currently available? Dr. Leshner. I think it's a fundamentally different approach. Bupropion is typically used as an antidepressant. It works on the norepinephrine system in the brain. It is used to treat the dysphoria that occurs during withdrawal from nicotine addiction and to treat the craving. We also are trying a compound, by the way, for cocaine addiction. I'd give it about a B minus. I don't know yet whether it will be better than the transdermal patch. It may be that it needs to be used in combination. Mr. Porter. Was the drug developed with NIDA financial support? Dr. Leshner. A lot of research has been done on the drug supported by NIDA. But I don't know, the research done by the pharmaceutical company was done before I came to NIDA. I don't know the degree of relation. Mr. Porter. Mr. Miller. cocaine medication development Mr. Miller. On cocaine, are the pharmaceutical companies involved in this? Is there much of a market for them? Nicotine you see a market for the product, as a motivation. Is there a market for cocaine? Dr. Leshner. Actually, there isn't a market for cocaine. No, there is not. It's been a terrible problem for us. It's why we've developed our own medication development program and worked so hard with pharmaceutical companies tomake their lives easier so they will become more interested. You will recall that Dr. Varmus a couple of years ago changed the CRADA policy so that there was a change in the pricing laws. It brought about six more companies into collaboration with our Institute, when they began to see financial incentives to help. So the market is a very big issue for us. Mr. Miller. Thank you. Mr. Porter. Mrs. Northup. prevention principles book Mrs. Northup. Yes, I'd like to go back to some questions about drug use. You know, in here, I noted somewhere you mentioned that you all had actually created a book that was a very user-friendly guide to the prevention principles. I'd like to see a copy of that, if you could have that sent to my office. Dr. Leshner. We will. prenatal drug use study Mrs. Northup. Also, you've done a study on the neurological effects of prenatal drug use. I'd love to see that, too. effectiveness of prevention programs Mrs. Northup. Now, to go back to questions, I think especially following the line of my earlier question about creating the dopamine trail or whatever, it's pretty clear that prevention is really important. And in terms of the use of your budget, that's really important. I know that you say that's one of your goals, but I'd be interested in knowing what percentage of the $30 million are actually going to prevention strategies. I also know that you've talked about these guides to prevention. Have you created a best practices sort of scheme that is then communicated to the Department of Education and Health and Human Services through appropriate agencies that they oversee, so that best practices are actually in effect in their programs? Dr. Leshner. Let me start with the second part, if I may. We have worked very closely within the last year or so with the Department of Education and the Drug Free School program. And of course, within the Department, Secretary Shalala has been a very strong supporter of our prevention program, and of our principle of using science to increase the effectiveness of prevention approaches. So we've had very good, actually, cooperation. We are planning a very broad dissemination of these principles that have been derived. What we are not doing, just to be clear, what we are not doing is endorsing one or another extant program. Because we think that what we get from science is principles, not a program that necessarily would work in all sectors. Mrs. Northup. Let me then ask it a little bit differently. Do you look at existing programs, for example, the DARE program that we have seen some disappointing statistics from. Do you do a different kind of analysis, examining how they address the medical research that you might do, and do you propose changes to make them more effective? Dr. Leshner. We do some studies looking at the efficacy of existing programs. But candidly, we're not very interested in the yes-no question for a particular program. We're more interested in, ``does it work; why does it work; what's the essential element that might make it work.'' However, having said that, we do have a number of relationships, particularly with very large programs like DARE or the Partnership for a Drug Free America, where we work collaboratively, and some days they think we bother them too much. But we do in fact try to take the science we support and make sure it's used. information dissemination Mrs. Northup. In my opinion, one of the most critical parts, lowering the use of drugs among teenagers, is real clear information. It's amazing the sort of conventional wisdom these kids pass around to each other about how marijuana helps you concentrate more and longer and better and all those things. I wonder how much you do to disseminate the clear effects of these drugs, so that their own pass-around information doesn't take root. Dr. Leshner. Well, I think your fundamental point is a very important one. We have learned the hard way that hyperbole and exaggeration is the worst form of drug prevention. So we have been working hard to provide science-based information. We are now, I think, on our second millionth copy of our brochure on marijuana facts for teens and marijuana facts for parents. So that in fact it's all science-based. Mrs. Northup. You can send a few of those copies over, too. Dr. Leshner. We will, we'll be happy to. prevention increase Mrs. Northup. Also, I don't think I got an answer about the $30 million that's in prevention. If you don't have that, could you please provide that? Dr. Leshner. Sure, I will. [The information follows:] Dr. Leshner: Fifteen to twenty percent of the $30 million increase that NIDA has requested will go to prevention research. Mrs. Northup. Okay. Mr. Porter. Thank you, Mrs. Northup. Mr. Stokes. needle exchange and aids Mr. Stokes. Thank you, Mr. Chairman. Dr. Leshner, one follow-up question on needle exchange. As a researcher, and as the Director of the National Institute on Drug Abuse, in your professional judgment, what should our Nation be doing with regards to AIDS-HIV and needle exchange? Dr. Leshner. I do believe, sir, that needle exchange can be an effective part of a constellation of HIV prevention programs. I believe that the statement that needle exchange can reduce the spread of blood-borne infections, including HIV, is wholly supported by the data. medical marijuana concerns Mr. Stokes. Okay. Doctor, the debate continues to focus on marijuana, especially as it relates to the use for medical purposes and the implications for contributing to increased drug abuse. What are your concerns regarding this matter? Dr. Leshner. My concern is that the question be resolved through science, and that the question not be resolved through political decision one way or another. I would like to have questions like this handled, just as we do for any other compound that's purported to be a medication. I would like to have it resolved through scientific study. We do that for all other kinds of medicines in this country. That's my own belief. drug abuse costs Mr. Stokes. Doctor, last year the Institute indicated that drug abuse costs the Nation an estimated $67 billion, and that new estimates under development would incorporate data reflecting each of the following major components: drug-related criminal justice expenditures, crack cocaine, AIDS epidemic, medical and social costs associated with the resurgence of TB and hepatitis, and prenatal exposure to drugs. Doctor, what is the cost of drug abuse to the Nation? Dr. Leshner. Sadly, we don't have a figure better than that 1990 number of $67 billion. I can tell you that a study done by the Center for Addiction and Substance Abuse at Columbia University tried to do the analysis you're referring to just for New York City, and found the number of $20 billion. The number, in my own belief, is substantially higher than $67 billion. We're in the process, we have a study that we've contracted for jointly with NIAAA that's looking at it, and the results are not yet quite in. effective drug treatments Mr. Stokes. I hope you will share that with us whenever you have that data. Doctor, what can you tell us this year that you could not tell us last year with regard to how close we are to having an effective treatment for any of the major drugs of abuse, like cocaine, and equally important, treatments that do not themselves create another adverse dependency? Dr. Leshner. I would like to say that we have very effective behavioral forms of treatment for drug abuse. They're not panaceas that work identically for all individuals. But there are a number of clinical trial documented efficacious treatments. Sadly, they're not used as broadly in the real world as we would like. That's a part of our treatment initiative. But in the last few years, we've seen tremendous development in the techniques of psychological therapies like cognitive behavioral therapy, family therapies that work particularly well for young people. We are in the process of having these manualized, we're putting them into manuals so they'll go out to the field. But there are treatments that can be very effective. It's a big task, of course, to find the right treatment for the right individual. cocaine craving Mr. Stokes. I understand that cocaine craving studies have been conducted, and two studies have used brain imaging techniques to determine which areas of the brain are activated during craving. Can you tell us anything about this? Dr. Leshner. There has been, as one chart showed, we are very interested in using the wonderful tool of brain imaging to help us understand what's going on in living, breathing individuals who are awake and craving. There has been a convergence of evidence now from three discrete laboratories, beginning to lay out the brain circuits involved in craving, and some of the mechanisms involved in craving. So there's been tremendous progress, particularly in the last year, three separate papers have been studied identifying a particular site of the brain called the amygdala, part of a circuit where craving is involved. And of course, the frontal lobe of the brain is activated during craving. So we have made a lot of progress in the neurobiology, the basic neurobiology, without yet a great deal of specificity. But again, we have a number of grants underway to look at that. Mr. Stokes. Thank you, Dr. Leshner. Mr. Chairman, I have a few additional questions which I'll submit for the record. Mr. Porter. Thank you, Mr. Stokes. Each of us has additional questions we would like to submit for the record. Dr. Leshner, thank you for your good testimony and the fine job you're doing at NIDA. We appreciate your coming here and testifying today, and we want to work very closely with you on one of the Nation's most serious problems. Thank you. Dr. Leshner. Thank you, sir, for your support. Thank you all. Mr. Porter. The committee will stand briefly in recess. [The following questions were submitted to be answered for the record.] [Pages 1011 - 1090--The official Committee record contains additional material here.] Tuesday, March 4, 1997. NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM WITNESSES DR. ENOCH GORDIS, DIRECTOR DR. MARY DUFOUR, DEPUTY DIRECTOR MARTIN K. TRUSTY, EXECUTIVE OFFICER STEPHEN LONG, DIRECTOR, OFFICE OF POLICY ANALYSIS CARMEN M. RICHARDSON, BUDGET OFFICER DR. HAROLD VARMUS, DIRECTOR, NIH DENNIS P. WILLIAMS, DEPUTY ASSISTANT SECRETARY, BUDGET, DEPARTMENT OF HEALTH AND HUMAN SERVICES Mr. Porter. The subcommittee will come to order. The subcommittee is now pleased to welcome Dr. Enoch Gordis, the Director of the National Institute on Alcohol Abuse and Alcoholism. Dr. Gordis, it's nice to see you. We appreciate your patience, we're running a little behind schedule. But we intend to give you a full hearing on your budget. Please proceed with your statement after introducing the people at the table with you. Introduction of Witnesses Dr. Gordis. At my left, your right, is Mr. Steve Long, who's our Director of the Office of Policy Analysis; Mr. Martin Trusty is our Executive Officer; Ms. Carmen Richardson is our Budget Officer. To my right, is Dr. Mary Dufour, who's the Deputy Director of the Institute. I think the other two gentlemen you know very well. Mr. Porter. I do. Opening Statement Dr. Gordis. With your permission, I will not simply read the formal statement. I just want to comment on some of the issues in it. And I think this will open up the questions in an effective way. As you know, the Institute is charged with providing the scientific basis for improved prevention and treatment of alcohol problems, and as such, we support about 90 percent of the alcohol research in this country. Alcohol problems cost the country a lot. The last estimate is about $98 billion to $100 billion a year. Somewhere between 10 and 50 percent of all hospital admissions are due to the complications of alcohol in many different organ systems. vulnerability to alcoholism This has been a really good year for NIAAA in the sense that many of the investments which Congress has seen fit to put into our scientific enterprise are beginning to show fruit in very important ways. And I'm going to touch on some of them. The first is the issue of the vulnerability to alcoholism, which we know from fifteen years of studies on twins and adoption studies, indicate that a significant portion of the vulnerability to becoming alcoholic upon exposure to alcohol is inherited. Based on these important population studies, seven years ago, we embarked on a collaborative study on the genetics of alcoholism, which is now taking place in six centers across the country. The first two years were devoted to creating assessment instruments to clearly define who had the condition and who didn't. Important surveys for doing that were defined, written up and have been translated and used internationally. And over the course of the years, many thousands of people were interviewed extensively. And what has been culled are 300 so-called informative families in which there is multi- generational alcoholism, that is, some people have it and some don't. From them, we have obtained blood samples of various biological markers for DNA and have preserved and stored cell lines, which are held in two repositories. We are pleased to inform the committee that during the past year, several striking findings are beginning to emerge in the genetic study. I should preface this by saying that over the course of the last few years, some important spinoff studies have occurred. But I will emphasize the findings related to genetics in this discussion. The first is that several chromosomal hot spots, that is, areas of the genome where the genes related to alcoholism are likely to be found, have been identified on chromosome numbers 1, 4, 8 and 16. The next task, of course, will be to work on these zones for the next few years to find those genes which are related to the vulnerability to alcoholism. I should point out that unlike many of the disorders in which there have been genetic triumphs, like cystic fibrosis, Huntington's, sickle cell and a very long list, complex disorders like alcoholism are due to the effects of a mix of genes. And therefore, the task of finding them, not one of which singly is responsible for the whole condition, is immeasurably more difficult. But with modern technologies, which are improving, even during the course of this study, that is being accomplished. The resources of this study, both the data as well as the blood samples and the DNA, will become a scientific resource for the general scientific community in 1999. And at that point, other investigators, in addition to the current ones, if they are qualified, will have access to it, too, because it's a very important national resource. animal models The other area where our field is distinguished is in the use of animal models for studying the genetics of alcoholism. Many of the behaviors related to alcohol can be mimicked in animal models. And for that reason, we are pleased to inform you that during the last couple of years, several of these loci on the animal genome, particularly the mouse, have been found relating to alcohol preference and to other aspects of alcohol related behavior. If the committee is interested, I'll be pleased to enlarge on the details later. And finally, we are using the contemporary techniques of knockouts, where a single gene theorized to have an effect on the condition is knocked out so it does not get expressed in the adult animal. And it turns out we've had two very interesting successes here in which knockout genes have shed light on what possible circuits in the brain are related to alcohol misuse. application of research advances Not stated in the written testimony I think is something important. And that is, what is the payoff for all this kind of work. Because there is a major payoff. I think they're in three real areas that are important. Once we find the genes which code for certain proteins, and we know what the functions of those proteins are, it's going to give us a clue to the physiology of this disorder and permit us to develop even more medications than we have now, although there's been progress on that front, as I'll tell you in a minute. The second thing we're going to be able to do is more targeted prevention efforts. There aren't human or financial resources adequate to do all the prevention we'd like to do. And by focusing on those most likely to get into trouble, we can make that route more efficient. And finally, by the more precise delineation of genetic influences, we will better understand the role of the environment. Because no one is saying that alcoholism is solely a genetic disease. Many environmental factors, beginning in the uterus and going through early development in the home and then all the environment around us, contribute as well. Another area where we've had major advances is in the area of neuroscience, which is influenced by genetics but really a separate discipline in some ways. The main task with alcohol is somewhat different than with illegal drugs. Alcohol does not act on a specific receptor like cocaine and heroin do. It seems to act on a multiplicity of receptors. Alcohol kicks up some activities and inhibits others. And the delineation of that activity has been a very important aspect of our work. Important advances have been made in understanding, on the one hand, the reward system which is more complex than dopamine in the case of alcohol. This is a positive feeling that makes people want to drink. And the other side of this, which is coming into the fore again, is interest in understanding the withdrawal state, or the dysphoria or the discomfort of not having alcohol once you are dependent upon it. Alcohol withdrawal seems to involve different neurotransmitters and differentcircuits. And both of these processes, of course, are candidates for understanding and for future medication development. The imaging which Dr. Leshner addressed is very effectively used in our field as well. In the interest of time, I will not touch upon it, except to say that the issue of different cravings is very important here, too. On a theoretical basis, although it sounds rather remote, our new understanding of how alcohol acts on cell membranes is leading to a total revision of how we understand alcohol's effect on the nervous system. We are learning in toxicology how alcohol damages the brain, the liver and the fetus, which I know is of great concern to the committee. And I'll be glad to enlarge upon that as well during the questions. treatment research I want to take the last couple of minutes on treatment and prevention. There are two kinds of treatment research which the Institute does. As you know, much of alcoholism treatment develops outside the mainstream of medicine. And therefore, many of the things which have been done by tradition and by convention did not develop with the usual rigorously controlled trials which are typical of other branches of health care. One aspect of our treatment research is to apply contemporary clinical approaches in research, blind design, randomization and so on, to therapies that have been used traditionally without testing. One example of that is the Project MATCH, which examined in a large-scale, 6-year study in 1,700 patients randomized to three arms of behavioral therapy: 12-step facilitation, cognitive behavioral therapy, and motivational enhancement, to see whether by typing the patients precisely it would be possible to define a patient treatment match that would yield better treatment outcome. Despite smaller studies in the literature and the hope from the Institute of Medicine that that would pan out, it turned out that by and large, no major matches were found. It turned out that all the patients did quite well. Except for psychiatric severity, where the patients with low psychiatric severity did somewhat better in the 12-step facilitation, the patients did equally well and no matches were found in the 10 that were explored. The other side of treatment research is the development of new medications, and we've also been doing very well on this. During the last two years, we've told you about the FDA approval of naltrexone for the treatment of alcoholism after withdrawal. Nalmefene and other opioid antagonists have likewise been shown effective. And a drug which has shown promise in Europe, which works by a different route called acamprosate, has been finally given an IND--investigational new drug--approval by the FDA. NIAAA has been helping the company design a treatment trial which will be conducted in this country during the next year and a half or two. prevention I know there's been interest in the last discussion on prevention. This is a very important part of our portfolio. The part I'd like to emphasize is somewhat parallel to what Alan Leshner mentioned in the previous testimony. It's very easy to think of interventions which have a surface plausibility, which are expensive and which don't work. The experience of science, and I'm glad to say it's happening, is that the same techniques of rigorous analysis of what works for medications development are the same as those which work in prevention. It's a more difficult field because we cannot account for everything that's going on in the world around us. But I'm happy to say that by virtue of rigorous studies of what is going on, several important trials have yielded important results, which hold promise for prevention of alcohol problems in the young, especially. Community trials are going on in several paired communities in California and South Carolina. A very interesting study by Dr. Cheryl Perry called the Northland study, in 20 communities, 10 which used the interventions and 10 which didn't, among kids between the 6th and 8th grade years, showed 25 percent reduction in the initiation of drinking and several other positive outcomes. [Clerk's note.--Later corrected to ``28.''] research dissemination I'd like to conclude by talking about the importance of research dissemination. We have major publications which have come out, some of which have been prize winning, on a variety of topics, including prevention, including genetics, including imaging. We have a booklet called Primary Care Recognition and Intervention which has just come out. It's been distributed to about 200,000 people, including primary care doctors. We have had help in this distribution from General McCaffrey's Office of National Drug Control Policy to the tune of about 60,000 copies. Dupont Pharma, which makes naltrexone, has distributed yet another 100,000. And this has been very widely received. The publications are here on the table, and during the course of this discussion, if you're interested in my discussing any elements, I'll be happy to do so. The budget request for NIAAA for 1998 is $208,112,000, exclusive of AIDS. I'll be happy to answer any questions. [The prepared statement follows:] [Pages 1096 - 1100--The official Committee record contains additional material here.] trends in adolescent consumption Mr. Porter. Dr. Gordis, thank you for that very good statement. I was struck by the statistic in your budget justification that alcohol is used by more Americans than any other drug, including tobacco. We're all concerned about the increase in drug use among teenagers. What are the recent trends in alcohol use among teens? Dr. Gordis. There have been some minor decreases, fractions of a percent, in high school kids, for example, Mr. Porter. But it is still distressing that by the time kids reach their senior year of high school, a little under 80 percent of them have used alcohol, and about a third of them have had five drinks on one occasion during the previous two weeks. So there is a welcome trend in the slight decline, but I think we still have a major issue of alcohol use among adolescents. Mr. Porter. In 1994, U.S. per capita consumption of alcohol sank to the lowest level in 32 years. How is the pattern of consumption distributed? What share of the population doesn't drink at all, and what share are heavy drinkers? Dr. Gordis. About one-third of the adult population does not drink. Among heavy drinkers, if we define it by people who are drinking, say, five drinks a day or more for men andfour for women, then we're in the range of 10 to 15 percent. And the rest are drinking less, but not zero. Mr. Porter. Alcohol-related traffic deaths rose in 1995, reversing a 10-year decline. How does that data fit with the declining per capita consumption? Dr. Gordis. I can't explain this one-year change in the direction, Mr. Porter. There has been a decline over the last 10 years, and whether this represents a new trend or not, I think we're going to have to see in the next couple of years. It's very difficult for the change in one year to be accounted for. rigorous design and findings of project match Mr. Porter. You described your Project MATCH, which to the surprise of many found that matching different patient characteristics to different therapeutic approaches does not substantially alter outcomes. This has been heralded as good news by those who point out that inexpensive treatments seem to work as well as expensive ones. But what does the study tell us about the ultimate question? How well do any treatments work? What is the retention rate in treatment for patients, and what is the relapse rate after one year of treatment? Dr. Gordis. This is a very important and complex issue. However, I'll do my best to summarize it. I think Project MATCH delivered contemporary treatment about as efficiently as can be done. The treatments were all standardized, that is, there were manuals of therapy which defined exactly what transpired during these verbal encounters between patient and therapist. This was not a trial of medication. And as you know, it is easy in the course of a conversation, even in a therapeutic one, for the quality of the therapeutic encounter to be degraded by informal conversation and so on. In order to ensure that that didn't happen, the treatments were standardized, that is, there were three separate books, which defined the treatments precisely. And in fact, they've been in wide demand outside this research protocol, about 30,000 copies have been printed and circulated throughout the country. The second way to ensure the quality is that many of these sessions were videotaped, so an outside observer could guarantee that the treatments were discriminable by somebody who didn't know which arm of the therapy was given. The therapists were all very well trained people. The reason I'm saying this preface is because it's important to understand that under the conditions of this study, I think we are maximizing the effects that current behavioral approaches can have, independent of the matching issue. Now, how well do the patients do? Aside from the fact that the three groups did more or less the same, the absolute sobriety rates for the year ranged between 25 and 40 percent, depending on whether the patients had had a period of inpatient treatment or not. This abstinence rate, which is quite good, is probably a little bit better than most current programs achieve. It's important to understand that alcoholism and other addictions are chronic relapsing disorders. So the way we would look at a condition, for example, arthritis, is not whether we can cure it absolutely, although that's the hope, but rather how many days free of symptoms and pain can we afford the patient by the best treatments that are available. We hope to cure alcoholism in our lifetime. We hope to get total abstinence or no problems from alcohol as a goal of all of our research. What we can say now is that somewhere between 25 and 35 percent of patients are likely to remain abstinent for at least a year. And as we know from long-term longitudinal studies like those of Dr. George Vaillant, the longer you stay in the abstinent state, the longer you are likely to stay in it. And the biggest dropoff tends to be in the first few months. Most treatment programs, and I think this is a precise answer to your question, will lose the majority of their patients, I believe, to relapse. Many of them will come back, but sometime during the first three or four months they will stop treatment. That's the most dangerous time for relapse. So in summary, I would say that a minority of patients remained permanently abstinent. A good chunk of the patient population will have intermittent abstinence, which is far better than drinking continually, both in human, financial and medical terms. And a fraction of the patients, which is not inconsiderable, will not do well at all. Mr. Porter. Dr. Gordis, some of the popular press coverage of the trials' findings gave the impression that the Federal Government spent $27 million on a study, and now we don't have any better idea than we did before on what works in alcoholism treatment. How have you responded to that characterization? Dr. Gordis. Well, the only accurate part of that statement is the cost. Other than that, the conclusions, I think, are erroneous. First of all, this was the largest, most carefully controlled study of behavioral treatment of alcoholism ever conducted. And it told us several important things. It told us first of all that among the 10 criteria which were selected a priori as patient characteristics for matching with these three very popular and well written up kinds of treatments, none offered particular matching advantage to one arm of the treatment or the other. On the other hand, it shows the limits of what we can accomplish with contemporary behavioral treatment. It also assures the treatment community that when you consider the dramatic drop in drinking that the patients in all three arms of the treatment showed from the time before they came in to the time they completed the study, that treatment actually is quite effective. Project MATCH demonstrated that any treatment program that delivers one of these treatment modalities in a quality way is likely to do a lot of good for the patient. The kind of statement which you made, which we've heard occasionally also, simply is not so. evaluations of alcoholics anonymous Mr. Porter. We discussed the fact last year that Alcoholics Anonymous had never undergone rigorous scientific evaluation. Does Project MATCH provide the scientific evidence that has been lacking, since it included an AA component? Dr. Gordis. Not in the strictest sense. But it does shed some light on the AA-related component of Project MATCH. Sometimes people have misunderstood the arm of Project MATCH dealing with 12-step facilitation as meaning, simply sending people to AA. That's not what happened here. All arms of the treatment involve a one-on-one therapeutic series of events between the patient and the therapist. The one involving 12-step therapy was a detailed examination of the first three steps of Alcoholics Anonymous with the patient by a professional trained therapist. Then the patient would go to AA meetings, was encouraged to do so, and would come back to this professional trained therapist to explore his or her reaction to the meeting, and what attitudinal changes might be suitable in view of thesereactions. That's not the same thing as sending patients to the AA. In fact, if we look at AA's own data from the headquarters office published about six years ago, AA is not a scientific organization but one must commend them for their candor in looking at this issue, AA was very concerned about meetings in general, and about the large loss of people who go to meetings early on. And it turns out that within about three months of the time that people go to their first AA meeting, only about 5 or 10 percent of them are still going to meetings. It doesn't mean that many people don't come back and finally get it together. But AA is quite aware of the tremendous loss in meeting attendance, even during the first few months. And I must say that the 12-step facilitation arm of Project MATCH did a lot better than that. The more general answer to the question of effectiveness of AA cannot probably be studied in its pure form. Let me tell you the reason why. If we were to study, for example, a medication, and it's been done with antabuse, which is a drug used in alcoholism treatment to provide an aversity of response to alcohol if you drink, you don't take people who take the drug and compare them to people who are unwilling to take it. In the antabuse study, which was done by Dr. Richard Fuller of our Institute some years ago in the VA system, he compared patients, all of whom were willing to take antabuse. Some patients got it, some got placebos. This was an excellent study. Ideally, to study AA, one would want to do the same thing, that is, take a group of people who would be willing to go to AA and some who don't. That kind of idealized situation could probably not be practicably applied to AA. And there are major problems with anonymity, and there are major problems with destroying the very phenomenon you're studying by too much observation. There have been studies on sponsorship in AA and some ancillary questions like that. But I think in the long run, the kind of rigorous control trial that's been applied to virtually every other aspect of health care, including alcoholism now, probably would be, it would be difficult to do AA studies along those lines, in my view. Mr. Porter. Thank you, Dr. Gordis. Mr. Miller. medications for alcohol treatment Mr. Miller. Where do we stand with respect to a medical treatment of alcoholism? What's available? Dr. Gordis. If by medical treatment you're talking about medications for alcoholism, there are several. The oldest one dates from the late 1940s. It's called antabuse. And it was a drug which did not obliterate the craving for alcohol. What it did was threaten the patient with an unpleasant reaction if he or she were to drink. It turns out that although there's been a loss of interest in that drug, because of the excellent control study on antabuse which I just referred to in my response to Mr. Porter's last question, it turns out that probably it needs a little bit more exploration. Because there's some evidence that under supervised conditions, or even in a marriage where one spouse stays in the marriage on the condition that the other takes it, the results can be better. It's a very interesting drug. And one of the things that we are supporting now is the development of a derivative of the drug. Its metabolism has been studied extensively by Dr. Morris Faimen in Kentucky. And we know now that the first metabolite of antabuse that the body produces is a sulfoxide derivative of the half of the antabuse molecule that is probably the business end of the antabuse molecule. And there's some hope that this would be a more effective use of antabuse and that it would have fewer side effects. So that's one thing we are actually working on. We have contracts out now to prepare the chemically pure new compound, and to try it out for toxicity. The more hopeful areas that I addressed in my opening remarks have to do with drugs which seem to abolish the hunger for the substance during the time the patient is off it. Two years ago, the FDA approved naltrexone, which is an opioid antagonist, for the maintenance of sobriety during abstinence after detoxification has been complete. Two things were demonstrated by studies, three, actually. First, naltrexone was not being used independent of counseling but in parallel. That's very, very important. But the second thing was that among the patients who took naltrexone, it did two things. It lengthened the time to the first abstinence violation or the first relapse. And among the people who did slip, that is, they started experimenting with alcohol again, it reduced the likelihood of them going on to a full-blown binge. So naltrexone was shown to be effective in these carefully controlled studies by investigators both in Philadelphia and at Yale, and FDA approved it, and now it is increasingly being used in the treatment community, but at a rate which I wish was faster. But it is being generally incorporated, but not to replace counseling, but as an addition to it. Nalmafene, which is another orally active opioid antagonist, has been studied extensively by Dr. Barbara Mason in Florida. And it turns out to be very promising, indeed. The drug in Europe called acamprosate, which is calcium acetyl homotaurinate, is a drug which probably acts differently than the other two. Originally thought to react on the GABA receptors, it's now known probably to act on the so-called NMDA receptor, which is a subtype of the glutamate excitatory receptors. And in European trials, this drug has shown promise also of helping to maintain abstinence. They've had larger numbers of patients in the European trials than here. But the design of the trials and the attention to detail I think were as good as with our naltrexone trial approach. What's happened is, Lipha Pharmaceuticals, the company that manufactures it, has obtained an IND to begin experiments in this country. And as I said before, the NIAAA is helping them design the experiments to test out this drug in this country. And in fact, the books that were developed with Project MATCH are turning out to be very useful to the pharmaceutical industry in the behavioral side of the treatment. a cure for alcoholism Mr. Miller. You mentioned a desire to have a cure for alcoholism. What would be the definition of a cure, a realistic one, five years from today? Dr. Gordis. I don't think we're going to have it five years from today, but I'm an optimist. The goal is to find a cure, but meanwhile to decrease the consequences of drinking and its abuse. A cure would be, I think ideally a cure would be somebody who either drank or didn't drink at will, who had no tremendous craving to have it, a social drinker, in my definition, is somebody who doesn't really care very muchwhether he has it or not. And a cure would be to restore alcohol to normal life priorities where it doesn't dominate one's life. Mr. Miller. Is that the medical route? The behavioral versus the pharmaceutical route, so you're having, I guess to do them together? Dr. Gordis. Yes, I would accept what you said absolutely, with one caveat. It's not versus. One of the nice things that's happening in research in general now is that this gulf between the behavioral world and the so-called biomedical world is narrowing. We know, for example, that in the case of obsessive compulsive disorder, something outside of our domain, but somewhat related, that behavioral therapy, when successful, has the same effects in PET scans in the head of the cordite neural regions of the brain as serotonin uptake inhibitors do in those patients who are successfully treated with medications for that disorder. This just shows that the potent therapy, even of a verbal kind, has the potential of altering the chemistry and the circuits of the brain much as drugs do. Drugs may be more efficient, on the other hand, they're somewhat more global. Behavioral therapy is somewhat more targeted to the behavior you want to change. And I think that this distinction between the two is gradually becoming obliterated, and we need both. Mr. Miller. One final question. I was talking with Dr. Leshner about this. The private sector is not spending a lot of effort and money on cocaine addiction. But the private sector, probably, and I hate to assume anything, the private sector is probably pursuing alcoholism, because there is a potential return for them, is that right? Is there a very large effort there? Dr. Gordis. There is some effort. I think there's probably more effort in the case of alcohol than there's been in the case of the illegal drugs. You see, naltrexone has been available already for 20 years or so. It was developed originally, of course it's an opioid antagonist, hopefully as a treatment for heroin use. By and large, it has only been slightly successful. Because although it does block the effect of heroin when taken, it does not abolish the craving for the drug, which is the thing that drives the relapse. So except for a small group of very well-motivated people, say like doctors who are addicted and are threatened with loss of their license, naltrexone has not turned out to be a potent therapy for heroin addiction. But it's interesting, in a confluence of both clinical and basic research, the basic research finding was that naltrexone in animal models inhibited certain kinds of ingestive behaviors, including alcohol and including calories, especially those from carbohydrates. That animal research, together with an observation made during drug treatment of heroin addicts who were also using alcohol, combined to lead to the experiments using naltrexone for alcoholism. And that's what led to this. Now, since the drug was already available, it had been manufactured by Dupont Merck under the name Trexan, the drug was made available for the treatment of alcoholism under the new name, naltrexone. We don't have anything in the pipeline in this country for new drugs created just for alcoholism, but there are several existing medications that I didn't mention that are being tried. Acamprosate, from Europe, is destined to be used only for alcoholism as far as I can see right now; that's a second example. There probably is some market for acamprosate. And I think as one company succeeds and makes some money, it will be an incentive for other companies to proceed along those same lines. Mr. Miller. Thank you, Mr. Chairman. Mr. Porter. Thank you, Mr. Miller. Mr. Wicker. practical applications for genetics research Mr. Wicker. Just one question, Dr. Gordis. Your testimony mentions significant strides in demonstration that vulnerability to alcoholism is inherited. And you go on to talk about a study and an assessment about genetics. And strides in chromosomal locations. You say each chromosomal location contains these genes, the next step is to identify the precise genes. So we're not quite there yet? Dr. Gordis. That's correct. Mr. Wicker. If you could just tell me, what do you envision as the practical application for this research, once you finally get the research over with? Dr. Gordis. I think there are several practical applications here. Two of the payoffs, I think, which I mentioned briefly earlier, are very practical. The most important one, I think, is that when we find a gene, we find is a recipe for the body's making of proteins. The protein is the functioning part of the body's machinery. The enzymes, the receptors, the structural elements of the cell and so on, much of that is protein. So the gene is a recipe which tells the body how to make a protein. If the gene is different in alcoholic individuals than it is in normal people, it means that there's something about the protein which is being made which is different. If it's different, it has a slightly altered function. It can be very different, or subtle differences which combine with other genetic changes, cause a whole picture where the patient is sufficiently different to be at risk. The first payoff from this kind of research will be, once we understand what these genes are and what their function is, to then find medications which are going to interfere with this abnormal function. Genetics research is going to be, I think, one of the most potent routes for developing new medications for the treatment of alcoholism. A second payoff from genetic research will be prevention. Because it's clear that the highest risk people are the ones most likely to get into trouble. So there will be an aspect of genetic research which will permit us, I think, to target prevention in a more effective way. genetics testing Mr. Wicker. When do you anticipate that individuals, that don't yet have a problem with alcohol, would be tested? Dr. Gordis. That remains to be seen, and that raises the whole issue of genetic testing in general. And I don't know if you want me to go into it. Dr. Varmus certainly is a person who has had to discuss these issues in so many ways and in such an articulate way that I don't think I would do as good a job. But the fact that we can test---- Mr. Wicker. That remains to be seen. [Laughter.] Dr. Gordis. The issue of when we do genetic testing for anything is a problem which I think genetics-oriented ethicists are discussing in many spheres of medicine. Even issues which are much closer to a very practical payoff as far as therapy and so on, such as testing for breast cancer genes, are under some debate. I think the issue ofalcoholism gene testing is a more complex issue. But we will wrestle with this when the time comes, bearing in mind all the potential traps there are in the ethics of genetics testing. Mr. Wicker. I'm guessing that you might have to test children or adolescents? Dr. Varmus. You might want to start with children in families where there's a known history of alcoholism. And you probably would want to start at the time when they become of legal age. It depends a little bit on what kind of remedies might be available. At that point, there may be a variety of strategies for trying to employ behavioral methods for averting alcoholism. I think that would be one of the key issues, what's available. That's the issue that we face in other spheres where genetic risk assessment is an issue. Of course, underlying all of this is the need to have protections in place so that people are not stigmatized, so they don't have a poor self-image, there are a whole host of things that pertain to testing of this kind. Dr. Gordis. We share some of the issues which this problem raises such as: discrimination in employment and in insurance. But in our field, there's the extra level of stigmatization, as Dr. Varmus just alluded to. And these are issues we're going to have to deal with. But it's not right down the pike yet. Mr. Wicker. Thank you. Thank you, Mr. Chairman. Mr. Porter. Thank you, Mr. Wicker. Ms. Northup. comparing drug and alcohol use and abuse Ms. Northup. Yes, Doctor, I'd like to pursue a line of questioning comparing drug and alcohol use and abuse. Let's just see where you all are going on these questions. Do you see alcohol as a drug? Dr. Gordis. Oh, yes. Ms. Northup. Okay. And do you see a difference between the other drugs and alcohol? Dr. Gordis. Yes, there are many differences. Ms. Northup. Including, and especially in my mind, rate of addiction? Dr. Gordis. Yes, there are differences in that, too. Would you like me to comment on some of the points you just raised? Ms. Northup. Well, do you have a rate of addiction for alcohol that you would think would be about the average in the adult population in this country? Dr. Gordis. Well, one can make some guess of the likelihood of addiction for alcohol, say, compared to cocaine. Cocaine is a far more addicting substance than alcohol, and so is heroin. Ms. Northup. And tobacco? Dr. Gordis. And tobacco is probably also more addictive. The reason why the alcohol problem is bigger as far as number of lives lost and cost is because so many more people are involved with it, and it's a legal substance and much easier to get. As far as the addiction potential of the substance, alcohol is somewhere in the middle. Ms. Northup. That's sort of contrary to the statistics that I have used and talked about in the past. I have heard there is about a 12 percent rate of addiction for alcohol, versus 60, 85 percent depending on what drug you're talking about. Dr. Gordis. Well, we know that most adults in this country who drink don't get into any trouble from alcohol. Ms. Northup. Right. Dr. Gordis. Only about 10 percent of them do. So that's telling you something. On the other hand, if you experiment with cigarettes, the chance of becoming an addicted smoker are quite high, and cocaine likewise. So addiction potentials, meaning the odds of any individual becoming addicted once exposed, are higher for tobacco, cocaine and heroin. The size of the alcohol problem is bigger because the population involved is bigger, and there are other reasons, too, such as cost. Alcohol has a whole range of medical complications, which by and large, these other drugs don't have to the same extent. [Clerk's note.--Later corrected to ``15''.] Ms. Northup. Well, let me ask you about another factor that I think would distinguish them. I sort of forgot where I was going on that. Dr. Varmus. I think you're saying the same thing. Ms. Northup. Yes, I think that you're saying the same thing, too. I guess the question I have is, what is your goal? I know what the other question is. Would you agree that in most other substances, maybe because of the addictiveness of them, and also because of other potencies, that what we would recommend to most people is that they don't use those substances at all. Dr. Gordis. Correct. Ms. Northup. And do you all make that recommendation to the entire population? Dr. Gordis. No. Ms. Northup. Okay. I guess that's the question I'm getting at, that is prevention. Your goal is not to begin recommending to the American public in general that they don't use alcohol? Dr. Gordis. Oh, not at all. Let me make another point in line with what you're talking about. You know, alcohol kills more kids and costs more than all the other illegal drugs together. It's the biggest problem for adolescents. But most of these people are not diagnosable alcoholics. You see, there are several aspects to this. When people talk, even among adults, about moderate drinkers, moderate drinkers can get into terrible problems also. consumption Ms. Northup. Right. Dr. Gordis. Because moderate drinking, the way we define these terms, is in terms of average use. Ms. Northup. Sure. Dr. Gordis. So if you drink seven drinks a week, that's one way of doing it. You can have those seven drinks in a two and a half hour period on Saturday night, that's also listed in many of the data analyses as seven drinks a week. So the issue of concentrated or binge drinking is important, even for the moderate drinkers. Ms. Northup. Sure. Dr. Gordis. But most of the kids who are killed on the highway, get into violence and so on, are not alcoholic by any formal diagnostic criteria. So the issue of alcohol abuse, which is the misuse of alcohol causing harm short of a dependent syndrome, is a terrible problem which affects adolescents in a very, very big way. effects of alcohol on development Ms. Northup. I have a question of alcohol and addictiveness. Let's go to addictiveness, do you find that age at which the onset of use of alcohol is a factor? For example, if a 13 year old uses alcohol, are they more likely to become addicted to alcohol? Dr. Gordis. Yes, in general that's probably true. I think it's true of alcohol or tobacco, the longer the initial experience with these substances can be postponed, the lower the odds of addiction or dependence setting in. Ms. Northup. Is there any pathological reason for that, or is it just that a future adult that's going to be attracted to drinking is going to be attracted at an earlier age, and therefore they are more prone to be addicted? Or do you think that the youngness of their cells and so forth actually make the addiction more likely? Dr. Gordis. A very deep and complex question. Ms. Northup. No answer. Dr. Gordis. The question you're asking is a developmental one. Is there something in the partially mature, but not completely mature, nervous system and the other organs, which makes the risk of addiction if you initiate alcohol at that time greater than if you initiate it at 20. Or are these issues of simply a psychosocial nature, like for example, by the time you're 20 or 21 or 22, you may be married, and we know that that has a beneficial effect on abusive drinking, short of dependence. You may have a job where the threat of losing it is more severe and so on. We know that there are indicators of risk in youth from a behavioral standpoint. People with behavioral disorders in youth, a mixture of shyness and aggressiveness at 5 years of age, for example, predict more trouble than at the age of 15 and so on. But the question you're asking, frankly, I don't know the answer to without looking it up or thinking about it some more. Because the question of the immaturity of the nervous system at age 13 making it more vulnerable for future addiction than at 19 is a very interesting one. And I'm not sure of the answer right now, but I'm certainly going to think about it. Ms. Northup. This strikes me as very important. Dr. Gordis. Yes, I think you're right. Ms. Northup. Let me ask you another question, though. Do you recommend no drinks to pregnant mothers? Dr. Gordis. Absolutely. Ms. Northup. Okay. And have you disseminated that information? Dr. Gordis. Oh, yes, in many, many ways. First of all, the Federal Government has helped us by mandating that on all beverage alcohol, there's a warning label which includes a warning about drinking during pregnancy. NIAAA has supported 20 years of research on this topic, in which we've looked into social aspects of it, as well as very interesting new neurological or biochemical mechanisms, which define how alcohol damages the fetus. Our prize winning publication, ``Alcohol Health and Research World,'' published this issue on fetal alcohol effects and drinking during pregnancy a couple of years ago. It's a kind of a bible for the field for people outside science. I think it's wonderful, and I commend it to your attention. This booklet, ``Drinking and Your Pregnancy,'' has just been prepared. It's being circulated by the thousands, with the help of NOFAS, an organization dedicated to fetal alcohol problems. We have a wide range of research on this topic. I think we're doing a pretty good job of circulation. Ms. Northup. So any doctor that would tell a patient, one drink a day would go contrary to any sort of evidence you show. Dr. Gordis. It's contrary to our recommendations. It is not contrary to everybody's opinion. I must say that there are still a minority of people who feel that since we haven't shown definitively what the threshold for danger is, that to say they shouldn't have one drink a day would impose a fear and a guilt on women and so on. But the tendency in research, based on very sophisticated tests of infant development and, intellectual function, has been to reduce the recommended level of drinking which is safe. Now, obviously, the heaviest drinkers are the ones who have the most physically malformed children. But there are very subtle and yet important neurological, psychomotor and intellectual development deficiencies which can be shown on a group basis, even at levels of alcohol consumption which are considered moderate. My own feeling is, and the way I put it is, you've got nine months to make the best baby you can. Save the drinking for later. Ms. Northup. I agree. Unfortunately, I don't think that's the universal message that is told to every woman in every doctor's office. Thank you. That's all, Mr. Chairman. correlation of heavy drinking to fetal alcohol syndrome Mr. Porter. Thank you, Ms. Northup. Let me follow up on that and ask, do researchers have any idea why only about 6 percent of children born to women who drink heavily during pregnancy show signs of fetal alcohol syndrome? Dr. Gordis. We don't know the answer to that question yet, Mr. Porter. There are wide ethnic variations in that number, too, by the way. In Native American population, it goes up higher, to 29 percent and higher birth rates with fetal alcohol syndrome. Among African Americans, the incidence is a little bit higher. We know many of the mechanisms now which are purported to cause malformations. And if you're interested in the scientific aspects of this, I'll be happy to answer that. There may be other factors, those we don't know yet, which contribute to differential risks. Some of them may be environment, such as different nutritional issues. People have different diets, and some of them are not so hot. There's a possibility there's a genetic issue here as well. That is that some of the babies may be born with certain genes, that is, those which deal with the rate of alcohol metabolism. They may even inherit such genes from the father, rather than the mother, which make them more likely to be vulnerable to fetal alcohol effects, given the same dose of alcohol taken during pregnancy. This is being explored now, but right now we don't know the answer to that question. effect of alcohol on estrogen Mr. Porter. Research findings were reported in December, that even small amounts of alcohol, like half a glass of wine consumed by women taking oral estrogen, causes their estrogen level to rise dramatically. This seems to put women in a dilemma. The combined effect of estrogen and alcohol could be beneficial in preventing osteoporosis and heart disease, but could put women at greater risk of breast cancer, since these outcomes are associated with estrogen levels. What should physicians be recommending for their patients at this stage? Dr. Gordis. A very important question. The studies you're referring to are done by Dr. Nancy Mello and her colleagues at Harvard, and there were similar studies done by Dr. Judith Gavalier at Oklahoma. And it turns out that even moderate doses of alcohol, that is, doses of alcohol which bring the blood level up to 30 or 40 milligrams percent, equivalent to say, two or three drinks, were able to kick up the estrogenlevel rapidly. This was estradiol, the so-called E2, among women who were taking that compound. And estradiol, of course, has a multiplicity of effects, especially in post-menopausal women. On one hand, it protects against menopausal symptoms, it protects against osteoporosis, the thinning of the bones which can lead to fractures and so on. On the other side, it increases the risk for breast cancer. And even without alcohol use, of course, these things should be explained by the physician to the patient. With alcohol use, I think the physician is obligated to explain that regular, moderate drinking, will increase, in effect, the dose of estrogen the woman is taking, and therefore probably has a modest increase, I would guess, on the risk of the negative side of estrogen-taking, given all its benefits. And the woman has two options, or the doctor does. One is to reduce the amount of the drinking, which may be the easiest thing to do, because the doctor then is in better control of what's going on. But the doctor might recommend a diminution in estrogen dose. The problem with that is, since the drinking is irregular and unpredictable, it puts the medical recommendation, I think, in a bit of a limbo. So my recommendation, given the literature that I read on this, and my thinking about it from the point of view of a clinician, would probably be to recommend that the alcohol be taken gingerly. serotonin Mr. Porter. You referred to findings researchers in Oregon reported that in knockout mice, the loss of a single gene that affects the neurotransmitter serotonin is enough to turn healthy rodents into heavy drinkers. The mice were also found to be abnormally aggressive. Serotonin seems to be implicated in a variety of diseases in which impulse control is impaired. Are you working jointly with the Drug Abuse and Mental Health Institutes in this research field? Dr. Gordis. As a matter of fact, serotonin is one of the topics which is being heavily investigated within our intramural program. And there are many collaborations going on, especially with the National Institute of Mental Health, on aspects of serotonin physiology and genetics, which relate to a variety of disorders, other than alcoholism. The experiments that you're referring to were done by Dr. John Crab and his associates in Portland, Oregon. And what it amounted to was the use of a model mouse where the serotonin 1B receptor had been knocked out by other researchers. So this animal was available. And its aggressiveness was already noted. But because of the fact that serotonin seems to be involved in many functions, such as sleep, sexual behavior, sedation, and also alcohol use, he decided to see what their behavior would be in relation to drinking. And it turned out that compared to the wild type animals from which the knockouts were derived, the animals drank about twice as much alcohol as their wild type colleagues. And there was another very interesting finding here, and that was that the physical dependence and withdrawal upon cessation of alcohol and tolerance could be distinguished. The animals which were the knockouts developed tolerance to the effect of alcohol much more slowly than the wild type animals. And yet, the ability of these two kinds of animals to demonstrate physical withdrawal upon cessation of chronic alcohol use was identical. This is a very important issue, because the question of whether tolerance and withdrawal share the same neural circuits has been argued in literature for a long time. And this experiment tends to distinguish them as far as their neural circuits not being identical. In the presence of Dr. Varmus, I hate to talk about an issue which is so close to his great skills on knockouts. It suggests that the serotonin 1B receptor is involved in the behavior relating to alcohol preference. It's not an iron-clad proof. Because as we know from knockout experiments, whether it's the lack of a serotonin receptor or the compensations that the animal may undergo by virtue of not having it since birth, which may affect other systems aside from the 1B receptor, is not certain yet. But certainly, it's a very promising avenue of research. liver transplantation for alcoholic liver disease Mr. Porter. Your Institute co-sponsored a meeting with NIDDK last year on liver transplantation for alcoholic liver disease. What were the conclusions from that meeting? Dr. Gordis. Well, the conclusions were those which have been collecting in the literature over a period of several years. About 25 percent of liver transplants for chronic liver disease, which is going to be fatal without transplantation, are done for alcoholic end stage liver disease in this country. There are about 3,000 done a year, and about 700 were done for alcoholic liver disease. It turns out that the survival rate and rejection rate of these patients with alcoholic liver disease is no different than the best survival groups for other categories of liver disease. That's number one. The second conclusion was that the recidivism rate to drinking again is considerably lower in this group than it is in general treatment programs, a question that you asked me about before. The reason for that second finding is likely to be the selection bias by which patients are selected and sorted before they enter the transplant program. Most programs demand a several month period of sobriety. When we're talking about trends we say that once you get through the first three months of sobriety, your likelihood of remaining sober later, is better. Second of all, they often are required to have efficient social supports and be involved already in some sort of treatment for alcoholism. So it turns out that among these patients, the survival rate was good as any other. Their return to drinking was less, and among those who died, it wasn't drinking which killed them, it was the same reasons that killed other people who died after liver transplant, rejection, failure, viral infection and so on. As for suggestions for the future, several recommendations were made. And in fact, we're now engaged in a collaborative effort with the National Institute on Diabetes, and Digestive and Kidney Diseases to put out a grant announcement on several issues which are of common interest to both Institutes. I think the two prominent questions which we'd like to investigate following this liver transplant issue are number one, can we improve the results if what we've learned about the efficient ways of doing alcoholism treatment can be brought to this community. There are two worlds here. There's the alcoholism treatment community on one hand, and then there is the liver transplant community on the other. But all the techniques that we've learned about treatment of alcoholism have really not been applied in a systematic way to post-transplant care. And that's one area where wereally ought to do some research, although in answer to one of the questions before, one of the grants we have on naltrexone is actually studying the use of naltrexone in post-transplant patients, just as an aside. The second issue, which is probably more difficult to do and more expensive, has to do with whether the genetic background of a donor liver has any effect on its survival in the alcoholic recipient. And I think you can see the implications of this, both as far as the theory and as far as the dimensions of such a project. But it's been raised as something that might be worth considering. Mr. Porter. Dr. Gordis, listening to you, it's like an encyclopedia on everything that's transpired in the field. You're obviously extremely knowledgeable and we appreciate the excellent job you're doing at NIAAA. Thank you for your testimony this afternoon. Dr. Gordis. Thank you very much. Mr. Porter. The subcommittee will stand in recess until 10:00 a.m. tomorrow. [The following questions were submitted to be answered for the record.] [Pages 1115 - 1176--The official Committee record contains additional material here.] Wednesday, March 5, 1997. NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES WITNESSES PHILLIP GORDEN, M.D., DIRECTOR, NIDDK L. EARL LAURENCE, DEPUTY DIRECTOR CHARLES R. ZELLERS, FINANCIAL MANAGEMENT OFFICER HAROLD VARMUS, M.D., DIRECTOR, NATIONAL INSTITUTES OF HEALTH DENNIS WILLIAMS, DEPUTY ASSISTANT SECRETARY, BUDGET, DEPARTMENT OF HEALTH AND HUMAN SERVICES Introduction of Witnesses Mr. Porter. The subcommittee will come to order. We're pleased to welcome Dr. Phillip Gorden, the Director of the National Institute of Diabetes and Digestive and Kidney Diseases, to testify. And Dr. Gorden, would you please introduce the people who are with you at the table and then proceed with your statement. Dr. Gorden. Thank you, Mr. Chairman. To my far left is Mr. Charles Zellers, our Budget Officer; Mr. Earl Laurence, our Deputy Director; Dr. Varmus and Mr. Williams I think you know. Opening Statement Mr. Chairman, Mr. Wicker, members of the committee. The NIDDK leads the national biomedical research effort to combat some of the most important, chronic and costly diseases in this country, including diabetes, endocrine, and metabolic diseases; digestive diseases and nutritional disorders; and diseases of the kidney, urologic tract and blood. In meeting this challenging research mission, we forge collaborations with other NIH components as well as with non- profit foundations and commercial enterprises. Our approach is to deploy resources and capitalize on emerging technologies across the spectrum of the diseases we address. We seek to understand the underlying cause and course of disease, and develop effective treatments and preventive strategies. At different points in time, based on scientific opportunities, we pursue all or some of these avenues, ranging from the most basic studies of molecular biology to major clinical trials. As a special way to emphasize this broad NIH approach, Dr. Varmus and I will co-sponsor a conference in the near future related to diabetes research. The conference will include all Institutes involved in diabetes research and will focus on special opportunities and directions that this broad interdisciplinary approach brings to diabetes research. This forum will offer a special opportunity for the Director of NIH and a number of ICD directors to meet directly with leaders of the diabetes research community. We believe this will be a constructive and informative approach. This continuum of research, from clinical science to very basic science, to which I have referred, is best illustrated by a few examples. Let me describe the point on this continuum that is closest to medical practice. For example, we are currently engaged in four multicenter clinical trials, all of which were made possible through knowledge derived through basic and pre-clinical research about biologic mechanisms. In diabetes, one trial focuses on immune modulation, to halt or delay the onset of insulin-dependent diabetes in high risk children and adolescents. A second diabetes trial centers on the use of drug therapy and lifestyle changes to prevent or delay the onset of non- insulin dependent diabetes, which usually occurs in later life and disproportionately affects minorities. Fundamental research also made possible our ongoing trials studying methods to ameliorate the course of kidney function deterioration in African-Americans with hypertensionand to pursue non-surgical approaches to treating benign prostatic hyperplasia, or BPH, one of the most prevalent conditions in our aging population. At the middle of the continuum, we are funding cutting edge research where clinical applications appear promising but are not yet completely feasible. A prime example is found in the NIH special emphasis area, ``The Genetics of Medicine.'' This includes NIDDK studies to sequence and clone the disease- causing genes; identify proteins they produce; and develop the means to replace or repair them, or circumvent the defects they cause. Diseases targeted here for which major discoveries have occurred include cystic fibrosis, polycystic kidney disease, diabetes, hemochromatosis, and hereditary pancreatitis. Other cutting edge research relates to the special emphasis area, ``The Biology of the Brain.'' This includes the NIDDK funded discovery of the obesity gene and its hormone product, leptin, which works in the brain to regulate both energy intake and utilization. Spinoff research has had an enormous positive impact on the U.S. pharmaceutical and biotechnology industries. Also at the center of the NIDDK research continuum are studies focused on the special emphasis area, ``New Approaches To Pathogenesis.'' An excellent example is research following up on the discovery that the bacterium, H pylori, is a causative agent of peptic ulcer disease, and possibly gastric cancer. In closing, I would like to turn to the first part of the NIDDK research continuum, the engine of basic science that drives all of our success stories. One example is transgenic technology. Another example is the development of experimental mouse models in which a particular gene has been deleted or ``knocked out'' to confirm hypotheses about disease-causing genes and to help researchers then develop and test therapeutic strategies. Examples here include models for Tay-Sachs disease, inflammatory bowel disease, bone developmental abnormalities and many others. Another technology of the future is structural biology, which enables us to visualize the three-dimensional architecture of molecules in order to study drugs to inhibit or to enhance activity in a very special way. Major examples of this technology include the integration of the AIDS virus; the mechanism of tumor suppressors; and the action of inflammatory mediators. It is the continuum of research from fundamental science to clinical science that we will vigorously support with our 1998 appropriation. Mr. Chairman, the budget request for the NIDDK for fiscal year 1998 is $821,164,000. I would be very pleased to answer any questions you may have. Thank you very much, Mr. Chairman. [The prepared statement follows:] [Pages 1180 - 1183--The official Committee record contains additional material here.] diabetes emphasis Mr. Porter. Thank you, Dr. Gorden, for your fine statement. As we discussed last week, I don't want to participate in a body count approach to Institute funding allocations. I agree with the position of the NIH leadership of identifying and funding cross cutting areas of scientific emphasis. But I think it is legitimate for the committee to try to ensure that all diseases share in these areas of specific emphasis to the extent their scientific promise permits. For example, diabetes research seems to dovetail nicely with at least three of the areas of scientific emphasis: new approaches to pathogenesis, new preventive strategies and genetic medicine. Dr. Gorden, do you plan to apply the $10 million increase in your Institute's budget for areas of special emphasis to diabetes research? Dr. Gorden. Yes, we certainly do, Mr. Porter. Of course, this will have to be balanced to some extent with our other programs. But certainly those areas are ones that diabetes research is included in. Mr. Porter. Dr. Varmus, we have already heard from the Eye, Genome and Allergy Institutes on their diabetes research. From your perspective of looking at NIH research in the aggregate, is diabetes increasingly a campus-wide effort with more institutes involved, and who are the other institute players in diabetes research? Dr. Varmus. Well, there have always been a large number of institutes involved in this research. In fact, I recently had a look at a report by the National Diabetes Research Coalition, which lists at the end of the document about nine offices, centers and institutes that play a role in diabetes research. As Dr. Gorden mentioned, he and I have decided to have a workshop in the near future, not so much to hear the latest findings as to define the various areas of diabetes research, including research on diabetes complications in the kidney, the eye, and the heart. We want the fundamental aspects of diabetes research aired in a trans-institute setting so that institute directors and program officers, as well as other scientists and advocacy groups, can hear about the opportunities that exist and assess the degree to which we are adequately supporting them. identifying areas of research emphasis Mr. Porter. Dr. Gorden, when the NIH leadership meets to discuss the areas of scientific emphasis that will be reflected in the budget, have you proposed new areas that would match your Institute's research portfolio well? Dr. Gorden. We certainly try to, Mr. Chairman. We put forward what we think are the most promising areas of research across the five or six particular categorical areas. And we believe very strongly in pursuing those areas, and we will do our very best to pursue them. budget increase Mr. Porter. Do you think a 2.2 percent increase in your budget is sufficient to pursue them? Dr. Gorden. Well, it will basically permit us to continue the things that we have in motion. It will not permit us to add any really substantially new items to our research agenda without something else having to give in its place. stress in diabetes Mr. Porter. Dr. Gorden, regarding type II diabetes, we often hear discussions of weight, diet, exercise and the like in reference to this form of diabetes. Has any research been done relating to stress and the ability of the individual to handle stress in their lives and whether this has a role in this disease? Dr. Gorden. There have been a number of studies that relate to glucose control and various aspects of stress in relationship to this. This is a somewhat difficult area to get a complete handle on. But there's no question that one's ability to care for themselves and one's ability to maintain the regimen that they are placed on is governed to some extent by what kind of stress they suffer in their lives, or they are exposed to. Certainly, stress is something that stimulates certain endogenous functions such as the sympathetic nervous system. The sympathetic nervous system has a great deal to do with glucose homeostasis, that is, the levels of glucose in the blood. So there are lots of indirect reasons that we could relate to stress, and certainly, it's a promising and important area that we need to consider. Mr. Porter. Is there any research being done now in this area? Dr. Gorden. We have several grants that relate generally to stress and glucose control. Mr. Porter. Thank you, Dr. Gorden. Mr. Wicker. immune modulation in diabetes Mr. Wicker. Thank you, Mr. Chairman. Dr. Gorden, it's good to have you before the subcommittee. And members of the subcommittee will note from Dr. Gorden's vitae that he was born in Baldwyn, Mississippi, which is in the first Congressional district. And I'm mighty proud to see him testifying so well before the subcommittee. I have a particular personal interest in the subject of diabetes, because of my little niece, Rebecca, who lives in Virginia Beach, and who was diagnosed several years ago with diabetes. She's doing quite well. She takes insulin every day. And I guess I would want you to comment on what progress has been made in that type of diabetes. I notice in your testimony you say there's a trial that's focused on the immune modulation to halt or delay the onset of insulin dependent diabetes in high risk children and adolescents. And you mentioned knowledge gained in that regard concerning the development of highly accurate tests for predicting the risks of developing diabetes. I wonder if you could elaborate for the subcommittee on that subject. Dr. Gorden. There are several aspects, Mr. Wicker. The first is that the individual who has diabetes already is one that clearly should, I think, gain an enormous comfort from a recent study called the Diabetes Control and Complications Trial, which was one of the largest clinical studies ever conducted in diabetes research. In fact, it was the largest. It was completed approximately three years ago. It was a multicenter trial involving 1,440 patients. It demonstrated unequivocally that careful glucose control can ameliorate or prevent the eye complications of diabetes by about 75 percent, the kidney complications by about 50 percent, and the neurologic complications by about 60 percent. So that this is the first time that we have known that therapeutic intervention clearly can ameliorate the rate at which these complications occur. So that we can tell this young woman that there's a great future for her, in a much more solid and positive way than we could before. This opens up the question, we now know that this is very effective. So we have two different kinds of problems. First, we have a problem related to any particular siblings that she may have. And that is, the possibility that they could develop diabetes. And so this is what this prevention trial refers to. It refers to the development of technologies to recognize children at high risk for developing diabetes. And it falls back on some really very imaginative research having to do with what we call tricking or modulating the immune system. Now, conventionally, we use words like vaccination or immunization and that has kind of a general meaning. We know we can prevent the measles and other things like that. For diseases like diabetes, it's possible to think about it in that way. So exposing a child prone to developing diabetes to an antigen, meaning something that might be related to triggering the disease, insulin in this case, which is a somewhat complicated explanation, but this is one that is being used, could be devised in some way to block this immune response. That's what we mean by immune modulation. That clinical trial is in effect. We have two phases of it. The second phase has just begun. So the first research issue is developing methods to recognize these children, and the second is having an intervention strategy, based on a lot of fundamental research and some results in animal models that suggest feasibility. So that's the second aspect of this pursuit. Now, the third aspect is one that we're really in the midst of right now. And it's a terribly important area. We refer to it as the Diabetes Prevention and Treatment Initiative. Because the Diabetes Control and Complication Trial, which was so seminal in its results, doesn't tell us how to achieve its effects. And for your young niece, she takes insulin, and we know that that's a very difficult thing for her. There are a lot of things about treatment regimens that this trial has taught us that we can transfer to her to make it easier. But we know it's still difficult. We've got to close that therapeutic gap. We've got to find ways to make that treatment more achievable and easier. And that's the goal of what we're really into right now. That's a difficult area. But it's one that we must and we will pursue. Mr. Wicker. If somehow we could have known years ago, before this little girl came down with diabetes, we could have known that she was at high risk, do we now have the technology to prevent, do we now have the knowledge to actually prevent that child from coming down with diabetes? Dr. Gorden. This is the nature of the experiment. And we don't know the outcome. The only thing that I can tell you is that, in animal models that simulate the human condition, the maneuvers that we're using will prevent diabetes in these animal models. And it is that basis primarily that has led us into the human experiment. We don't know the outcome.It's too early for us to get a hint about what this is going to be. But we're convinced that we're on the right track. We're convinced that this is an appropriate approach. If this is the wrong reagent, it's the one that is safe now and we have approval to use the forms of treatment that we're using. But there are others in the pipeline, and they may prove to be the right trigger. But this is a real thrust of research, and we think we're clearly going in the right direction. And the answer, we hope, will be a very positive one, which we clearly could not have given to you several years ago. Mr. Wicker. As a scientist, are you willing to speculate about a time line? Dr. Gorden. I'm always hesitant, Mr. Wicker, because I like to talk to you as I would to a patient. And I don't want to create a sense of false hope about setting a time because I don't really know if I could deliver, and I wouldn't know quite what to say to you then. restoring insulin production Mr. Wicker. What about research in the area of restoring the defective organ, I guess it's the pancreas? Dr. Gorden. Yes. Mr. Wicker. How are we doing on that? Dr. Gorden. There are fundamentally two approaches, each of which has a set of ramifications. First, it's clinically possible to do pancreas transplantation. It is being done, and, in fact, it works. It is not a type of transplantation that we would do, except under very special conditions. And so it's generally done in the context of kidney transplantation, which has been a great miracle for the diabetic patient. There has been some experimentation using pancreas transplantation without kidney transplantation. But at the present time, for a child, this would involve very toxic immunosuppressive agents. Because we do have alternatives, we would not want to use that approach. The other approach is to use what we call islet cells, that is, the insulin producing cells of the pancreas. And there are techniques to isolate those cells and there have been very successful animal experiments in which this has been carried out. There are two fundamental problems. One problem is the immune problem, that is, the same problem you have with any transplantation where the body will attempt to reject something that it sees as foreign. That's one problem. And there's a set of approaches that are being taken to deal with that. One is some sort of shielding device that one might use. One is a sort of an immune policeman that would sit there and help guard those cells against the attack by the immune system. And there are a number of examples of that that I could elaborate on. Mr. Wicker. There you're talking about transplanting a few cells---- Dr. Gorden. Yes. Mr. Wicker [continuing]. Into a non-functioning organ? Dr. Gorden. Exactly. The cells would be transplanted into some other area, not the pancreas, where they normally exist. We put them in the liver or some other place in the body. And this is actually being done. But just to mention the second problem. One problem there is the immune rejection, the second problem is the ability to sustain the growth of these cells. That is, these cells don't appear to like particularly being isolated themselves and growing in a sustained way. So the problem really has been not getting it to work. It does work at a clinical level, and it works in patients. But it works over a relatively short term, and we don't have very many examples where we've been able to get this to go out, say, a year. We have a few, and so that offers us an approach. So that this is an area that we continue to look at and we continue to support, and we continue to recognize the problems. It's really not moved quite as fast as we would like to see it move. But we're still encouraging this area of research. So this is something I think we will look forward to, but we can't give you, as a final clinical product. prevalence of diabetes Mr. Wicker. Is it true that the number of Americans with diabetes has skyrocketed since 1983, and to what would you attribute this? Dr. Gorden. Well, certainly the prevalence of diabetes, that is, the total number of diabetic patients has increased. There's another term that we use, we call it incidence, which has to do with the rate of new people entering the system. We believe that this is due largely to the fact that people are healthier and living longer, there are more diabetics of an older age, that this would increase the prevalence of the disease, if diabetics are not dying at a younger age, and doesn't necessarily infer that there's an infusion of something that's causing more people to have diabetes. We think that's relatively stable, although we do know that certain groups are more prone to develop diabetes. For example, Native Americans, Hispanic Americans, and African Americans, have a higher prevalence of diabetes. So in particular areas, particular regions where there are larger populations like this, then one will see an increase in the prevalence of diabetes, because of the population admixture. Mr. Porter. Thank you, Mr. Wicker. Mr. Dickey. Mr. Dickey. Dr. Gorden, how are you doing? Dr. Gorden. Fine, thank you, sir. Mr. Dickey. I knew who you were, I didn't have to look at your name. Dr. Gorden. You could just tell when I spoke. I just wanted to get a little credit, if I could, because the Chairman wanted to be certain that I had spoken at the Rotary Club in Baldwyn, Mississippi, and Mr. Wicker and Mr. Lott can attest to the fact that I've done that. And so I want the Chairman to know that, and thank you. Mr. Dickey. Now, can we get on with other things? Dr. Gorden. That's right. [Laughter.] funding for diabetes research Mr. Dickey. In the last 10 years, overall funding at NIH grew by 63 percent, or 7.25 percent per year, while funding at NIDDK grew by just 40 percent or 4.95 percent a year. When diabetes is the fourth leading cause of death by disease, can you explain why NIDDK did not receive the same rate of growth as NIH as a whole? Dr. Gorden. Well, Mr. Dickey, I think that what's important for us and what's expected of us is to take the resources that we have and do the very best job we can. I believe that's what the Director of NIH expects of us, and I believe that's what you expect of us. And that's what we try to do. I can't really explain beyond telling you what we're trying to do and telling you of the directions that we're trying to take, and to tell you how we're trying to make things really happen with the resources that we have, and how we're trying to augment those resources in a variety of ways. Mr. Dickey. Does this reflect, this reduction in your increase, your decision or your Department's decision, or is it happening without your consent or against your request? Dr. Gorden. Mr. Dickey, as you know, we take the appropriations that we receive that start with the Administration and end in the Congress and that's what we basically use as our resource base. We have a variety of inputs into that at various times. But as I say, in the end, I think our responsibility is to do the very best with what we have. Mr. Dickey. Are you saying that we as laymen could better decide how much you could spend adequately to combat---- Dr. Gorden. No, what I'm saying is that I think our fundamental responsibility is to use the appropriation that we receive in the very best way that we can. professional judgment budget Mr. Dickey. Have you ever asked for any more than you've received? Dr. Gorden. Well, we do submit a professional judgment budget at the very early phase of the process. And that budget is something that we routinely do, and it clearly is larger than the budget that we receive, so that we do clearly ask for things that we do not receive, yes, sir. Mr. Dickey. How much more did you ask for this year than the President's budget provided? Dr. Gorden. I could give you a percentage. The professional judgment budget that we submitted was an 11.4 percent increase over the 1997 budget, and our President's budget is approximately 2.23 percent. I believe that's correct. The number of dollars is $75 million. Mr. Dickey. Thank you. What are you having to not do because of this 9.2 percent reduction from your request? Let me ask you this, particularly. How much of that has had to be taken away from the research that has as its target the finding of a cure for diabetes? Dr. Gorden. Well, I think that fundamentally, our search for the cure, as you have put it, is framed in a number of different ways. It's framed around clinical trials and it's framed around very basic research. And so it's very important that we continue some balance in these two areas. Just to give you an example of what we've tried to do to maintain a momentum, Mr. Dickey, we were just discussing two clinical trials that we have in operation now. One is an attempt to prevent Type I or juvenile onset diabetes. We were just discussing the nature of that trial and some of the ingredients in it. We had also discussed a trial called the Diabetes Control and Complications Trial, which was a major multicenter trial, which was very expensive. We knew that we could not begin new trials until we ended the first trial, because of the expense of this trial. As that trial ended, we began to focus on what we were going to do next, and how we were going to focus that money. So we planned on two separate clinical trials, one in non- insulin dependent diabetes, the adult onset diabetes which we had further developed and had this ready to go. But then, our basic science research was really showing some promise, and indicated some ways that we might interdict the process of Type I, the juvenile onset diabetes. Now, what do we do? We felt we needed to go ahead and do a study of Type I. We basically put a plan into motion. We asked two institutes to help us, the National Institute of Child Health and Human Development and the National Institute of Allergy and Infectious Diseases. We asked the Juvenile Diabetes Foundation, the American Diabetes Association, and we asked for some industry support. We told them why we wanted to do this and what this was all about, and we received support. Then we got to the Type II trial. We actually had just received, in addition to this kind of support, funds from two different NIH Institutes, just to give you a flavor of the multi-institute collaboration, and the way that we go about trying to get things done. We've completed a negotiation with industry because of a new drug that has just been approved by the FDA, which we think has a great promise in treating diabetes, and in possibly preventing Type II diabetes. But we had no budget to include that trial. So we went to industry. We told them what we wanted to do; we said it would be very important to include them in our trial. And we've used the Federal Technology Transfer Act to achieve that kind of balance, so that we can address some of the concerns that they have. My major point is that diabetes is a very difficult problem. There are many people who suffer from it. There are children, adults, and their families. Research needs to be supported. Our responsibility is to get things done across NIH and within our Institute. We're the lead Institute for diabetes research. It's our responsibility to get things done. We feel that's our responsibility to you and to the Director of NIH. And that's the way we're trying to do it. Now, there's no question that we need resources and we certainly want to emphasize the fact that that continues to be important. Because it's a very, very mature and very moving research agenda. genetics of diabetes Mr. Dickey. What is the state of research into the genetics of diabetes? Dr. Gorden. We've made several, I think, important discoveries. Sometimes when we use the word diabetes, it sounds as if we're talking about a single thing. When we talk about, say, high cholesterol or high blood pressure, we think we're talking sometimes about a single disease. In fact, these are manifestations of multiple different kinds of things, and so is diabetes. So we broadly separate diabetes into, we call it insulin- dependent Type I and non-insulin dependent Type II diabetes, and that, there are two different diseases. But the blood sugar goes up and there are complications in the eye and the kidney and the nerves that are the same. And that seems to be a sequel to the fact that the blood sugar is very high and it's not what the body is accustomed to having. So there are different sets of genes involved in these two different conditions. So we've made a lot of progress in identifying the locus, that is, the place in the human genome that these genes exist. And to some extent, we've identified genes in Type I diabetes. In Type II diabetes, we've identified at least four causes, that is, we've identified the insulin receptor, which is a major component of how insulin works, as a geneticabnormality in diabetes. In the last year, we've identified three genes in what's called ``Maturity Onset Diabetes of the young.'' And we've also made, I think, as much progress in the area of what we call ``complex genetic diseases.'' When we talk to you about a disease like cystic fibrosis, this disease is due to a single gene. You injure that gene and you have this disease. Non-insulin dependent diabetes seems to be a complex genetic disorder, that is, you have susceptibility areas that get weakened within the genome. And there may be three, there may be five, there may be ten. We really don't know. But we've made progress in beginning to try to identify where some of these genes are, and we think we have an approach to this. And so it's a terribly important area, it's one that's very important in hypertension and Alzheimer's disease and depression. Those are diseases that are fundamentally this type of complex genetic disorder. And I think that is one that we're clearly in the forefront of, but it's one that we can't sort of bring to final fruition right now. diabetes education program Mr. Dickey. I understand that NIH will be participating in the diabetes education program. What additional funds will be needed to carry out this important endeavor,and will the funds be taken out of diabetes research? Dr. Gorden. What we've done, Mr. Dickey, as I mentioned, at the completion in 1993 of the Diabetes Control and Complications Trial, which showed such a dramatic effect on control, that is, how you control your blood sugar, we began to hear from the community we felt that there was a need for us to develop models similar to what had been developed in cholesterol and hypertension, which had been so successful. We started what we called an ``outreach program,'' and we started in a small way to deal with aspects of diabetic foot care. But in the last year, we have sort of begun to call this an ``education program,'' and we have put funds in it up to approximately $1 million. We have also gotten co-funding from the CDC for this project. And we're looking for some other support. We think it's very important to get this message out to the public and to the practicing physicians about the importance of glucose control. And so yes, funds for everything we do come from essentially the same place. So this program does affect our research budget. And we're trying to do this in a measured way, so that we can really achieve the most practical effect from it with the least impact on our research budget possible. We have clearly got it moving, and we will build on it as we have the opportunity to build on it. Mr. Porter. Thank you, Mr. Dickey. Did you have a follow-up question, a short one? Mr. Dickey. Mr. Chairman, I don't have any more questions. Mr. Porter. Well, I would say to members, the ones who were here early like Mr. Dickey got extra time, you got 13 minutes, Mr. Dickey. Mrs. Lowey. special research areas in diabetes Mrs. Lowey. Thank you, Mr. Chairman. And I do want to apologize to you, Dr. Gorden, Dr. Varmus and colleagues, for being detained. But I'm delighted to be here today. One of the questions I'd like to begin with is whether you think there are any particular areas of research in diabetes that deserve special emphasis that currently are underfunded. Dr. Gorden. Well, there are a number of areas, and we've talked about two fundamental areas, that is the clinical science arena, the numbers of clinical trials we have, and the sort of basic science arena. As I mentioned in my statement, this sort of continuum which is, and diabetes research is well- represented by that, from the very fundamental basic science. And we have certain areas, as everyone does, where opportunities sort of lend themselves to more immediate application and some that move at different rates. So that it's difficult, there are certain areas that we were talking about before that have to do with prevention and treatment. These are very important areas for us to pursue. upcoming diabetes conference And one of the things that we plan to do in the very near future, Dr. Varmus and I plan to co-sponsor a conference in which multiple NIH Institutes, which are involved in diabetes research, will be present, and we will interface, essentially, with leaders in the diabetes research community that relate to all these different components that we have and other Institutes have. And we'd like to kind of see what the meeting of the minds would bring out. We clearly have an agenda that is ongoing. We'd like to see where that agenda perhaps ought to be turned or moved or enhanced in one way or another. And this would be one of the important goals of this particular conference that we will certainly be talking to you about more in the future. locating diabetes information Mrs. Lowey. One of the questions I have asked in past years is whether there is, is there a national directory, does NIH actually have a directory of research projects? The response I have gotten in past years is that there are forms and people who are working in an individual area, whether through the internet or their own journals, really know what other people are working on. But is there any national directory, I would say, for all research, or for diabetes research, so that you really have a handle on who is doing what? Dr. Gorden. NIDDK is the lead Institute for diabetes research. We have a home page in which one can feed into and really get a great deal of the information base that either would give you the information that you would be seeking or lead you in a direction in which you could get that information. I think most Institutes do have that kind of facility available. And I think that now that this sort of thing is being utilized more and more, this is probably a good avenue for one to approach this. It would be difficult to sort of encompass all of NIH research in one place. I think it would have to be decentralized to some extent. But as long as one would simply focus on where the lead application of that kind of research was coming from, I think one could easily get that information. Dr. Varmus. Could I interject a note of caution here? Many people are interested in the idea of assembling all the people and information available regarding any specific research area. I think one has to be very careful about the purpose of such an aggregation of information. Because it's very expensive to put it together, very hard to keep it updated. One also has to be very careful about the purpose of such a data base. If it's simply to identify the investigators around the country who are working on diabetes in order to send outnewsletters, that's fine. If it's an attempt to keep up the complete repertoire of ongoing projects and results, it would become extremely burdensome to investigators. It's very difficult to coordinate centrally and, frankly, not as useful as having national meetings on diabetes to which investigators go. women's health Mrs. Lowey. Thank you, Dr. Varmus and Dr. Gorden. I'm also interested in an update on the status of your research collaboration with the Office of Research on Women's Health, which is looking at cardiovascular disease in women with Type I diabetes. I understand that this is a long-term study, but can you tell us what progress has been made thus far, and what you hope to accomplish in the coming year. Dr. Gorden. Yes. we were talking about our Diabetes Control and Complications Trial just a moment ago. And we have a program in which we are following all of those patients. And one of the important things that this particular project is involved in is studying what we refer to as macrovascular disease. And one of the initial thrusts of this project was to get a baseline measurement of this population that we continue to follow, that we call carotid ultrasound, to get some idea of the vessel status of those individuals as they have been treated with these different regimens. That initial measurement has been made. It has been made with the resources that we received from the Office of Research on Women's Health. And we plan to continue that, both the collaboration with them and this project. And it is a very active, ongoing project in which we have many other things to do. And it's one that we're pursuing with some vigor. artificial pancreas Mrs. Lowey. I thank you. And lastly, what is the status of efforts to perfect a biomedical pancreas, which would enable people with insulin-dependent diabetes to make their own glucose, in medical terminology, to achieve---- Dr. Gorden. Euglycemia. Mrs. Lowey. Okay, euglycemia. Dr. Gorden. Good. Mrs. Lowey. Thank you. Dr. Gorden. This is an area that relates to finding ways to take cells that make insulin, islet cells that make insulin, and do two things. One is to find ways to protect them from the immune system, so that when they're put into an individual, they will not be recognized as foreign. And the second goal of this research is to find ways to get these cells to grow in a sustained way over a long period of time. And these are two areas, there are a variety of techniques, some very basic, that are very interesting, that are being used for immune protection. Some have to do with the co-expression of cells that can serve as sort of ``policemen'' in a sense, and guard these transplanted cells from the immune system. Some involve mechanical encapsulation devices. And some involve still other types of technology. So this is an area that is actively being explored. But at the present time, it only has a relatively limited clinical application with respect to long- term results. So we're continuing to try, and we're continuing to press this area. But we are not able to present it as a therapy that would be available to someone tomorrow. Mrs. Lowey. Thank you, Dr. Gorden. Thank you, Mr. Chairman. Mr. Porter. The gentlelady returns one minute of her time. Mrs. Lowey. Oh, I'll take it. [Laughter.] costs of treating diabetes Mrs. Lowey. Actually, I remember a few years ago, one of my constituents testified before this committee and talked about the extraordinary expense that she faced with her daughter in being diagnosed for juvenile diabetes. And I was thinking about that this morning, wondering, with the impact of managed care, how has that affected this process? She was talking about something like $25,000, it still rings in my head, because it was so amazing to me. But I assume this included a whole battery of tests and the other procedures that had to be taken. And she said that she retired from her job to take care of her young child, but thank goodness, she had that insurance while this battery of tests was being done. Do you have any first-hand information on that? Have the tests gotten cheaper? Or how has one fared under managed care with this, based upon your information? Dr. Gorden. Well, we would certainly hope that the message that managed care would receive is that this treatment works, and this treatment reduces the complications of the disease. And if a managed care company plans to have an individual as one of its clients for a number of years, it would be cost- effective for the managed care company to permit that patient to use the most modern facilities, and resources that are available. And we have actually some quantitative data to show the cost-effectiveness of that approach. And looking at the difference in cost of say, equipment, for more conventional treatment versus what we would call intensive treatment. And we have data to show that the increase in initial costs is more than offset by the savings that one has in the morbidity of the complications of the disease. That's the message that we're giving managed care. And I have the sense that that's being heard. We certainly have seemed to have gotten the message into the Medicare system. And I think that there are a variety of efforts that are being made to do that. And the feedback that we're getting suggests to us that this is really having an effect. So I can't answer your question completely, certainly, for every managed care orgainzation. But, I think the message is clear, and I think we will continue to press that message. And I'm very optimistic that that's going to be heard, and that they will understand that. Mrs. Lowey. Are the costs still so high? I was amazed at that initial diagnostic work and treatment. Dr. Gorden. It would depend to some extent on what you're actually including. If you were to truly take the measures that were used in this trial, it may approach those costs. Our estimates are something under $5,000 for intensive treatment. But then it would depend to some extent on the numbers of people who were involved. Is there a dietician; is there a nurse practitioner; is there another trial coordinator of some kind helping manage your care? So one could imagine that this could, and also depending on where you are in the country, costs could range up to perhaps what you say. But it depends on this constellation of things. Mrs. Lowey. Thank you. Thank you, Mr. Chairman, for that additional minute. Mr. Porter. It ended up being an additional four minutes. [Laughter.] intramural research Mr. Porter. Mr. Miller. Mr. Miller. I'd like to take a few minutes to get a better understanding, in a more generalized question, but using your Institute to understand better intramural versus extramural, and the role of the small business setaside. And again, I'm just trying to get a grasp of the issue. Dr. Varmus may want to chime in here. A little bit over 10 percent goes to intramural research? Dr. Gorden. Eleven point four percent, yes. Mr. Miller. For your Institute? Dr. Gorden. For our Institute. Mr. Miller. What is the average for the entire NIH? Dr. Varmus. Well, it was 11.3 percent when I came on board, and now it's about 10.5 percent. Mr. Miller. Is it basically all in Bethesda, or is that nationwide? Dr. Gorden. We have two components. Our major component is in Bethesda, and we have another very significant component in Phoenix, Arizona, a study in diabetes. This is located at the Phoenix Indian Hospital, and is involved in a longitudinal study and clinical studies of the Pima Indians, that have the highest prevalence of diabetes in the world. And so this has been an extremely productive study in which we can follow the population of patients and follow them over time, and also study genetic factors and what we call pathophysiology, the sequence of events that develop in the individual before they develop diabetes, during the intermediate phase and, finally, what happens when they develop the full-blown disease. So this has been an extremely valuable resource. We have done this in collaboration with the Indian Health Service. And it's worked out extremely well for us over a long time. It's extremely highly regarded internationally. Mr. Miller. How much money do you spend in that program, for example? Dr. Gorden. Let's see if we could give you a reasonably accurate number. It's about $7.5 million a year. Mr. Miller. Okay, out of your $90 million. In making intramural decisions, do you start new programs versus phasing out current studies? And have you phased out any to conclusion and say, we really want to start a new program? How do you go about making that decision and have you made any such decisions? intramural decision-making Dr. Gorden. Yes. We make those decisions all the time. It's a continuous process. It works in several ways. In our Institute, and in I think most NIH Institutes, we have a division of intramural research, and we have a director of that division. And we depend very much on that individual to help guide and advise about how that ought to be and where resources should be put. Should we put more resources here and less resources there? This is a continuous process. We have a Board of Scientific Counselors that meets on a regular basis to review all of our laboratories in a continuous way. We take their review and their advice and we put it together with our own sense and assessments. I meet on a very regular basis, having been part of the intramural program for many years myself, with the Director of Intramural Research. And we forge a program collectively with the advice of the Board of Scientific Counselors, and with the advice of a number of other people, including our National Advisory Council, who are briefed on a regular basis about the activities in the intramural program. So that we will make a major commitment to enhance promising areas. As an example, we have perhaps one of the leading structural biology programs in the world. We have garnered a group of people who are world class, and they are using the most advanced technology that is available. For us to support that, it means that that has to be a very high priority, because this is very expensive. We have to really know that this is productive. And so that this facility has a major trans-NIH presence, everyone, not only just on the NIH campus, but essentially nationally and internationally, knows about this group and what they do. That's a kind of a fundamental commitment that we will make to enhance a particular area. We also make it a point to keep abreast of our clinical activities. We have clinical activities in diabetes, digestive and kidney diseases, and nutrition and areas that represent the sort of fundamental mission of the Institute. And we're constantly looking at ways to enhance those. We're very much a part of the new NIH Clinical Research Center. We're very active participants in the Clinical Center, so our Institute should be one that has a very strong clinical presence. We have done a number of pilot studies or sort of inventive types of clinical studies that have come out of our intramural program, a number of which I could discuss. Mr. Miller. So that you'll start them there and then---- Dr. Gorden. Absolutely. A very good example would be, in sickle cell disease, in which we started a program to use a particular compound to enhance hemoglobin concentration in individuals with sickle cell disease. We have a very talented investigator who began those programs as part of a clinical pilot study. That was so successful that it then translated into a multi-institution study that was primarily sponsored by the Heart, Lung and Blood Institute. We've done this with the treatment of hepatitis, where we made pivotal observations about the use of certain drugs like interferon. Then multicenter clinical trials have been sponsored by the National Institute of Allergy and Infectious Diseases. So the intramural program has been a resource in which we can rapidly move into clinical and fundamental areas, and then we can exploit those either ourselves, or with our colleagues in other Institutes. Mr. Miller. You have the same job as Dr. Varmus has, you have to allocate limited resources and make those tough choices, as we do up here, too. Dr. Gorden. Absolutely. small business research Mr. Miller. So I respect that. May I ask one more little set of questions, and that is the small business set-aside. I'm just trying to get a better understanding of it, rather than questioning everything you're doing. How much is there in that area? What is the total amount of money in your budget that's in effect a small business setaside? Dr. Varmus, we talked about it briefly on the telephone before these hearings. Dr. Gorden. The percentage in the 1997 budget is 2.5 percent. That is the official percentage. The actual dollar amount for NIDDK is $17,878,000. Mr. Miller. Okay, because I was just looking at the--on this book here for the 1997 fiscal year SBIR is $15,878,000 under research projects. Dr. Gorden. Right. Mr. Miller. And then you drop farther down and I see the $23 million. I'm trying to figure the difference. Dr. Gorden. It falls into two categories, which to some extent get a little bit blurred. But we do categorize them as grants and contracts. In our case, we have $15.8 million in grants and $2 million in contracts, which is the total that I gave you for fiscal year 1997. That's the $17,878,000 of the total of those two. And just as an example, Mr. Miller, of what we were just talking about in answering Mrs. Lowey's question about devices for treatment of diabetes, we would like very much to see the encapsulation devices, how we grow cells, how we use this sort of resource, we would like very much to see this go into industry. We would like to stimulate industry to do this in the whole glucose monitoring area, where we're trying to develop devices to measure glucose. We have devices now that are somewhat detached from the person that we use, strips and things to measure glucose control. This type of device development we would very much like to steer towards small business. And we make a very big effort. The recent work with the obesity gene has had an explosion in the biotechnology industry. We would like to see more of our small business resources go into those really promising areas. And we make a great attempt to see that happen. Mr. Miller. Has the quality of your small business applicants improved in recent years? There's been a concern that they don't rate as high. You have a difficult time because your demand for grants is far greater than the money you have available. Have you seen an improvement? In addition to that question, answer this and then I'll conclude. Basically, the small business all goes to the private sector, I assume? Dr. Gorden. Yes. Mr. Miller. The rest of extramural, what percentage of that goes to the private sector versus the non-profit academic sector? Dr. Gorden. 100 percent of this goes into industry, small business. Mr. Miller. Right. Dr. Gorden. In the area of the non-small business funds, the vast majority goes to either research institutions that are either academically affiliated, but are generally non-profit institutions, or to academic institutions. I can't give you an exact number. I could try to get that for you. I don't have an exact number. All I could do is give you a qualitative answer. Clearly, the vast majority goes to research institutes, or to academic institutions. Mr. Miller. Do the big pharmaceutical companies get NIH grants, like a Merck or somebody? Dr. Varmus. Extremely small. Not Merck, as far as I know. It's almost all small business. Mr. Miller. So the remainder of extramural basically goes to the non-profit sector, or research institutes and all that? Dr. Gorden. Yes. Mr. Miller. So there's a very small amount that would fall in that area. Dr. Gorden. Right. Mr. Miller. Thank you. Thank you, Mr. Chairman. Mr. Porter. Thank you, Mr. Miller. We're delighted our ranking member, Mr. Obey, can join us. He is ranking on the entire Appropriations Committee, and it means he has responsibility for 13 subcommittees, and his time is very, very dear. So you're recognized. Mr. Obey. Thank you, Mr. Chairman. I apologize for not being here. We've got three Cabinet Secretaries up here today, and we have a Democratic caucus, which was absolutely fruitless to attend, but I did anyway. [Laughter.] Mr. Obey. I hope you are not going any better. [Laughter.] ulcers Mr. Obey. Let me just ask one question about ulcers. Can you tell us, what is the status of our knowledge now with respect to ulcer causation and treatment? I know in the old days, people used to think, they used to try to reduce tension, take plenty of Maalox, all the rest. Now we've discovered that the significant portion of the problem is bacterial. How would you sum up what we now understand about that problem? Dr. Gorden. I would say first, Mr. Obey, it's really one of the seminal events in medical research, to make a discovery of the real cause of a disease. With respect to duodenal and gastric ulcer, we believe that there is a very, very strong correlation with this bacterium, H. pylori, and that it is the etiologic or causative base of most ulcers with perhaps two exceptions. Those exceptions are the ulcers that occur in the context of the so-called non-steroidal anti-inflammatory drugs that people take for arthritis or pains. The Motrin type of drugs or that general nature, or aspirin. Those drugs lead to ulcers in a certain proportion of patients. There's another relatively uncommon but very important tumor that produces a substance, gastrin, which causes the gastric acid to go very high. And that is another important cause, although relatively rare. So those two, with those two exceptions, we believe most or all peptic ulcers are associated with helicobactor. And the most remarkable thing about it is that this has been a chronic disease, that is, we could treat it and we had, as you pointed out, Maalox, and we even had better things than that. We had drugs, such as Zantac, we had acid blocking drugs that were actually very good. But what those drugs did was control a chronic disease. Now what we've done is taken a chronic disease and converted it to an acute disease. That's really something we'd like to do with a lot of things. Because now, we can treat ulcers for two weeks as an acute illness, and we believe we can completely eradicate peptic ulcer disease. Mr. Obey. What percentages are you talking about? Dr. Gorden. We believe we can eradicate---- Mr. Obey. No, I mean the percentage of ulcers that are caused by that problem. Dr. Gorden. I would say that the percentage is about 85 percent is caused by the H. pylori process, and about 15 to 20 percent are this other category, which are associated with non- steroidals and aspirin and other drugs of that nature.And this syndrome called Zollinger-Ellison syndrome. Those ulcers will not be affected by the H pylori treatment. nutrition Mr. Obey. Mr. Chairman, just one other question. And maybe Dr. Varmus would like to comment on this, because it goes beyond your Institute. I often have constituents express confusion, and my wife, who's interested in nutrition, also expresses it. The confusion people have with respect to dietary recommendations, because they often seem to be conflicting in terms of what reduces the chance or what increases the chance of cancer, versus what increases the chance of other diseases, including heart disease. What can you say with respect to those tradeoffs, and what we know about them and what wise people would do? Dr. Varmus. I'll just make one brief, general comment and then turn it over to Dr. Gorden, whose Institute has a coordinating office on nutrition that is overseeing a lot of these activities. Attempting to correlate diet with disease has been traditionally one of the trickier areas in epidemiology. That is so in part because the attempts to assign a pathological effect to a certain kind of diet tends to be based on fairly small effects. And such effects are very difficult to substantiate unless you use very large populations in multiple studies, because many other variables affect the population: where they're living, other aspects of lifestyle, genetic composition of the population, and so forth. That being said, there are nevertheless some clear indicators that have developed with respect to the role of fat in the causation of coronary artery disease, especially in the generation of late onset diabetes, and perhaps in the causation of certain cancers, particularly cancer of the colon. Do you want to comment? Dr. Gorden. I think that it is a complicated area, and I think that, with respect to the Federal Government, there's been an attempt to try to channel what is usually referred to as ``a single voice,'' that is, between the Department of Agriculture, that has a major input, and the Department of Health and Human Services, including the NIH, which has a major input. So that as Dr. Varmus says, there are certain fundamental things that can be recommended. That issue I think is the clearest one. The weight issue is very clear. In other words, dietary guidelines that would help people maintain a normal weight, that's a very clear guideline. We have supported in the past something called the RDA, the Recommended Dietary Allowances. And the recommended dietary allowance is the amount of a nutrient, either a vitamin or other nutrient, that is consistent with a healthy lifestyle, so that there are a variety of things that are there, but there are also a variety of opinions about different things. And sometimes it has to do with food additives and whether we should be adding things. And sometimes, as Dr. Varmus mentions, the epidemiologic studies with food suggest certain kinds of things that don't turn out to be true when you purify a particular substance. Beta carotene would be an example. These are the things I think that lead to tremendous confusion. And of course, there's a lot of advertising and things that people are constantly being barraged with. It is a very difficult area. I think we need to constantly try to produce the very best science we can, and then we need to basically find ways to translate that in a meaningful way. And I think it continues to be an ongoing struggle. You're absolutely correct in pointing out the confusion. effects of alcohol Mr. Obey. I swear to God, any time that there's any study at all that relates to alcohol, the networks have it and trumpet it. What do we know about the ``beneficial'' versus negative effects of alcohol, example, wine? Dr. Gorden. Well, of course, there was always tremendous reluctance to add alcohol into the Federal dietary guidelines. Mr. Obey. I'm not suggesting that. [Laughter.] Dr. Gorden. Well, no, in fact it actually has been added into the Federal dietary guidelines. But of course, the major concern is that when you recommend something at a given level, it gets exaggerated, and then all of a sudden, it becomes something that, if you take a little bit, and that is good, then if you take a lot of it, it must really be good. This is really a problem. There does appear to be some basis for a benefit of alcohol with respect to say, cardiovascular disease. We do have some evidence to support the notion that there's a so-called good and bad cholesterol. The so-called LDL, which is referred to as bad cholesterol, and HDL is referred to as good cholesterol. Alcohol actually has a component of stimulating the good cholesterol. Now, that ought to be good, and there have been some studies to demonstrate that a modest intake of alcohol actually will improve cardiovascular outcome. And this is the basis for this sort of recommendation. And of course, as you say, it is very easy to get confused. Mr. Obey. What about counterbalancing that with the concerns that alcohol causes cancer? Dr. Gorden. This is the real concern, because we certainly know the morbidity that alcohol can cause in so many ways, in terms of morbidity of liver disease, accidents, on and on. This is the problem with this sort of recommendation and this is why there's been so much reluctance to make this kind of recommendation. Dr. Varmus. One of the difficulties here is defining what's meant by moderate alcohol use. That was sometimes considered to be one or two drinks a day. Dr. Gordis informs me that there is increasing evidence that as few as one or two drinks a week may have beneficial effects. It's obviously important to determine what is actually required to get the modest beneficial cardiovascular effects. Mr. Obey. Are there any studies that compare the benefits that accrue from that with the negatives on the cancer side? Dr. Gorden. I don't think most of the studies have been done to do exactly what you say, but have been done to actually try to show the efficacy of what we refer to as moderate alcohol intake. They have not been done to try to show the other side, that is, what if you exceed what we call moderate. I don't know of studies that would actually point to that. I think people have just simply accepted that excess alcohol has a major risk and have not really gone into the comparative studies. Dr. Varmus. The problem here, as elsewhere, is defining very low risk levels. When the dose is very low, it's very hard to saywhether there's no effect or a small effect on cancer incidence. h. pylori applications Mr. Obey. Thank you, Mr. Chairman. Mr. Porter. Thank you, Mr. Obey. Going back to H. pylori, some in the clinical research communities cite the H. pylori case as an example of what they see as NIH's reluctance to fund clinical research, because the researcher involved was repeatedly turned down for NIH funding. Why do you think this research didn't fare well in peer review? Dr. Gorden. It's a little bit difficult to answer that question. I can give you certain, I guess, conventional answers. We're talking about basically Dr. Barry Marshall, who did apply for several NIH grants and did not receive them. Dr. Marshall, of course, is responsible for a major discovery, that the bacterium H. pylori causes most ulcers. The fact that the grants were not awarded has to do with the fact that we depend largely for advice from expert panels on how we make awards. The fact that they weren't awarded means that we did not get promising reports from these expert panels. But I'd like to say, Mr. Chairman, that this is something that is a fact and something that we're not very proud of, and I hope that this would not convey the idea that this is representative. This is clearly an aberration. It's a major aberration. And we can point to many other areas in which we as an organization or as an institution should be wiser than our expert panels. I don't for one minute accept that as an excuse. But it did happen. And I believe that we have to learn from that example, and hope that we can do better in the future. I think that many of the things that this related to were sort of fundamental observations. And I'm not really sure that this would be an example of any sort of negative aspect of the peer review system on clinical research. Because I think this was a failure of both the study section, the expert panel; council, which is the second level of peer review; and the Institute, including myself, to recognize this sort of thing. All of us basically can serve as a checkpoint. And we all are responsible for being certain of support for clinical research. So this is clearly an aberration. It is certainly an embarrassment, and we have to accept that and accept responsibility for it. Mr. Porter. I didn't mean to suggest otherwise. I just meant to suggest that it probably is a learning process for everyone. Dr. Gorden. Yes, absolutely. The conventional answer is that the grant was really not well constructed. It may very well be that the way the grant was constructed that it really wouldn't lead to any practical significance, and that one could argue that. On the other hand, I think we have to be a little wiser than that, and we are many times, when we look at something, we say, this is really a grant that's not constructed well, but we have a responsibility to try to get this reconstructed in some way that will be more acceptable. So I think that we do this all the time. Mr. Porter. I believe that Dr. Varmus has told me a major effort is underway to do exactly that. Dr. Varmus. Well, let me comment about the notion that this might be indicative of a general pattern of not funding clinical research. As you know, I've been very responsive to the claims by the clinical research community that we're undervaluing their efforts. And the NIH clinical research panel, headed by David Nathan, has been looking carefully at the extent to which we support clinical research. There clearly are difficulties and things that need to be repaired in that area. But one of the surprises, I think, to everybody is the very large segment of our research portfolio that is in the clinical arena. The number is something on the order of 30 percent. Dr. Gorden. And certainly, that's quite representative of NIDDK where we have 30 to 35 percent. So it wasn't in any way a deviation from our clinical research that had to do with this. This is clearly an aberration. ulcer diagnosis and treatment Mr. Porter. Do you expect to see an increase in H. pylori diagnosis with the availability of the new breath test, which is cheaper and less invasive than the current diagnostic methods? Dr. Gorden. Yes, we certainly think that this would be a valuable tool. The other advantage of the breath test, there are really three ways to detect H. pylori. One is by an antibody test. The other is by endoscopy and actually biopsy. And the third is the breath test. And the breath test actually detects active infection. It's simple and straightforward, it's non-invasive. And we think that it will have an extremely positive effect on detection and just working out what we need to do about H. pylori in general. We have a considerable discussion going on about the whole issue of H. pylori's role in ulcer disease. Mr. Porter. Today many of the things that were previously used as treatments for peptic ulcer are now on the market as non-prescription drugs like Pepcid AC and Zantac and there are so many of them, they advertise so heavily you can hardly keep up with them. Do you think that has given a kind of a alternate message as to the cause of peptic ulcer, and what's your sense of how widely known the H. pylori finding is by both practitioners and patients? Dr. Gorden. Well, Mr. Porter, one of the things that we did when we all began to recognize the importance of H. pylori, I think Dr. Varmus mentioned this in his opening statement, is we held a consensus conference. And one of the purposes of this consensus conference was to really put a national imprimatur on the importance of this discovery and how ulcer can be treated. And I think it had an enormous effect. The feedback we get suggests that it was perhaps the timing, whatever reason, it had an extremely positive effect. We think throughout the digestive disease community that this is part of the culture of the physician. We believe that this is permeating very much the entire medical practice community in a very significant way. Now, there are other issues here that are under intense discussion. Now, many of the reasons that people take the kinds of drugs that you mentioned are really not due to peptic ulcer. They are due to conditions that we call non-ulcer dyspepsia. We don't know exactly what that is. But we know it is a syndrome that simulates the symptoms of an ulcer. It may be pain, it may be bloating, it may be a variety of symptoms. And that this is the reason that peopleare taking this. We're looking into the question of now if individuals come in with this sort of a general diagnosis, should they be screened for helicobactor, and if there's evidence, say, from the breath test, should all these people be treated? These are things that are being actively discussed now. But it's not the issue of ulcer. I think that knowledge really has penetrated very much into the community. It is the ancillary, other conditions that we're not certain, about the effect of the relationship of H. pylori to these conditions in which they simulate the same symptoms. And I think we'll come out with a sensible kind of recommendation that will take a little bit longer to percolate through the community Because it won't be quite as straightforward as the ulcer recommendation, which I think has really penetrated to a very significant extent. Mr. Porter. I was thinking more of the patient community and people taking these kinds of readily available drugs, which provide them some relief from a peptic ulcer, but never allow them to get to a physician and receive a real cure. Dr. Gorden. I think there is a risk of that. And what we're encouraging is, if someone has something that's sustained for several weeks to several months, that that is the time they really should stop the self-medication and actually see a physician, and that we would hope then to have the broad practice community sort of channeled into this whole notion of the possible relationship of H. pylori to that condition. But I think it's a little bit tricky, and there are some problems related to the over-the-counter medication. But we believe that the more people become aware, the better this will work itself out. drugs that work selectively Mr. Porter. The science section of yesterday's New York Times described interesting work underway to produce custom designed drugs that would offer many of the benefits of estrogen, without the risks that dissuade many women from taking it. We discussed yesterday the dilemma women face in deciding whether to take estrogen to prevent osteoporosis and heart disease, but risk breast and uterine cancer. When will these new designer drugs be available to relieve women of this difficult decision? Dr. Gorden. This is again one of these really modern kinds of miracles of science. Our endocrine program has been involved in the study of how steroid hormones work for a number of years. Estrogen falls into the class of steroid hormones. And previously, it was thought that estrogen and the receptor for estrogen bind each other and you give a signal and that's sort of an all or none signal, that you don't modify that signal. It's becoming clear through a number of studies that it's not quite that simple, that there's a whole constellation of things that go on when that signal in these two proteins come together. And they have to do with things that are called co- factors and co-stimulators and repressors and certain other terminology that's used. So it turns out that this receptor, this estrogen receptor, has a certain kind of plasticity. And the conformation of this receptor seems to be able to communicate different things, and we might then be able to make this much more tissue-specific. That is, what we would like is to generate positive effects in the cardiovascular system and in bone, and actually to not have those effects occur in, say, uterus and breast, which is the major concern. And it would certainly appear that we have the wherewithal to do that, there are a variety of either agonists or antagonists or other kinds of reagents that are being looked at now. And this is really, I think, an extremely active area of research that we're involved in and several other Institutes are involved in. And it goes beyond estrogen. It certainly goes to the whole cascade of steroidal hormones, so that one could begin to see implications for prostate cancer and other cancers, which we know are hormone--responsive types of cancer. So I think the ramifications of this are enormous. digestive diseases Mr. Porter. Research indicates that a group of peptides known as trefoil proteins act to repair various forms of gastrointestinal tract injury. They are being studied for possible use in preventing the ulcers that are sometimes the result of prolonged use of anti-inflammatory drugs. Would these drugs also potentially treat other gastrointestinal inflammations, like the inflammatory bowel disease? Dr. Gorden. We certainly have a lot of preliminary evidence that that may be true. These are natural products that are stimulated when the intestine needs to repair itself. They seem to be involved in both the protection and reparative processes. And as I mentioned earlier, this technology involves so-called ``knockout genes,'' where you could actually eliminate this particular protein. It has several different forms. If you eliminate one form it does one thing, another form, it does another. It seems that, when you eliminate it and don't allow it to be expressed, certain types of intestinal injury take place in terms of inflammation. When you eliminate another form of this trefoil peptide, neoplasia or cancer seems to occur. So we think that this is an extremely promising clue to the mediation of gastrointestinal injury. You allude to the non- steroidal anti-inflammatory drugs and how they injure or have the potential to injure mucosal linings. We think that this is, we would say it is in sort of a pre-clinical stage, that is, pre-clinical testing. But we would imagine that this kind of approach would very rapidly move into some sort of drug development program in the near future. This is being primarily spearheaded from our Digestive Diseases Center in Boston, among other places. But we have indications from them that this is likely to be the case. urology Mr. Porter. Dr. Gorden, you and NIH have been under pressure for some time from the advocacy groups to establish a new study section dedicated to urology or to increase the number of urologists in existing study sections. An innovative pilot study is underway to address these concerns. Can you describe this effort, and give us your impression of how it is working? Dr. Gorden. Yes. There's been considerable discussion with the Division of Research Grants. We had the new Director of the Division of Research Grants, Dr. Ehrenfeld, meet with our National Advisory Council the last time we met. And I think we're making a considerable amount of progress. One of the possible solutions for the concerns of urologists that they're not being totally represented within the context of these review groups is to have what we call a ``special emphasis panel,'' in which we might, say, take a set or subset of grants that are generally related to urology and havespecific time receipt for them, so that they would be reviewed perhaps somewhat less frequently than in the routine study sections. But this would permit a larger aggregation of these grants to be reviewed at one time. And this has been piloted, and we have seen the result of it. And my impression is that the urology community is very pleased, it is very excited about this approach. And when discussing it with Dr. Ehrenfeld, she felt that this was something that we probably ought to encourage. And so we've been involved in trying to help relate the urology community to the Division of Research Grants. We're very pleased to see some resolution of this. There are other ways that we have of dealing with this. We've dealt with it in our own review process to review special aspects of urologic research. And in fact, urologic research has been one of the fastest growing areas of the Institute. So that clearly it's thriving, it's becoming a very scientifically competitive research group. And I think all those things are going to bode well for this process, which I am pleased with. prostatitis Mr. Porter. This is a related question. The prostatitis community is very anxious for your Institute to support research in this area. An NIDDK workshop concluded that several preliminary steps must first be taken, including an agreement on diagnostic criteria and the development of treatment outcome measures. How long do you think it will take to complete this preliminary work so that prostatitis research can productively be supported? Dr. Gorden. This is again one of the areas that we really haven't gotten a research handle on, Mr. Porter. We convened this workshop to try to give us a focus on this. We do a lot of work that relates in an indirect way, for instance, in our longitudinal prostate study, the prostate biopsies, we have a lot of information on this kind of thing. But to kind of energize what I think this community is asking us to do, we're proposing a set of grants that would help us define diagnostic criteria so that we can develop a research focus. We have what we call an RFA, or a Request for Applications, out right now. We expect to have applications back in the near future and fund those this fiscal year. And this will give us an entree into how we might better conduct research in this area. It's one of the important things that we need to deal with, but we need to find our way before we can really expand this area. hepatitis Mr. Porter. Hepatitis seems to be an expanding target for research. As soon as a vaccine is developed for one type of hepatitis, scientists identify yet another variant. Can you describe the universe of hepatitis infections and the state of knowledge about the various forms? Dr. Gorden. Well, certainly it's been a very exciting area of discovery in the last several years. Hepatitis has sort of grown a little bit like the alphabet. And we used to use the term infectious hepatitis, and that refers to what we now call hepatitis A, which is the type of hepatitis that one gets from eating contaminated foods. Fortunately, now we have a vaccine against that hepatitis. It usually is a self-limiting illness and doesn't usually lead to chronic disease, although rarely it causes a very acute fulminant type of hepatitis. Hepatitis B is a type of hepatitis that approximately 10 percent of people develop a chronic form, and when they develop the chronic form of this disease, it can result in one of two things. It can result in scarring or cirrhosis of the liver, or it can result in liver cancer. There have been some important inroads in the treatment of hepatitis B. It basically has been eliminated from the blood supply, because there are clear-cut tests. And now fortunately, we have a vaccine against hepatitis B. So two of the forms of hepatitis we have vaccines for. The third very important form of hepatitis, we used to refer to the terminology, non-A, non-B. But then in the last several years, there's been a new form defined called hepatitis C, which is probably the most prevalent form of chronic hepatitis. And it was the type of hepatitis that people who were getting multiple blood transfusions were receiving. And we're still seeing that reservoir of patients who got hepatitis from blood transfusions. It's still a very important part of hepatitis. Although the transmission through the blood supply has decreased virtually to zero. In approximately 40 to 45 percent of the cases, we really don't know how it's transmitted. And this is an important area of scientific investigation now. We do have some treatments for it. They are not ideal. We're having a consensus conference this month to talk about the treatment of hepatitis C and the sort of impact of hepatitis C on liver disease. Unfortunately, we do not have a vaccine. But we do have a very accurate way of testing for it. Now, beyond that, there are several other forms. There's a new form, something called Delta hepatitis, which is a variant of hepatitis B, and there's a new hepatitis virus, which we call hepatitis G. And at the present time, we really don't know the exact significance of hepatitis G. But it is an area that is under active investigation. polycystic kidney disease Mr. Porter. The past year has been a fruitful one in research on polycystic kidney disease. How does your Institute plan to capitalize on the new scientific opportunities? Dr. Gorden. Mr. Porter, this is an example of what we really call scientific opportunity. For many years, we knew that there was a genetic form of cystic kidney disease, referred to as polycystic kidney disease. The early chromosomal methods to localize the genetic defect, because it ran in families in a way that we knew was familial, gave us an idea that there was more than one form, in other words, we knew that more than one type of gene was involved. And then a very pivotal discovery was made, and that was what that gene is, or what we call ``polycystic kidney disease 1.'' And that has led to the discovery of the protein that's abnormal. We supported two years ago a group of research applications to exploit what the function of this protein is. And in the last several months, we've seen enormous fruits of those grant applications, and we've seen some really important findings come out about the mechanism by which this genetic defect possibly leads to this cyst formation. And it really has a lot of ramifications that relate to the concepts that are being investigated in cancer and tumor suppressors and other types of things. Very interesting phenomenon. Almost on the heels of that discovery, our investigators at Albert Einstein discovered the cause of the so-called second form, ``polycystic kidney disease 2.'' And we now have two separate proteins that we feel might in some way interact with each other, but might have sort of a separate etiologic track of their own. We know that there are other rare forms of cystic disease, but now we know the fundamental cause. And so we think it's incumbent that we vigorously pursue this to understand completely what this genetic defect causes in terms of the protein that's abnormal, what this protein does and how it leads to cyst formation. We even have some clues about some therapeutic manipulations that might be actually instituted for this disease. But these are in a very, very preliminary stage. So I think it's really an extremely promising area, one that we plan to vigorously pursue and I look for some really important things to come from that in the near future. Mr. Porter. Dr. Gorden, last year you indicated that you did not favor the development of research centers specifically for polycystic kidney disease. Is PKD a research focus for any of your existing George O'Brien Kidney Research Centers, or the Pediatric Nephrology Centers? Dr. Gorden. Well, it certainly is a venue for those centers. And we welcome and openly encourage people with that interest to apply for these centers. So it's a completely open field in either of those two areas, either the George O'Brien or the pediatric centers. The fundamental reason, and so that that venue is open to individuals who have an interest in polycystic kidney disease, the reason that we have not encouraged yet another set of centers is because we believe we have more versatility in pursuing this through the research project grant mechanism, since we already have these centers which are available to individuals. And the important thing is for investigators to put together a real consortium that really constitutes a center. If that isn't possible or isn't necessarily one that is the most fruitful approach, it's best done by project grants, which we can control in a much more rapid sort of way. And we have much more versatility with the project grant mechanism. cooley's anemia Mr. Porter. Dr. Gorden, the committee has encouraged for some time the development of oral chelator drugs for Cooley's anemia patients, to spare them the painful daily 12-hour administration of the only currently approved drug. Are you close to initiating clinical trials for alternative therapies? Dr. Gorden. We have actually had under study several compounds, Mr. Porter. As you mentioned, this is a very devastating disease, particularly for children and young adults who develop this iron overload syndrome, because of the severe hemolytic process, that is, the breakdown of blood cells and the accumulation of iron. We have an excellent treatment that can be given parenterally, that is by injection, and it works very well. But it's very difficult, and it's very hard to get people to do this over a very long period of time. And that's why there's been this interest. We have tried to get pharmaceutical companies to develop these compounds, but without much success. So we've taken it upon ourselves, and we've investigated at least three or four compounds. Unfortunately, what seems to happen is that, when we get a compound that has some reasonable efficacy, we have two kinds of problems. One is that the sheer amount of the drug that patients have to take to accomplish what we're trying to accomplish is large. And it's sometimes more debilitating than actually the parenteral injection. And the second problem we've had is toxicity. We've been unable to develop a compound so far that we really feel is safe. It's an area that we're continuing to pursue. We just had a group of experts come in and advise us in this area. It's one that we're totally open to in terms of pursuing. We truly understand the need for it. And we're going to have to either continue this, if we can find some other promising compounds to pursue, or try to steer the course of research in a little bit different direction. But it's certainly an area that we will aggressively pursue. diabetes regimen Mr. Porter. Dr. Gorden, you mentioned your diabetes control and complications trial, which indicated that diabetes can be managed through a precise program. Have there been any follow- up studies to determine if the regimen can actually be maintained in everyday settings by ordinary families? Dr. Gorden. There have been no formal studies, Mr. Porter. But one thing that we do have is the population itself, that is, the population that participated in the Diabetes Control and Complications Trial. When they were involved in the study, we had the so-called conventional arm of the study, and we had the intensive arm of the study. We were able to maintain the level of what we call hemoglobin A1C, which is a chronic measure of blood glucose concentration, about in the range of about seven for the intensively controlled group, and around nine for the conventional group. At the end of the study, the patients were basically taken care of by their own private doctor. Now, these are people who have had a lot of experience in treatment. Now, what's happened over the last two years? What's happened over the last two years is that both groups have tended to come together. Our very latest analysis suggests that the conventional group is no longer nine, they're eight, and the intensive group is no longer seven, but they're eight. And one of the most important things that we found is that this beneficial effect that I have told you about in terms of protection, let's say, from retinopathy of the eye, is remembered. That is, there is a memory for the fact that they were in the intensive group. So they continue to do much better, continue to maintain the benefit that they received at an earlier time. Something that we know from other sorts of pharmacologic interventions, is that, when you intervene over a period of time, that effect will be sustained over a longer period of time. We believe that the trend for diabetes control is getting better. And we believe we're seeing this in this sort of microcosm of patients. But we really do not believe that we have in a national sense the facilities to maintain this level of control that was maintained. This is why it's so important that we try to develop alternative treatment strategies. We've got to find ways that can make this possible for people in the real world and real time. And that's really a goal that we have. And it's one that has been rather resistant to our achieving, but we're committed to that area, and we plan topursue it vigorously. impact of diabetes trial Mr. Porter. I think you just answered this, but let me ask it in any case. We've heard the concern voiced that an unintended consequence of the control and complications trial may be an impression that diabetes is a manageable disease and that this may discourage further research. I think you just said it will not. Dr. Gorden. I'd like to comment on that, if I could, Mr. Porter. I think that's a slightly different issue. Unfortunately, this really doesn't relate so much to the insulin-dependent form of diabetes, but it relates more to the non-insulin dependent form of diabetes. There was a kind of view that if your blood sugar was just kind of moderately elevated and you really didn't have any symptoms---- Mr. Porter. What would that be? Dr. Gorden. Well, let's say 150 to 200. And you had no symptoms, because that level of blood sugar elevation, say anywhere from 50 to 100 percent elevation, usually does not cause symptoms. So everyone felt fine. And unfortunately, the community of physicians and so forth was somewhat content with that, because no one really complained. Well, this is really one of the major points of our prevention trial in Type 2 diabetes. Because we clearly know now that the complications of diabetes are related to two things: the chronicity of blood sugar elevation and the intensity. So it is both the magnitude and the intensity. So that if you have mild elevation over a very long period of time, it clearly is doing you harm. So what we're trying to do is to say that we can interdict that process while it's still mild and prevent the occurrence of actual hyperglycemia for a period of time. We'd like to believe we could do it forever. But even if we could do it for five to ten years, that would be extremely important in this chronicity effect. So one would be exposed to hyperglycemia for a shorter period of time. And this would create a healthier patient population. We can't completely eliminate diabetes, but it would create a healthier population of patients with diabetes. And this is the goal. So we're really focused on two things. One, prevention. And treatment of mild diabetes. Because the more severe form, that I think is abundantly clear what we have to do about that. We've got to focus and get people to understand that we've also got to treat the mild form of diabetes as well as the more severe form. So I think that's a little bit different twist to the question that you asked. Mr. Porter. But the question was, is this going to discourage research. And I think you said no. Dr. Gorden. It absolutely should not. Because the problem still remains. In other words, why is this true? We're desperate to find alternative approaches to controlling the blood sugar. For instance, we're looking at inhibitors of so-called ``advanced glycosylation products.'' We're looking at certain kinds of inhibitors of chemicals, enzymes that we believe might be related to the complications of diabetes. If we could find ways to control this tertiary effect of the elevated blood sugar at the cell level, then the need for control would be somewhat diminished, if we could add those two things together. This would be a tremendously additive effect in trying to achieve our goal of less intense effect of the blood sugar and less intensity of the elevation of blood sugar. So we're working at both fronts to try to achieve that. Another example of that kind of thing is the recent clinical trial showing that certain types of blood pressure controlling agents, so-called ``ACE inhibitors,'' have an effect in ameliorating the progression of kidney disease of diabetes independent of their blood pressure controlling effect. So there's something else that these drugs do, probably related to the microvascular circulation of the kidney. It's that kind of thing that we're trying to achieve. We can show that we can decrease the deterioration of renal function in those patients by 50 percent with these drugs. obesity Mr. Porter. Last December, your Institute's Task Force on the Treatment and Prevention of Obesity published the results of its literature review on the effect of prescription weight loss drugs. The Task Force concluded that the drugs may help patients lose weight and maintain weight loss in the short term, but that very little is known about the effects past one year. The Task Force did report that most patients regained weight when they stopped taking the drugs. Should obesity be treated as a chronic disease like diabetes where patients will be medicated for their entire lives? And what research is your Institute supporting to address some of the questions identified in the Task Force's report? Dr. Gorden. First of all, I'd like to say that we put together this task force of experts on obesity to address this very important problem of both the dissemination of information and the direction of research. And it's been extremely successful. The issue of pharmacologic treatment of obesity is a very important issue. I think what you've said is essentially what we know about it, that is, there are drugs that have been approved and can be used, we believe, over a relatively short period of time. We're uncertain about the effects of these drugs over a very long period of time, in terms of either their efficacy or potentially, their toxicity. Now, to kind of amplify the point is that here's an area that there's been an absolute explosion in the science of understanding weight control and the mechanisms of weight control. There's been an explosion that has really kind of penetrated the entire biomedical research community and had a tremendous impact on the biotechnology and pharmaceutical industry. And we believe that this is going to have tremendous ramifications. I mean, just in the last two years, we've had more of a molecular understanding of the events involved in weight maintenance, weight gain, or weight loss than perhaps we've had in the last 2,000 or 3,000 years. It's really been dramatic, and it's something we could amplify on. But we've talked about this before, the concept of this newly discovered hormone, leptin. But it's not just that. It's the ramifications that that had on other discoveries, which have been so rapid over the last two years, it's been incredible. Mr. Porter. I have two questions on leptin. We've talked in previous years about the complex relationship between the hormone leptin and obesity. How do researchers explain the fact that despite the evidence implicating leptin and its receptor in weight control, mutations of their genes do not seem to be at fault in human obesity? Dr. Gorden. Well, at the present time, we can't totally explain that. There is an attempt to find mutations in human obesity. And they of course could occur either in the leptinsystem or some other place. But we have to sort of fall back on analogies that we understand a little bit better, say, non-insulin dependent diabetes, where we understand and have studied the relationship of insulin to so-called ``insulin resistance'' over the years. So that even normal or elevated amounts of insulin are typical of non-insulin dependent diabetes, just like normal or elevated amounts of leptin are typical of most patients who are obese. So the concept of leptin ``resistance'' has grown. And this is an area that is being pursued. But what I think is going to be important is to understand in a much more complete way the connections that this leptin system is involved in. Very recently, our Phoenix group that I mentioned earlier, that studies the Pima Indians, found that in fact, those individuals who were prone to gain weight over a period of, say, two to three years, were individuals who had relatively low leptin levels. So there's a lot we clearly don't understand yet about the role of leptin in this sort of biology and the potential role of leptin, either as a therapeutic model or something that's going to lead us to a more appropriate therapy for this condition. The answer to your question, should it be treated as a chronic condition, absolutely. Mr. Porter. And what role might leptin have in controlling diabetes? Dr. Gorden. Well, that's a very interesting question also. We have two different kinds of approaches here. In one approach, a recent paper suggests that perhaps leptin could in fact increase the resistance of diabetic cells to insulin. But that type of study has been conducted largely in isolated cell systems, and we don't really understand what that means in the whole body context, which may have a completely different context. Certainly there is a very strong link between non-insulin dependent diabetes and obesity. At least 80 percent of patients are obese. We know that weight reduction ameliorates the hyperglycemia; we know that weight reduction can prevent the onset of disease, from a variety of epidemiologic studies, so that anything that relates to obesity is going to have clear implications in diabetes. So here's an area that has really literally just opened up for investigators who are interested in obesity and diabetes, just in the last two years. Mr. Porter. Dr. Gorden, we were hoping that Mr. Bonilla of Texas would be able to join us. We had an indication that he would be here. And I've kept asking you questions not only because I wanted the answers to them, but because I wanted to give Mr. Bonilla a chance to arrive. He has not arrived. I have a meeting with the Speaker right at this moment. So let me end by complimenting you on the fine work you do at your Institute. You also are well known for controlling administrative costs better than most of your colleagues, and we admire that as well. We thank you for your tremendous knowledge and ability to speak in such a way that we can understand what it is that the answers are meant to convey. That has been very, very helpful to all of us, and we very much appreciate the wonderful job that you're doing there. Thank you so much. Dr. Gorden. Thank you very much, Mr. Porter. I appreciate it. Mr. Porter. The subcommittee will stand in recess until 1:30. [The following questions were submitted to be answered for the record.] [Pages 1214 - 1307--The official Committee record contains additional material here.] W I T N E S S E S __________ Page Adderly, Donna................................................... 2155 Alexander, Duane................................................. 1635 Baldus, A.C...................................................... 2001 Baldwin, Wendy................................................... 1 Barros, C.F...................................................... 1915 Beldon, Bill...................................................711, 805 Benowitz, S.C.................................................... 2249 Berkowitz, S.J................................................... 583 Burgess, E.S..................................................... 495 Bursenos, S.J.................................................... 1443 Casady, D.S...................................................... 1635 Cassman, Dr. Marvin.............................................. 2095 Collins, F.S..................................................... 495 Counts, G.W...................................................... 583 Cushing, Mary.................................................... 1377 Du Buy, Y.H...................................................... 1737 Dufour, Dr. Mary................................................. 1091 Fauci, A.S....................................................... 583 Ficca, S.A....................................................... 2249 Fitzsimmons, W.T................................................. 1809 Fivozinsky, C.L.................................................. 419 Fulton, B.E...................................................... 1635 Gekas, Hon. George............................................... 2431 Gorden, Phillip..............................................1177, 2431 Gordis, Dr. Enoch................................................ 1091 Gottesman, Michael............................................... 1 Grady, Dr. P.A................................................... 1377 Hall, Dr. Z.W.................................................... 2001 Haseltine, Dr. F.P............................................... 1635 Hausman, Dr. S.J................................................. 1491 Hodes, R.J....................................................... 1915 Hodgkins, G.E.................................................... 2095 Hudson, Kathy.................................................... 495 Hyman, S.E....................................................... 1809 Itteilag, Anthony...............................................1, 2249 Jaron, Dr. Dov................................................... 1573 Johnson, Laurie.................................................. 711 Jones, D.M....................................................... 983 Jordan, Elke..................................................... 495 Katz, Dr. S.I.................................................... 1491 Kerr, W.D........................................................ 805 Kerza-Kwiatecki, M.S............................................. 1491 Kirschstein, Dr. R.L..........................1, 1377, 1443, 1915, 2249 Klausner, R.D.................................................199, 2431 Kleinman, D.V.................................................... 1737 Kupfer, Carl..................................................... 419 Laurence, L.E.................................................... 1177 Leasure, C.E., Jr................................................ 711 Lenfant, Dr. Claude...........................................865, 2431 Leshner, A.I..................................................... 983 Levine, S.U...................................................... 1309 Lindberg, D.A.B.................................................. 1309 Lipman, D.J...................................................... 1309 Little, Francine................................................. 1 Long, Stephen.................................................... 1091 Luecke, D.H...................................................... 805 Maddox, Dr. Y.T.................................................. 1635 McGowan, J.J..................................................... 583 McLaughlin, Jack................................................. 419 McManus, Edward.................................................. 419 Merritt, Sheila.................................................. 865 Miller, Richard.................................................. 1443 Millstein, R.A................................................... 983 Mink, Hon. P.T................................................... 2431 Moore, Marshall.................................................. 805 Morella, Hon. C.A................................................ 2431 Moul, Ellen...................................................... 1377 Nakamura, R.K.................................................... 1809 Nethercutt, Hon. G.R., Jr........................................ 2431 Olden, Kenneth................................................... 711 Paul, W.E....................................................2155, 2431 Penn, Dr. A.S.................................................... 2001 Pine, J.R........................................................ 1809 Pine, Martha..................................................... 2095 Poppke, D.C...................................................... 1309 Rabson, Alan..................................................... 199 Ramm, Dr. L.E.................................................... 1573 Richardson, C.M.................................................. 1091 Rosenthal, Laura................................................. 983 Ross, K.S........................................................ 1915 Roth, Dr. Carl................................................... 865 Schambra, P.E.................................................... 1443 Shafer, Dr. W.S.................................................. 2095 Sherbert, R.L., Jr............................................... 2001 Slavkin, H.C..................................................... 1737 Smith, K.A....................................................... 1309 Snow, J.B., Jr................................................... 805 Sparks, P.T...................................................... 805 Strachan, R.J.................................................... 1491 Summers, A.E..................................................... 1573 Taylor, E.S...................................................... 1737 Trusty, M.K...................................................... 1091 Vaitukaitis, Dr. J.L............................................. 1573 Varmus, Dr. Harold.....1, 199, 419, 495, 583, 711, 805, 865, 983, 1091, 1177, 1309, 1491, 1573, 1635, 1737, 1809, 1915, 2001, 2095, 2155, 2249, 2431 Vennetti, J.C.................................................... 495 Wehling, James................................................... 865 Weiblinger, G.M.................................................. 1809 Wertheimer, Wendy................................................ 2155 Wetle, Terrie.................................................... 1915 Williams, D.P........1, 199, 419, 495, 583, 865, 983, 1091, 1177, 1309, 1377, 1443, 1491, 1573, 1635, 1737, 1809, 1915, 2001, 2095, 2155, 2249, 2431 Williams, T.D.................................................... 583 Wilson, S.H...................................................... 711 Zellers, C.R..................................................... 1177 I N D E X ---------- National Institutes of Health Overview Page Administrative Costs............................................. 53 AIDS/HIV: AIDS and Minorities.......................................... 111 AIDS Research................................................ 83 Culminations in HIV Research................................. 3 HIV Vaccine.................................................. 29 Inspiration in HIV Research.................................. 4 Areas of Research Emphasis....................................... 79 Awareness Relating to Biomedical Research........................ 67 Biomedical Engineering Research.................................. 116 Budget Estimates: Budget Estimates............................................. 11 Budget Estimates, Justification of........................... 148 Five Year Budget............................................. 91 FY 1998 Budget Request....................................... 43 Funding for NIH.............................................. 96 Impact of 7.5 Percent Increase............................... 22 1st President's Budget Proposal.............................. 5 Professional Judgment Budget................................. 11 Cancer: Ovarian Cancer............................................... 33 Advances in Ovarian Cancer Research.......................... 34 Child Abuse and Neglect.......................................... 134 Child Development and the Brain.................................. 34 Clinical Research: Clinical Research at Academic Medical Centers................ 143 Clinical Research Panel....................................129, 144 Clinical Research Program.................................... 80 Funding for Clinical Research................................ 80 Initiatives for Clinical Research............................ 145 IOM Recommendations................................19, 81, 142, 145 Peer Review of Clinical Research............................. 145 Progress in Support for Clinical Research.................... 22 Subscribers Participation in NIH Protocols................... 21 Third Party Payments, Impact of.............................. 35 Cloning: Cloning...................................................... 13 Cloning of Humans............................................ 26 Earlier Cloning Experiment................................... 14 Ethical Implications......................................... 17 How Genes Turn On and Off.................................... 16 Legislating Cloning.......................................... 18 Medical Uses of Cloning...................................... 15 Scientific Significance of Cloning........................... 15 Use in Bone Marrow Transplants............................... 16 Comparison of Medicare Costs and Disease Research Costs.......... 36 Congressional Earmarks........................................... 85 Consensus Development Panels..................................... 23 Contraceptive and Reproductive Health Training Programs.......... 136 Contraceptive Research........................................... 70 Coordination with Other Agencies................................. 82 Culminations of Research......................................... 2 Department of Defense, Collaboration with........................ 89 Department of Education, Cooperation with........................ 130 Diabetes: Commitment to Diabetes Research.............................. 30 Diagnosis and Detection of Diabetes.......................... 31 Increase in Diabetes Research................................ 131 Initiatives for Diabetes Research............................ 131 New Approaches to Pathogenesis............................... 65 NIH-Wide Diabetes Research Efforts........................... 64 Direct and Indirect Costs........................................ 72 Director's Discretionary Fund, FY 96 and 97...................... 45 Employment Rates for African-American Males...................... 120 Ethical, Legal and Social Implications Working Group............. 94 Ethics Training.................................................. 29 Extramural Construction.......................................... 107 Extramural Programs.............................................. 86 Full Time Equivalents (FTES): FTE Detail by Grade Level.................................... 59 FTE Ceiling.................................................. 61 FTE Total by Institute....................................... 48 FTE Total by Mechanism....................................... 49 Human Embryo Research............................................ 92 Grants: Administrative Burdens on Grantees........................... 88 New and Competing Research Project Grants.................... 142 Number of Applications....................................... 51 Research Project Grants...................................... 104 RPGs as Priority............................................. 113 Success Rates...............................................12, 110 Imaging Research................................................. 32 Indirect Cost Cap................................................ 66 Inspirations of Research......................................... 3 Instrumentation.................................................. 61 Intramural Programs.............................................. 87 Mammography: Mammography.................................................. 108 Mammography Policy........................................... 25 Medicare Spending by Disease, 1995............................... 37 Minorities: Inclusion of Minorities in Clinical Research................. 122 Investment in Minority Research Programs..................... 116 IOM Study.................................................... 103 Minority Health Standing Advisory Committee.................. 102 Minority International Research Training Program............. 100 Minority Investigators....................................... 113 Number of Minority and Women Investigators................... 105 Pipeline..................................................... 127 Reseach Centers in Minority Institutions..................... 128 Research Related to Minorities............................... 95 National Bioethics Advisory Commission........................... 28 National Center on Sleep Disorders Research...................... 52 Needle Exchange.................................................. 24 Neuroscience..................................................... 126 Obstetrics and Gynecology, Research in.........................135, 138 Office of Research in Minority Health (ORMH): Funding for Office...........................................96, 97 ORMH Co-funding.............................................. 99 Role of the ORMH............................................. 103 Opening Statement................................................ 6 Oversight and Administrative Activities.......................... 4 Panel on Potential Research on Marijuana......................... 24 Pediatric Research: Number of Intramural Pediatricians........................... 138 Pediatric Research........................................... 137 Permanent Separations Profile.................................... 121 Pipeline for Young Investigators................................. 93 Population Research.............................................. 70 Prenatal Research................................................ 71 Public Education................................................. 50 Pulmonary Hemorrhage Among Cleveland Infants..................... 104 Priority Setting: Allocation of Research Dollars............................... 40 Criteria for Funding Allocations............................. 40 Establishing Priorities...................................... 12 NIH Priority Setting Process.................................42, 73 Priority Setting at NCI...................................... 76 Reducing Health Care Costs....................................... 41 Research Infrastructure.......................................... 114 Research on Learning............................................. 130 Research Management and Support (RMS): Cap on Management and Support Costs.......................... 94 One-Percent Evaluation Funding In............................ 49 RMS Funding 1990-1998........................................ 50 Research Spending Per Death for Selected Disease................. 67 Research Training................................................ 86 Shannon Awards................................................... 61 Small Business Innovation Research Grants........................ 115 Spending by Disease.............................................. 56 Taps and Assessments: One-Percent Evaluation Set-Aside............................. 61 Taps and Assessments......................................... 63 Toll-Free Numbers................................................ 54 Women in Clinical Trials......................................... 141 National Cancer Institute Abortion and Breast Cancer....................................... 255 Access to Care................................................... 236 Advances Against Cancer.......................................... 273 Angiogenesis..................................................... 231 Areas Impacting on Cancer........................................ 232 ASSIST........................................................... 252 Behavioral Research.............................................. 321 Breast Cancer-ABMT............................................... 236 Cancer Genetics.................................................. 259 Cancer Genetics Network...................................... 260 Cancer Genetics and Molecular Biology........................ 305 Genetics Testing............................................. 261 Cancer Survivors...............................................230, 272 Breast Cancer Survival....................................... 235 Five-Year Survival Rates..................................... 230 Office of Cancer Survivorship................................ 242 Cancer Vaccines.................................................. 263 Cancer Centers Program Review Group.............................. 269 Cancer Genome Anatomy Project.................................... 269 Cancer Mortality by Race......................................... 317 Decline in Cancer Mortality.................................. 271 Cancer Prevention................................................ 203 Clinical Trials................................................204, 278 African American Women and Clinical Trials................... 299 Breast Cancer-Molecular Markers.............................. 207 Clinical Trials in FY 1998................................... 286 Clinical Trial Educational Efforts........................... 267 Clinical Trial Agreement with The Department of Defense...... 265 Clinical Trial Agreement with The Veteran's Administration... 266 Dissemination of Clinical Trial Results...................... 284 Women in Clinical Trials..................................... 328 Clinical Treatment............................................... 236 Cloning.......................................................... 318 Collaborative Efforts............................................ 307 Combination Therapies............................................ 308 Comprehensive Cancer Centers..................................... 251 Construction..................................................... 246 Coordination Efforts with DOD..................................237, 238 Coordination of the National Cancer Program...................... 251 Detection Technologies For Breast Cancer......................... 225 Other Detection Technologies For Breast Cancer............... 224 Diet and Cancer................................................258, 311 Dissemination of Cancer Information.............................. 319 Environmental Links to Breast Cancer............................. 233 San Francisco Bay Area....................................... 234 Environmental Justice Research Activities........................ 313 Environmental Justice Collaborative Activities............... 315 Estrogen and Breast Cancer....................................... 325 ``Five A Day'' Program........................................... 249 FTE Decrease..................................................... 245 Funding Allocation Decisions..................................... 226 Funding for NIH.................................................. 228 Gynecologic Cancer Research...................................... 328 Human Papillamovirus............................................. 241 Imaging.......................................................... 263 Imaging Technologies......................................... 297 Infectious Causes of Cancer...................................... 294 Institute of Medicine Cancer Study............................... 317 Intramural Program at Frederick.................................. 244 Justification of The Budget Estimates............................ 331 Mammography....................................................221, 295 Mammography Imaging.......................................... 265 Screening.................................................... 223 Measure of Successes............................................. 268 Minorities and Cancer............................................ 229 Advances in Minority Health.................................. 227 Cancer in Minority Population................................ 312 Excess Cancer Death Rate..................................... 271 Office of Special Populations................................ 229 Molecular Characteristics of Cancer.............................. 310 NCAB Subcommittee................................................ 224 NCI Panels and Advisory Boards................................... 329 New Cancer Drugs................................................. 268 NIH Reauthorization.............................................. 231 Opening Statement................................................ 199 Ovarian Cancer.................................................240, 327 Professional Judgment Budget..................................... 238 Opportunities................................................ 239 Prostate Cancer................................................236, 278 Prostate Cancer Initiatives.................................. 300 Prostate Cancer Treatment and Early Detection................ 302 African Americans and Prostate Cancer........................ 304 Radiation Therapy................................................ 246 Role of Stress in Cancer......................................... 277 San Antonio Cancer Institute..................................... 251 Science Information System....................................... 323 Implementation of The Science Information System............. 324 Statement of The Director........................................ 212 Tobacco Use and Children......................................... 247 Biology of the Brain............................................. 431 Cataract Surgery................................................. 437 Contact Lenses................................................... 437 FDA Approval..................................................... 429 Fetal Tissue..................................................... 434 Glaucoma Gene..................................................427, 429 Introduction of Witnesses........................................ 419 Long-Range Research Plan......................................... 436 Macular Degeneration...........................................429, 434 Marijuana use for Glaucoma....................................... 434 Neuron Survival.................................................. 428 Nutritional Supplements for Retinitis Pigmentosa................. 436 Opening Statement................................................ 419 Private Foundations.............................................. 435 Professional Judgement Budget.................................... 426 Radial Keratotomy Versus Laser Technique......................... 428 Retinopathy of Prematurity....................................... 430 Statement of Director............................................ 422 Transplanted Retinal Cells....................................... 433 Vision Conditions Needing More Research.......................... 437 Budget Increase.................................................. 506 Bureaucratic..................................................... 531 Center for Inherited Disease Research.....................497, 529, 543 Cloning: Cloning and Ethics........................................... 547 Cloning Humans............................................... 515 International Cooperation.................................... 511 Potential for Hoax........................................... 514 Scientific Opportunities...................................507, 536 Why a Sheep.................................................. 515 Designer Drug Strategies......................................... 513 Diversity........................................................ 544 Ethical, Legal, and Social Implications........................499, 535 Finding the Gene...............................................497, 505 Finishing Faster: Additional Funds Needed...................................... 525 Finding A Cure............................................... 507 Future Health Care Delivery...................................... 512 Genetic Discrimination and Privacy.............................519, 529 Genetic Testing: Breast Cancer................................................ 508 Counseling and Control....................................... 510 Guidance..................................................... 526 Health Insurance Portability and Accountability Act of 1996...... 537 Howard University Center......................................... 543 Human Embryo Research............................................ 516 Human Genome Project: Creation of.................................................. 541 Mapping Progress............................................. 534 Intramural Program............................................... 540 Minorities and Women............................................. 533 Newest Research Institute.................................495, 523, 532 Opening Statement................................................ 501 Oral Remarks..................................................... 495 Ovarian, Breast, and Cervical Cancer............................. 546 Prostate Cancer.................................................. 496 Protection of Patient Medical Information........................ 538 Sequencing: Complete DNA Sequence........................................ 498 Beyond the First Sequence.................................... 498 Large Scale Sequencing....................................... 528 National Institute of Allergy and Infectious Diseases Introduction of Witnesses........................................ 583 Opening Statement................................................ 583 AIDS: AZT...................................................586, 588, 618 Behavioral Research.......................................... 614 Clinical Trials............................................602, 606 Global Threat................................................ 612 Minorities................................................... 632 Office of AIDS Research...................................... 611 Pediatric.................................................... 657 Protease Inhibitors..............................601, 605, 614, 623 Therapy....................................................605, 608 Treatment Strategies..................................586, 605, 612 Vaccines.........................................593, 601, 609, 633 Women........................................................ 654 Asthma........................................................... 636 Basic Research............................................594, 599, 601 Benefits of AIDS Research........................................ 654 Budget Estimates, Justification of............................... 661 Cholera.......................................................... 619 Chronic Fatigue Syndrome.............................603, 623, 631, 641 Clinical Trials.................................................. 649 Cloning.......................................................... 640 Diarrheal Diseases.............................................602, 630 Drug Issues...................................................... 617 Emerging Infectious Diseases..................................... 647 Grant Success Rate............................................... 648 Hansen's Disease................................................. 620 Hemophilia....................................................... 617 Hepatitis A...................................................... 626 Lyme Disease..................................................... 603 Malaria........................................................618, 633 Media Involvement................................................ 616 Multiple Sclerosis............................................... 603 Patient Registries............................................... 639 Primary Immune Deficiency........................................ 622 Priority Setting................................................. 628 Research Accomplishments......................................... 643 Rotavirus........................................................ 602 Sexually Transmitted Diseases........................602, 628, 652, 658 Topical Microbicides............................................. 655 Tuberculosis.........................................619, 626, 630, 640 Vaccines.............................................596, 597, 603, 642 National Institute of Environmental Health Sciences Air Quality...................................................... 763 Air Quality Standards.................................730, 736, 745 Artificial Sweeteners............................................ 725 Asthma.........................................................728, 763 Autism........................................................... 731 Beryllium........................................................ 770 Breast Cancer.................................................... 766 Budget........................................................... 747 Budget Formulation............................................... 762 Cancer........................................................... 764 Clinical Program...............................................748, 750 Clinical Research................................................ 754 Clinical Trials.................................................. 762 Cloning.......................................................... 756 Collaboration with Industry...................................... 723 Collaborations................................................... 757 Congressional Visit.............................................. 719 Contract Mechanism............................................... 727 Endocrine Disruptors...........................................719, 723 Environmental Genome Project..................................... 720 Environmental Health Hazards..................................... 756 Environmental Justice..........................................752, 767 EPA.............................................................. 749 Funding Increase................................................. 717 Grant Funding Mechanisms, Major.................................. 758 Gulf War Syndrome................................................ 724 Justification of the Budget Estimates............................ 772 Knowledge ``Bottleneck''......................................... 754 Link Between Science and Public Health........................... 721 Minorities, Improving Health of.................................. 752 Mixtures......................................................... 718 Nanofabrication.................................................. 726 National Toxicology Program....................................734, 768 New Testing Methodologies......................................720, 734 Opening Statement................................................ 711 Particulate Matter............................................... 736 Pulmonary Hemorrhage Among Cleveland Infants, Epidemic of........ 764 Retesting of Chemicals........................................... 728 Secondhand Smoke................................................. 746 Smoking.......................................................... 730 Statement of the Director........................................ 713 Success Rate..................................................... 759 Superfund......................................................734, 750 Toxicity Test Systems............................................ 747 Vitamin D and Prostate Cancer.................................... 718 National Institute on Deafness and Other Communication Disorders Autism Research.................................................. 811 Balance Disorders in Elderly..................................... 816 Clinical Trials................................................818, 831 Cloning Technology............................................... 828 Collaborative Effort in Hearing Aid Technology................... 822 Eating Behavior and Nutrition.................................... 815 Government Performance and Results Act........................... 818 Hair Cell Regeneration........................................... 811 Hearing Aid Research............................................. 827 Hearing Impairment: Consensus Conference Findings................................ 813 Incidence.................................................... 824 Introduction of Witnesses........................................ 805 Investigator-Initiated Research Applications..................... 832 Justification of the Budget Estimates............................ 834 Loss of Voice.................................................... 816 Multi Cultural Language Assessment............................... 830 Opening Statement................................................ 805 Otitis Media..................................................... 823 Partnership Program.............................................. 832 Public Information Activities.................................... 821 Presbycusis...................................................... 826 Research Funding................................................. 821 Sense of Smell................................................... 816 Sensory Regeneration............................................. 815 Specific Language Impairment..................................... 820 Statement of Director............................................ 807 Stochastic Resonance............................................. 812 Vaccine for Otitis Media.......................................819, 826 National Heart, Lung, and Blood Institute Allocating Funds................................................. 888 Asthma.........................................................876, 928 Benefits from Research........................................... 890 Cardiovascular Disease in Mississippi..........................887, 926 Cell Death....................................................... 875 Child and Adolescent Trial for Cardiovascular Health (CATCH)..... 916 Chronic Obstructive Pulmonary Disease..........................921, 922 Clinical Trials and Research..............................925, 939, 942 Comprehensive Heart, Lung, and Blood Center...................... 911 Cooley's Anemia.................................................. 882 Cost Recovery.................................................... 902 Diet and Blood Pressure.......................................... 936 Education Programs........................................893, 900, 932 Folic Acid....................................................... 918 Gender Differences............................................... 930 Gene Therapy..............................................875, 878, 914 Government Performance and Results Act........................... 895 Heart Disease Death Rate......................................... 915 Heart Diseases...................884, 892, 902, 912, 926, 927, 932, 938 Human Cloning Research.........................................892, 941 Hypertension and Children........................................ 935 Hypertrophic Cardiomyopathy...................................... 905 Imaging Technology.............................................866, 873 Infants and Congenital Heart Disease............................. 934 In Utero Bone Marrow Transplantation............................. 874 Knowledge ``Bottleneck''......................................... 940 Lung and Blood Diseases..............................868, 880, 887, 896 Lung Volume Reduction Surgery..................................895, 924 Major Opportunities.............................................. 927 Minority Health............................879, 881, 925, 931, 933, 938 Organ Damage..................................................... 935 Primary Pulmonary Hypertension.................................906, 909 Salt Intake...................................................... 901 Selected Areas of Research....................................... 898 Select Pay....................................................... 903 Service Centers.................................................. 894 Sleep Disorders Research.........876, 893, 901, 907, 908, 922, 923, 936 Smoking........................................................884, 927 Specialized Centers of Research.................................. 899 Statement of the Director........................................ 870 Stroke Research................................................877, 919 Women's Health............................................913, 920, 944 National Institute on Drug Abuse AIDS and Drug Abuse.............................................. 1002 AIDS/HIV and Drug Abuse.......................................... 1017 Alaska Needle Exchange........................................... 995 Alcohol and Substance Abuse...................................... 993 Biology of the Brain............................................. 1028 Brain Development in Adolescent Drug Users....................... 1050 Brain Imaging.................................................... 1032 Bupropion........................................................ 1006 Clinical Research................................................ 1038 Clinical Trials.................................................. 1041 Cloning.......................................................... 1040 Cocaine Craving.................................................. 1009 Cocaine Medication............................................... 999 Cocaine Medication Development...............................1005, 1006 Collaborative Effort............................................. 1027 Comparing United States Drug Abuse............................... 1003 Cost to the Nation............................................... 1029 Craving.......................................................... 1012 Demographics of Addicts.......................................... 1003 Disease Specific Budgets......................................... 996 Drug Abuse Budget Increase....................................... 994 Drug Abuse Costs................................................. 1009 Drug Intoxication................................................ 1030 Effect of Welfare Reform on Addicts.............................. 1052 Effective Drug Treatments........................................ 1009 Effectiveness of Prevention Programs............................. 1007 Essense of Addiction............................................. 1001 Extent of the Problem............................................ 1020 Genetic and Environmental Influences............................. 1034 Impact of Drug Abuse............................................. 1030 Improving the Health of Minorities............................... 1037 Information Dissemination....................................1007, 1048 Introduction of Witnesses........................................ 983 Justification of the Budget Estimates............................ 1054 Knowledge ``Bottleneck''......................................... 1039 Marijuana for Medical Purposes................................... 1026 Medical Marijuana Concerns....................................... 1008 Medical Use of Marijuana......................................... 997 Methadone Treatment.............................................. 998 Minority and Women's Health...................................... 1044 Minority Related Research........................................ 1004 National Institutes of Health Disease-Specific Budgets........... 996 Needle Exchange...............................................997, 1023 Needle Exchange and AIDS......................................... 1008 Needle Exchange Programs......................................... 1004 Nicotine Addiction............................................994, 1000 NIDA-SAMHSA Coordination......................................... 1053 Opening Statement................................................ 983 Our Nation's Youth............................................... 1047 Outreach......................................................... 1037 Prenatal Drug Use Study.......................................... 1007 Prevention Increase.............................................. 1008 Prevention Principles Book....................................... 1006 Prevention Program............................................... 1005 Prevention Programs for Elementary and Secondary School Students. 1016 Prevention Research.............................................. 1012 Progress......................................................... 1031 Relationship Between Marijuana and Abrupt Termination of Pregnancy...................................................... 1011 Relationship with ONDCP.......................................... 992 Research......................................................... 1012 School Based Drug Prevention..................................... 1014 Search for a Cure................................................ 1046 Statement of the Director........................................ 988 Successor Drugs of Abuse......................................... 999 Tobacco.......................................................... 1014 Vaccine Development.............................................. 992 National Institute on Alcohol Abuse and Alcoholism Adolescent Consumption, Trends of................................ 1101 Alcoholics Anonymous, Evaluations of............................. 1103 Animal Models.................................................... 1092 Brain Function in Adolescents.................................... 1140 Chromosomes Associated with Alcoholism........................... 1123 Clinical Research................................................ 1136 Clinical Trials.................................................. 1139 Cloning.......................................................... 1138 Comparing Drug and Alcohol Use and Abuse......................... 1108 Consumption...................................................... 1109 Coordination..................................................... 1122 Coordination of Research Findings................................ 1142 Cure for Alcoholism.............................................. 1105 Dissemination of Research Findings............................... 1131 Effects of Alcohol on Development................................ 1110 Estrogen, Effect of Alcohol on................................... 1112 Extent of the Problem............................................ 1124 Fetal Alcohol Syndrome, Correlation of Heavy Drinking to......... 1111 Fetal Alcohol Syndrome........................................... 1125 Fetal Alcohol Syndrome and Early Childhood Development........... 1143 Genetic Testing.................................................. 1107 Genetics Research, Practical Applications of..................... 1107 Incidence by Gender.............................................. 1121 Institute of Medicine Assessment................................. 1132 Justification................................................1145, 1176 Knowledge of ``Bottlenecks''..................................... 1137 Liver Transplantation for Alcoholic Liver Disease................ 1113 Major Research Opportunities..................................... 1125 Medications for Alcohol Treatment................................ 1104 Medications, Promising........................................... 1118 Minorities, Improving the Health of.............................. 1135 Moderate Drinking................................................ 1117 Naltrexone Research.............................................. 1133 New Opportunities for Developing New Drugs....................... 1119 Opening Statement................................................ 1091 Pregnancy........................................................ 1128 Prevention....................................................... 1094 Prevention Research versus Behavioral Research................... 1121 Project Match, Rigorous Design and Findings of................... 1101 Project Northland: Positive Outcome and Lower Drug Use........... 1121 Research Advances, Application of................................ 1093 Research Dissemination........................................... 1095 Safe and Drug Free Schools....................................... 1115 Serotonin........................................................ 1112 Significant Research Opportunities............................... 1125 Statement of the Director........................................ 1096 Tobacco and Alcohol Use.......................................... 1134 Treatment Research............................................... 1094 Vulnerability to Alcoholism...................................... 1091 Welfare Reform................................................... 1141 Witnesses, Introduction of....................................... 1091 National Institute of Diabetes and Digestive and Kidney Diseases Administrative Issues............................................ 1218 Artificial Pancreas.............................................. 1194 Budget Estimates, Justification of............................... 1184 Chromium Diabetes Study.......................................... 1236 Clinical Research................................................ 1251 Clinical Trials.................................................. 1254 Clinical Trials--Participation................................... 1249 Cloning.......................................................... 1253 Collaborative Efforts........................................1225, 1246 Cooley's Anemia.................................................. 1209 Costs of Treating Diabetes....................................... 1194 Crohn's Disease.................................................. 1257 Diabetes Education Program....................................... 1191 Diabetes Education and Research.................................. 1224 Diabetes Emphasis................................................ 1184 Diabetes Gene.................................................... 1243 Diabetes in African Americans.................................... 1256 Diabetes in Minorities........................................... 1244 Diabetes Initiative.............................................. 1240 Diabetes Prevention.............................................. 1237 Diabetes Prevention Trials....................................... 1225 Diabetes Regimen.............................................1209, 1219 Diabetes Research............................................1228, 1231 Digestive Diseases............................................... 1205 Disease Funding.................................................. 1214 Drugs That Work Selectively...................................... 1204 Effects of Alcohol............................................... 1201 End-Stage Renal Disease.......................................... 1241 Funding for Diabetes Research..........................1189, 1217, 1223 Genetics of Diabetes............................................. 1191 Helicobacter Pylori.............................................. 1249 H. Pylori Applications........................................... 1202 Health Status of Women and Minorities............................ 1245 Hepatitis........................................................ 1207 Hepatitis C...................................................... 1214 Identifying Areas of Research Emphasis........................... 1184 Immune Modulation in Diabetes.................................... 1185 Impact of Diabetes Trial......................................... 1210 Improving the Health of Minorities............................... 1251 Intramural Decision-Making....................................... 1196 Intramural Research.............................................. 1195 Introduction of Witnesses........................................ 1177 Justification of the Budget Estimates............................ 1258 Knowledge ``Bottleneck''......................................... 1252 Liver Disease in Children........................................ 1221 Liver Disease Information........................................ 1219 Locating Diabetes Information.................................... 1193 New Methods for Treating Diabetes................................ 1237 Newly Diagnosed Diabetics/Early Intervention..................... 1227 Nutrition........................................................ 1200 Nutrition and Diabetes........................................... 1255 Obesity..........................................1211, 1222, 1241, 1244 Opening Statement................................................ 1177 Organ Donations.................................................. 1250 Outside Input for Diabetes Research.............................. 1226 Peer Review...................................................... 1230 Polycystic Kidney Disease..............................1208, 1217, 1255 Prevalence of Diabetes........................................... 1188 Professional Judgment Budget..................................... 1189 Prostate Cancer.................................................. 1247 Prostatitis...................................................... 1206 Public Education Activities...................................... 1216 Public/Private Research Partnerships............................. 1255 Research Centers................................................. 1215 Restoring Insulin Production..................................... 1187 Review Process for Clinical Studies.............................. 1226 Risk for Diabetes................................................ 1239 Small Business Research.......................................... 1197 Special Research Areas in Diabetes............................... 1192 Statement of the Director........................................ 1180 Stress in Diabetes............................................... 1185 Treating and Preventing Diabetes................................. 1223 Ulcer Diagnosis and Treatment.................................... 1203 Ulcers.......................................................1199, 1228 Upcoming Diabetes Conference..................................... 1192 Urology......................................................1206, 1218 Women's Health................................................... 1193 National Library of Medicine Bioinformatics................................................... 1325 Electronic Patient Records....................................... 1338 Genetic Databases............................................1336, 1346 Gpra Standards................................................... 1341 High Performance Computing...................................1337, 1347 Human Genome Map.............................................1316, 1324 Iaims Program.................................................... 1337 Internet.........................................1312, 1326, 1331, 1339 Justification of The Budget Estimates............................ 1355 National Information Infrastructure.............................. 1309 Next Generation Internet Initiative..........................1326, 1352 Opening Statement................................................ 1309 Outreach.....................................................1324, 1330 Personal Services Contracts...................................... 1337 Project Phoenix.................................................. 1342 Pubmed.......................................................1339, 1348 Statement of the Director........................................ 1319 Telemedicine.........................1314, 1327, 1328, 1334, 1343, 1351 Toxicology Center................................................ 1337 Underserved Populations.......................................... 1345 User Fees........................................................ 1349 Video Tapes...................................................... 1349 Visible Humans................................................... 1310 World Wide Web...............................................1333, 1343 National Institute of Nursing Research Aging............................................................ 1402 Alzheimer's Disease.............................................. 1400 Breast Cancer.................................................... 1399 Breast Self-Exams................................................ 1389 Cardiovascular Disease........................................... 1378 Cardiovascular Disease in Children............................... 1396 Chronic Illness.................................................. 1395 Clinical Research Conference..................................... 1385 Collaborative Efforts............................................ 1401 Communication with Health Care Providers......................... 1384 Counseling for Genetic Screening................................. 1389 Cultural Diversity............................................... 1378 Currency with Research........................................... 1386 End of Life...................................................... 1379 End of Life Care................................................. 1397 Future Research Emphases......................................... 1379 FY98 Budget Request..........................................1379, 1413 Infant Colic..................................................... 1396 Irritable Bowel Syndrome......................................... 1378 Justification of the Budget Estimates............................ 1384 Minority and Women's Health...................................... 1406 Minority Researchers............................................. 1403 Nurse Education Act--FY 1988 Budget.............................. 1393 Nursing and Oncology............................................. 1410 Nursing Publications............................................. 1385 Opening Statement................................................ 1377 Opportunities for Ethnic Nurses.................................. 1392 Outreach and Information Dissemination........................... 1405 Pain Research................................................1377, 1399 Professional Judgment Budget..................................... 1384 Provider Care.................................................... 1398 Quality of Care.................................................. 1393 Quality of Life.................................................. 1394 Research Training Issues......................................... 1387 Rural and Ethnic Populations..................................... 1391 Sister to Sister Study........................................... 1405 Stroke........................................................... 1406 Targeted Research................................................ 1404 Transplantation.................................................. 1379 Traumatic Brain Injury........................................1386, 397 Women's Health................................................... 1411 Women's Health Issues............................................ 1388 Fogarty International Center Biodiversity Program............................................. 1455 Budget Increase..............................................1460, 1461 Emerging Infectious Diseases.................................1463, 1464 External Panel Review............................................ 1452 Fellowship Programs..........................................1450, 1451 Former Soviet Union--State of Science............................ 1454 Human Frontier Science Program................................... 1453 International Agreements......................................... 1460 International Activities Expenditures........................1458, 1459 Justification of Budget Estimates.............................1466-1489 Minority International Research Training Program.............1462, 1463 Opening Statement................................................ 1443 Other Countries Leading in Biomedical Research................... 1450 Vitamin A Supplementation....................................1464, 1465 National Institute of Arthritis and Musculoskeletal and Skin Diseases Antibiotic Treatment............................................. 1507 AIDS Research.................................................... 1529 Arthritis Treatment.............................................. 1522 Breast Cancer and Osteoporosis................................... 1535 Breast Implants and Autoimmune Diseases.......................... 1512 Budget Estimates, Justification of............................... 1537 Budget Request, FY 1998.......................................... 1494 Cartilage Repair................................................. 1512 Central Nervous System Lupus..................................... 1514 Clinical Research................................................ 1530 Clinical Trials.................................................. 1533 Collaborative Research........................................... 1515 Depression and Osteoporosis...................................... 1513 Epidemiological Data Concerning Repetitive Motions Injuries...... 1520 Ergonomics...................................................1500, 1502 Fibrodysplasia Ossificians Progressiva........................... 1514 Funding for Disease Areas........................................ 1517 Gender and Autommunity........................................... 1511 Gulf War Syndrome................................................ 1513 Human Cloning....................................1502, 1503, 1505, 1532 Health Status.................................................... 1528 Low Back Pain.................................................... 1518 Minority Health Research......................................... 1530 Musculoskeletal Disorder.....................................1500, 1518 Osteoarthritis................................................... 1526 Osteoporosis...........................................1493, 1509, 1510 Psoriasis........................................................ 1535 Professional Judgment Budget..................................... 1507 Repetitive Motion Injury.....................................1499, 1525 Research Centers................................................. 1517 Research Opportunities........................................... 1522 Research Challenges.............................................. 1532 Rheumatoid Arthritis............................................. 1493 Sexualy Transmitted Diseases..................................... 1536 Skin Cancer..................................................1493, 1524 Statement of the Director....................................1491, 1495 Stress and Arthritis............................................. 1511 Success Rate..................................................... 1536 Systemic Lupus Erythematosus.................................1493, 1528 Total Joint Replacement.......................................... 1492 Trauma Injuries.................................................. 1521 National Center for Research Resources National Center for Research Resources.......................1573, 1604 Broader Participation............................................ 1602 Clinical Research................................................ 1591 Chimpanzees in Research.......................................... 1579 Chimpanzee Retirement........................................1580, 1581 Coordination of Imaging Activities............................... 1586 Education........................................................ 1597 Euthanasia of Research Animals................................... 1583 Extramural Construction.......................................... 1600 Extramural Facilities Construction...............1585, 1587, 1588, 1592 Extramural Programs.............................................. 1596 Faculty Investigators............................................ 1598 Funding for Selected Programs.................................... 1588 General Clinical Research Centers................................ 1583 Interest in Biomedical Research.................................. 1590 Introduction of Witnesses........................................ 1573 Minority and Women's Health...................................... 1600 Minority Research Investigators.................................. 1597 NCRR Appropriations.............................................. 1595 NCRR Strategic Plan.............................................. 1582 Near Infrared (University of Kentucky)........................... 1590 Office of Research on Minority Health............................ 1597 Opening Statement............................................1573, 1575 Pipeline......................................................... 1596 RCMI Clinical Initiative......................................... 1601 RCMI Cofunding................................................... 1600 Regional Primate Research Centers............................1586, 1587 Research Centers in Minority Institutions........................ 1592 Research Infrastructure in Minority Institutions................. 1595 Review Committees................................................ 1598 Shared Instrumentation Grants.................................... 1588 Use of Animals in Research....................................... 1579 Virtual Laboratories............................................. 1585 National Institute of Child Health and Human Development AIDS............................................................. 1681 Alcohol and Drug Addiction....................................... 1673 Asthma........................................................... 1649 Autism........................................................... 1643 Autism Centers................................................... 1644 Autism Research Investigators.................................... 1644 Child Day Care................................................... 1674 Childhood Nutrition.............................................. 1667 Children with Learning Disabilities.............................. 1660 Children with Reading Disabilities............................... 1655 Clinical and Basic Research...................................... 1689 Clinical Research................................................ 1665 Clinical trials.................................................. 1691 Cloning.......................................................... 1691 Diabetes Research................................................ 1679 Drug Dosages for Children & Pediatric Pharmacology Res. Units.... 1653 Drug Use before Pregnancy........................................ 1657 Early Child Care................................................. 1646 Funding--Disease Areas........................................... 1671 Grant Funding.................................................... 1666 Health Status of Minority Children............................... 1684 Infant Mortality................................................. 1676 Infertility Research............................................. 1656 Infertility...................................................... 1673 Intervention Programs............................................ 1660 Intramural Clinical Research..................................... 1669 Justification.................................................... 1693 Learning Disabilities............................................ 1688 Learning Disabled Children....................................... 1644 Learning to Read.............................................1648, 1654 Maternal Mortality............................................... 1656 Middle School Children........................................... 1652 Minority Representation in Basic Research and Training........... 1689 National Center for Medical Rehabilitation Research.............. 1672 Obesity Research................................................. 1680 Opening Statement................................................ 1635 Perinatology Research--District of Columbia...................... 1665 Phonics Based Reading System..................................... 1659 Phonics Based System............................................. 1661 Phonics.......................................................... 1663 Premature Labor and Delivery..................................... 1646 Prevention Problem Behavior...................................... 1651 Protection from Asthma........................................... 1650 Pulmonary Hemorrhage in Infants.................................. 1687 Research Bottlenecks............................................. 1690 Research Centers................................................. 1670 Research on Fatherhood........................................... 1663 Research Opportunities........................................... 1685 SIDS Back to Sleep Campaign...................................... 1645 SIDS.........................................................1670, 1688 Spinal Cord Injury............................................... 1668 Strengthening Families........................................... 1670 Teenage Drug Use and Pregnancy................................... 1658 Vaccine Development.............................................. 1666 Web Page......................................................... 1649 National Institute of Dental Research 50th Anniversary................................................. 1772 AIDS/HIV......................................................... 1775 Biomimetics...................................................... 1749 Bone Research................................................1762, 1780 Cleft Palate..................................................... 1755 Clinical Trials.................................................. 1768 Clinical Research................................................ 1777 Cloning.......................................................... 1778 Congressional Justification...................................... 1782 Dental Amalgams.................................................. 1748 Dentist Scientist Program........................................ 1756 Diabetes, Oral Complications of.................................. 1750 Flouridation.................................................1749, 1754 Future Expectations.............................................. 1750 Health Status.................................................... 1767 Immune Systems................................................... 1770 Introduction of Witneses......................................... 1737 Knowledge ``Bottleneck''......................................... 1771 Medicare Coverage for Dental Care................................ 1755 Minorities, Improving the Health of.............................. 1776 Minority Groups, Reaching Ethnic and............................. 1762 NIDR Strategic Plan.............................................. 1759 Opening Statement................................................ 1737 Oral Cancer............................................1757, 1764, 1769 Osteoporosis and Oral Bone Loss.................................. 1751 Pain Research................................................1752, 1780 Priority Setting................................................. 1760 Public Education.............................................1774, 1780 Research Centers.............................................1759, 1765 TMD..........................................................1750, 1753 National Institute of Mental Health Basic Neuroscience............................................... 1852 Brain as the Touchstone of NIMH Research......................1828-1829 Brain Development and Mental Illness..........................1840-1842 Children...........................................1854-1856, 1866-1867 Prevention of Childhood Mental Illness....................1823-1824 Proceedings of Workshop (Inclusion of Children in Clinical Research)...............................................1837-1839 Research Needed on Childhood Disorders....................1829-1830 Treatment of Mental Illness in Children...................1834-1840 Circadian Rhythms and Mental Illness..........................1843-1844 Clinical and Services Research................................... 1852 Eating Disorders.............................1844-1845, 1849-1850, 1856 Funding Amounts FY 1996-FY 1998.................................. 1846 Gene Therapy..................................................1868-1869 Global Burden of Disease......................................1818-1819 Table 1...................................................... 1811 Inclusion of Women and Minorities.............................1865-1866 Initiative to Track Enrollment of Women and Minorities........... 1827 Justification of Budget Estimation............................1870-1913 Managed Care..................................................1857-1858 Mental Illness in the U.S.....................................1859-1862 Mental-Physical Relationship..................................1867-1868 Minority Employment.............................................. 1826 Minority Investigators and Research Subjects..................1825-1827 Needle Exchange Programs......................................1821-1822 New Drugs for Schizophrenia...................................1831-1832 Nutritional Factors...........................................1850-1851 Opening Statement of Director.................................1809-1817 Prevention of Childhood Mental Illness........................1823-1824 Proceedings of Workshop (Inclusion of Children in Clinical Research)...................................................1837-1839 Regulation of Emotion............................................ 1853 Relationship of Mental Illness to Other Physical Illnesses....1842-1843 Research Needed on Childhood Disorders........................1829-1830 Schizophrenia.................................................... 1859 Setaside for Mental Health Services Research..................... 1821 Sexual Abstinence in AIDS Prevention............................. 1823 Social Work Research............................................. 1830 Suicide and Suicide Prevention................................1862-1865 Training......................................................... 1858 Training of Minority Researchers................................. 1831 Translation of Research into Treatment........................1832-1834 Treatment of Mental Illness in Children.......................1834-1840 UNOCCAP (Use, Needs, Outcomes,and Costs for Child and Adolescent Populations)................................................1819-1820 Victims of Torture............................................1846-1849 Vulnerability.................................................... 1854 World-wide Burden of Disease (Table 1)........................... 1811 World-wide Burden of Depression...............................1824-1825 National Institute on Aging Aging--The Exercise and Nutrition Linkage........................ 1955 AIDS............................................................. 1963 Alzheimer's Disease and Ibuprofen................................ 1941 Alzheimer's Disease..................1915, 1934, 1935, 1948, 1954, 1960 Alzheimer's Disease Genetic Discoveries.......................... 1917 Biological Processes............................................. 1958 Biology of Aging................................................. 1920 Caloric Restriction.............................................. 1949 Collaborative Activities......................................... 1959 Demographic Research............................................. 1934 Demography of Aging.............................................. 1921 Disability Research..........................................1933, 1956 Embryo Research.................................................. 1936 Falls in the Elderly............................................. 1939 Genetic Research................................................. 1943 Health Care Savings.............................................. 1937 Health Status and Clinical Trial Participation................... 1861 Hypertension..................................................... 1952 Immune System.................................................... 1963 Long Term Care...............................................1943, 1965 Managed Care..................................................... 1955 Menopause........................................................ 1964 Number of Chronically Disabled Americans Age 65 and Over......... 1924 Nursing Homes--Individualized Care............................... 1950 Opening Statement............................................1915, 1926 Osteoporosis..................................................... 1937 Predictive Testing............................................... 1944 Projected Population Age 100 Years and Over...................... 1931 Prolonging Independence--Delaying Disability..................... 1956 Prostrate Cancer................................................. 1940 Protective and Risk Factors for Alzheimer's Disease.............. 1919 Quality of Life.................................................. 1936 Research Centers................................................. 1946 U.S. Life Expectancy at Age 85, 1900-1995........................ 1932 Unraveling Longevity............................................. 1963 World Population by Age.......................................... 1922 National Institute of Neurological Disorders and Stroke Accident Prevention.............................................. 2048 Alzheimer's Disease.............................................. 2039 Amyotrophic Lateral Sclerosis.................................... 2022 Brain Diseases in Children....................................... 2039 Childhood Diseases............................................... 2035 Clinical Research................................................ 2041 Clinical Trials.................................................. 2044 Cloning.......................................................... 2043 Congressional Justification...................................... 2051 Diseases of Aging................................................ 2010 Epilepsy Research............................................2033, 2040 Estrogen and Stroke.............................................. 2020 Future of Brain Research......................................... 2011 Human Embryo Research............................................ 2023 Introduction of Witnesses........................................ 2001 Knowledge Bottleneck............................................. 2042 Mad Cow Disease and Prion Hypothesis............................. 2021 Minority Research Investigators.................................. 2037 Multiple Sclerosis............................................... 2034 Neurodegenerative Disease Initiative.........................2018, 2019 New Treatments and Discoveries................................... 2038 Nicotine, Possible Therapeutic Effects of........................ 2020 NINDS Budget Increases........................................... 2012 Opening Statement................................................ 2001 Parkinson's Disease..........................................2016, 2028 Prion Hypothesis and Mad Cow Disease............................. 2021 Research Centers Grants, NINDS................................... 2026 Specific Disease Funding......................................... 2026 Spinal Cord Injury Research......................2012, 2016, 2024, 2049 Statement of Director............................................ 2005 Stroke Research......................2010, 2020, 2031, 2036, 2047, 2049 Targeted Research................................................ 2018 National Institute of General Medical Sciences Biology of the Brain Initiative.................................. 2121 Budget Policy.................................................... 2142 Budget Tables.................................................... 2144 Cell Biology and Biophysics...................................... 2130 Compliance with NRSA Payback Requirement......................... 2112 Employment Prospects for Research Trainees....................... 2110 Evaluation of National Research Service Award Training........... 2112 Gender Differences in Response to Trauma......................... 2115 Genetics and Developmental Biology............................... 2133 Goals of the Director............................................ 2108 Goals to be Accomplished and Priority-Setting Process............ 2140 High Risk Research............................................... 2109 Inclusion of Underrepresented Minorities......................... 2118 Innovations in Management and Administration..................... 2141 Interim Funding.................................................. 2108 Introduction..................................................... 2123 Justification of Budget Estimates................................ 2124 MARC Program.................................................2122, 2138 MBRS and HBCU Participation...................................... 2120 MBRS Program.................................................2119, 2137 Medical Scientist Training Program............................... 2112 Minority Opportunities in Research...........................2117, 2137 New Approaches to Pathogenesis...................2132, 2133, 2134, 2135 New Investigators................................................ 2110 NIGMS Organizational Chart....................................... 2125 Opening Statement................................................ 2095 Other Areas of Interest.......................................... 2141 Percentage of Ph.D's Awarded to Minorities....................... 2114 Pharmacology Research Associate Program.......................... 2140 Pharmacology, Physiology, and Biological Chemistry............... 2135 Protease Inhibitors.............................................. 2118 Rationale for Stipend Increases.................................. 2112 Research Advances................................................ 2130 Research Areas Pursued by Young Investigators.................... 2113 Research in Chemistry and Physical Sciences...................... 2108 Research Training Collaborations with Industry................... 2111 Scientists Employed as Temporary Workers......................... 2111 Special Initiatives.............................................. 2138 Special Programs................................................. 2137 Stimulation of Research Fields................................... 2110 Stipend Levels................................................... 2116 Story of Discovery: From Chemistry to Gene Therapy............... 2129 Training Programs of the Howard Hughes Medical Institute......... 2114 Office of AIDS Research AIDS Statistics.................................................. 2163 AIDS in Minority Populations..................................... 2170 AIDS in Minority Populations..................................... 2203 AIDS Research Proportion of NIH Funding.......................... 2171 AIDS Research Addressing Minorities.............................. 2170 AIDS Research Proportion of Total NIH Request.................... 2167 Benefits of AIDS Research to Other Diseases...................... 2164 Changing Faces and Scientific Priorities......................... 2190 Clinical Trials of New Therapeutic Agents........................ 2188 Cooperation with Industry........................................ 2183 Demographic Groups With Increasing AIDS Cases.................... 2163 Direct Support for OAR........................................... 2174 Federal Biomedical Research Plan................................. 2175 Flexibility for OAR to Change ICD Distributions.................. 2165 Inclusion of Minorities in AIDS Research......................... 2193 Justification................................................2205, 2248 Latest Advances in AIDS/HIV Therapies............................ 2202 Minorities on Research Training Grants........................... 2168 Minority Participation in Clinical Trials........................ 2197 Needle Exchange.................................................. 2187 NIH Panel on Principles of Therapy for HIV Infection............. 2181 OAR Discretionary Fund........................................... 2176 OAR Collaboration with ORMH and ORWH............................. 2192 Opening Statement................................................ 2155 Pediatric AIDS................................................... 2178 Prevention Science Working Group................................. 2172 Projected AIDS Deaths Without a Vaccine.......................... 2164 Proportional Increases for NIH Institutes........................ 2171 Prospects for International Availability of an AIDS Vaccine...... 2163 Recipients of AIDS Research Funds................................ 2177 Reluctance of Monitories to Participate in Clinical Trials....... 2171 Research Plan.................................................... 2186 Role of the Office of the Director............................... 2167 Small Business Innovation Research Grants (SBIR)................. 2196 Social and Behavioral Factors of AIDS............................ 2192 Status of Minority and Women's Health............................ 2167 Status of the Development of an AIDS Vaccine..................... 2186 The Investment in Minority Research Programs..................... 2196 The New Generation of AIDS Researchers........................... 2172 Three Percent Transfer Authority................................. 2166 Total AIDS Research Funding...................................... 2166 Training for HIV Researchers..................................... 2184 Witnesses, Introduction of....................................... 2155 Office of the Director and Buildings and Facilities Administrative Cost Study........................................ 2264 Area Program..................................................... 2301 Behavioral Research.............................................. 2335 Budget Request for ORMH.......................................... 2338 Building and Facilities.......................................... 2257 Child Abuse and Neglect.......................................... 2324 Cholestin........................................................ 2262 Clinical Research Issues......................................... 2304 Concluding Remarks............................................... 2292 CRC Advanced Appropriations...................................... 2262 CRC Cost Estimates............................................... 2263 Credit Card Purchases............................................ 2303 Decrease in OD Funding Level..................................... 2323 Electronic Grant Submissions..................................... 2311 Employment Separation Rates...................................... 2345 Enrollment for Women's Health Initiative......................... 2308 Extramural Associates Research Development Awards Program........ 2328 Extramural Biomedical Facility Construction Research Infrastructure................................................. 2344 Grant Scoring.................................................... 2310 Herbal Medications............................................... 2266 Inclusion of Women and Minorities in Clinical Trials...2309, 2332, 2347 Institute of Medicine............................................ 2343 Introduction of Witness.......................................... 2249 Justification of Budget Estimates................................ 2358 Listing of NIH Facilities........................................ 2290 MARC and MBRS Programs.......................................2270, 2334 Medical Nutrition Therapy........................................ 2266 Minority Health Initiative....................................... 2300 Minority Programs................................................ 2336 Funding for Minority Programs............................2338, 2345 Funding for Minority Researchers............................. 2271 Inclusion of Minorities in Research.......................... 2330 Increasing Minority Participation............................ 2327 Minorities in Clinical Trials................................ 2351 Minority Funding.........................................2270, 2291 Minority Research Grants..................................... 2272 Minority Researchers......................................... 2337 Recruitment and Retention of Minorities...................... 2350 Representation of Minorities in Research Protocols........... 2349 Underrepresented Minorities..............................2326, 2352 National Agenda on Research on Women's Health.................... 2269 National Biomedical Research Service Positions................... 2298 National Foundation for Biomedical Center........................ 2315 New Component for Women's Health Initiative...................... 2308 NIH Organizational Structure..................................... 2289 Office of Alternative Medicine.........................2265, 2318, 2323 Alternative Medicine Research................................ 2316 Office of Alternative Medicine Budget........................ 2301 Office of Alternative Medicine Clearinghouse................. 2302 Office of Behavioral and Social Sciences Research................ 2315 Office of Dietary Supplements.................................... 2266 Office of Research on Minority Health and NIEHS Collaborations... 2293 Opening Statement................................................ 2249 Opening Statement--Dr. Kirschstein............................... 2251 ORMH--Standing Advisory Committee................................ 2341 ORWH's Budget Level.............................................. 2268 Pediatric and Neurodegenerative Initiatives...................... 2306 Plans for New Institutes......................................... 2290 Progress of Minority and Women's Health.......................... 2326 Quotas........................................................... 2274 Radioisotope Contamination....................................... 2295 Radiology and Imaging............................................ 2262 Recombinant DNA Advisory Committee............................... 2314 Renovation of Clinical Center.................................... 2263 Research Needs of Children....................................... 2323 Research of Human Subjects....................................... 2313 Re-Submission of Unfunded Grant Applications..................... 2313 SBIR Grants...................................................... 2295 Science Education Activities at the NIH.......................... 2275 Senior Biomedical Research Service Positions..................... 2295 Status of Minority and Women's Health............................ 2326 The Ryan Commission.............................................. 2316 Unified Information Technology System............................ 2264 Women and Minorities in Biomedical Careers....................... 2333 Women in Biomedical Careers...................................... 2269 Women's Health Initiative........................................ 2298 Adequacy of Spending on Diabetes................................. 2484 Advice In Decision-Making........................................ 2435 AIDS: Expenditures for AIDS and Other Diseases..................... 2473 NIH Expenditures on AIDS Research............................ 2494 Research Coordination........................................ 2482 Research Funding............................................. 2495 Scientific Opportunity....................................... 2471 Stabilizing Infections....................................... 2494 Vaccine Initiative........................................... 2500 AIDS and Scientific Opportunities................................ 2471 AIDS Research Coordination....................................... 2482 AIDS Research Funding............................................ 2495 AIDS Vaccine Initiative.......................................... 2500 Areas of Emphasis................................................ 2485 Biography, William E. Paul, M.D.................................. 2468 Biography, Harold E. Varmus, M.D................................. 2459 Biography, Dennis Williams, Ph.D................................. 2470 Budget: Constraints.................................................. 2436 Doubling NIH's............................................... 2497 NIH Budget for 1998.......................................... 2508 Budgetary Constraints............................................ 2436 Cancer: Mortality Rates.............................................. 2488 Ovarian...................................................... 2501 Ovarian...................................................... 2503 Ovarian, Detection of........................................ 2490 Research Article............................................. 2489 Cancer Mortality Rates........................................... 2488 Cancer Research Article.......................................... 2489 Clinical Research............................................2501, 2502 Clinical Research Report......................................... 2505 Coding for Parkinson's Research.................................. 2477 Commitment Base..............................................2434, 2476 Committee Report Language........................................ 2472 Congressional Biomedical Research Caucus......................... 2475 Congressional Support............................................ 2503 Cost Savings from Research....................................... 2500 Criteria For Decision-Making..................................... 2434 Curriculum Vitae, Phillip Gorden, M.D............................ 2467 Curriculum Vitae, Richard Klausner, M.D.......................... 2460 Curriculum Vitae, Claude Lenfant, M.D............................ 2465 Detection of Ovarian Cancer...................................... 2490 Disease: Imprecision of Coding........................................ 2435 Trans-NIH Categories......................................... 2478 Doubling NIH's Budget............................................ 2497 Drug Rehabilitation.............................................. 2506 Early Childhood Development...................................... 2506 Earmarks in DOD for Research..................................... 2507 Effect of Public and Congressional Input......................... 2499 Expenditures for AIDS and Other Diseases......................... 2473 Factors in Resource Allocation................................... 2492 Factors In Resource Allocation................................... 2472 Final Authority for Decision-Making.............................. 2486 Funding for Autism............................................... 2489 Funding for Population Research.................................. 2480 Genetics Research Opportunities.................................. 2496 Imprecision Of Disease Coding.................................... 2435 Information Dissemination........................................ 2503 Information Dissemination of Research Findings on Learning Disabilities................................................... 2507 Information Transfer............................................. 2499 Information Transfer in Prevention............................... 2506 Information Transfer to Other Agencies........................... 2506 Learning Disabilities: Research on.................................................. 2507 Information Dissemination of Research Findings on............ 2507 Limitations To Planning Science.................................. 2434 NIH Budget for 1998.............................................. 2508 NIH Definitions of Selected Population Groups.................... 2479 NIH Health Funding By Group...................................... 2481 NIH Expenditures on AIDS Research................................ 2494 NIH Resource Allocation Procedures............................... 2485 NIH Spending On Minority Initiatives............................. 2479 Nobel Laureates.................................................. 2474 Observations And Principles For Resource Allocation.............. 2433 One Percent Transfer Authority................................... 2486 Opening Statement of the Director NIH............................ 2433 ORWH's Priority Setting Process.................................. 2504 Ovarian Cancer................................................250, 2503 Pace Of Research................................................. 2437 Parkinson's Disease.............................................. 2436 Parkinson's Disease And Related Research Awards, FY 96........... 2457 Politics and Research............................................ 2501 Prepared Statement Of Director, NIH.............................. 2439 Priority Setting................................................. 2493 Priority Setting Interaction of ORWH and NIH..................... 2505 Public Relations for NIH......................................... 2482 Research on Learning Disabilities................................ 2507 Resource Allocation By NIH....................................... 2437 Science Cannot Be Purchased...................................... 2436 Stabilizing AIDS Infections...................................... 2494 Statement of the Hon. George R. Nethercutt, Jr................... 2484 Statement of the Hon. George Gekas............................... 2476 Statement of the Hon. Patsy Mink................................. 2490 Statement of the Hon. Constance A. Morella....................... 2498 Strategic Plan................................................... 2478 Technology Transfer.............................................. 2502 Trans-NIH Disease Categories..................................... 2478 Unanticipated Research Results................................... 2496