and lipids, medical ethics, and other appropriate medical specialties. Their responsibilities will include trial protocol review, periodic evaluation of trial progress including recruitment, compliance to protocols and making recommendations to NCI, NHLBI and their advisory groups as to whether or not the trial should proceed as planned. Decision Point: A decision to undertake a full-scale trial shall await the results of the feasibility study and review by the National Cancer Institute, National Heart, Lung and Blood Institute and their advisory boards. If the feasibility study is successful, as judged by successful recruitment and dietary adherence, and a decision is made to implement a full-scale trial, women participating in the feasibility study would continue as part of the full-scale trial. The primary objectives of the full-scale trial are to determine whether a low-fat dietary pattern can reduce 1) breast cancer incidence, 2) combined breast cancer and colorectal cancer incidence, 3) fatal and non-fatal coronary heart disease incidence, and 4) total mortality. The full-scale trial would enroll 24,000 women at 12 Clinical Centers with 60 percent randomized to the control group and 40 percent to the intervention group. Women enrolled in the full-scale trial would be followed for a minimum of 13 years and a maximum of 15 years. DIETARY STUDY ISSUES Dr. BRODER. In brief, there are essentially two or three camps that have strong feelings on this point of view. The diet fit study that you are discussing is a prospective randomized trial to test whether a reduction in fat would have significant benefits to women in terms of cancer reduction and reduction of heart disease and vascular disorders. In brief, there is a school of scientists and laypeople who feel that the answer is known that a reduction in fat with the evidence at hand is something that we should already be adopting, and this school of thought feels there is a strong data base for asking for a reduction so that individuals consume no more than 30 percent of their calories as fat, and, therefore, there is no need to study this issue. The answer is known. And this group, therefore, is not in favor of this study because they feel we should simply be using our educational resources and our informational resources and so on to address this point. There is another group which feels that the answer is not known, but the particular protocols that have been suggested are not going to give an answer. There is sentiment in some quarters of our scientific community that there is a strong difference between animal fat and dairy fat, and that you cannot just link all fats together, and that one has to be careful in designing a study that one does not get the wrong answer by not controlling for that variable. There is another group that feels that it is total calories that count and not just the fat per se. I am giving you a flavor of some of the differences, but the most significant concern that I personally feel is that we do not have an adequate preliminary data base on poor and minority women as to whether we have enough cultural sensitivity and appropriateness in addressing how one would implement a low-fat diet for that group. Poor women and minority women have the worst cancer statistics and, therefore, from my own personal point of view, it would be unthinkable that we could make a large scale commitment without ensuring that we have done our homework and that we understand how to do fat reduction interventions in that population and make such individuals integrally part of the studies. FEASIBILITY OF DIETARY INTERVENTION IN TARGET POPULATIONS Therefore, what the Institute has done is set up a feasibility study over approximately 3 years. The NCI has committed a total out-year cost of about $7.5 million to do a feasibility study in minority and poor women and to ask whether we can do a culturally appropriate dietary intervention in those groups, and then reassess our position. I cannot give you a commitment today that we will do the large scale diet fit intervention study. There are some technical and scientific issues that for purposes of time I am not sharing with you, but I would be happy to give them to you for the record. Senator HARKIN. I guess what I hear you saying is that you are doing a review right now. Dr. BRODER. Sir, we are doing a feasibility study. We actually will launch a feasibility study in poor and minority women. If you ask: Can you do a low-fat intervention? The answer is, yes. It is possible to get certain women to participate in a study and effectively reduce the percentage of their total caloric intake that is fat to 30 percent or to 20 percent or 25 percent, whatever the goal is. But, if the question is also whether this can be done in certain target populations where we have a special need-these issues have not been resolved. I do not think that you can say that the answer is yes. What you do in an educated middle-class community is not necessarily what you would do in an impoverished or minority community. I feel this is a gap. We have to address this point and see whether we can effectively do the study in this group. And that is the feasibility study, to determine whether we can accomplish this goal, and then, if so, how to do it. And again, there are many issues that I am still leaving off for purposes of time. But this study will be underway. FARM CHEMICALS AND CANCER Senator HARKIN. Are you doing any studies to look at the possible link between the use of farm chemicals and the increased type of cancers like non-Hodgkin's lymphoma and leukemia that's higher in midwestern farming States? Dr. BRODER. Yes, sir, we are. In fact, our Division of Cancer Etiology has made a special effort to study these issues and has studied in particular a chemical referred to as 2,4-D. And in fact, I can take great pride in saying that the Division of Cancer Etiology was instrumental in helping to adopt some commonsense but terribly effective ways of dealing with this problem of lowering the exposure of farmers and agricultural workers. And we believe that with some of the sound recommendations that have been made, that we can minimize, not necessarily eliminate entirely, but minimize to a very significant degree the risks that are attached with 2,4-D and the risk of non-Hodgkin's lymphoma. NEW TECHNOLOGIES FOR INFORMATION DISSEMINATION And in addition, we have done as much as we can to disseminate this. I have brought some of the technologies that we use for disseminating knowledge. We have compact disks that we can put our information services on that can be put into what is called a CD read-only memory computer, and individuals can get the latest information that we have. This little disk can hold 350 books worth of knowledge. And we feel this is a cost-effective way, and we are using these types of technologies to get the word out and to make sure that we are reaching communities both in the United States and in other countries as well. QUESTIONS SUBMITTED BY THE SUBCOMMITTEE Senator HARKIN. Thank you very much, Dr. Broder. There will be some additional questions from various Senators which we will submit to you for your response. [The following questions were not asked at the hearing, but were submitted to the Institute for response subsequent to the hearing:] QUESTIONS SUBMITTED BY THE SUBCOMMITTEE DELAYED OBLIGATION OF FUNDS Question. Dr. Broder, I noticed that of the funds you have requested for 1992, $63,446,000 would not be available until September 19 or with less than two weeks remaining in the fiscal year. For each of the NIH institutes, a similar proposal is made resulting in $400,000,000 of the NIH $548,212,000 increase delayed until the end of the fiscal year. I am sure that OMB has proposed this as a gimmick to keep outlays down, and the Congress may well need to follow suit ... but what operational difficulties will this create for the Cancer Institute? Answer. The delay in releasing approximately $63 million of FY 1992 funds could impose some operational difficulties on the Institute. Over the years the NCI has been very conscious of balancing its workload for both grant and contraet awards among each of the quarters of the year. This minimized excessively heavy peak periods for the processing of grants and contracts. Without such an endeavor, staffing levels would need to be at a level sufficient to handle peak times. With the knowledge that the funds would be released on September 19, 1992, the program and administrative staff could complete the negotiation phases with recipient institutions prior to September 19th. They would delay the actual signing of legal documentation until funds are received from OMB through the apportionment process. It is conceivable that delays in processing requirements could surface at this time. Given that there are only 11 days in the balance of the fiscal year, this could compromise our ability to make complete awards. However, we of course would prefer to have these funds available under these circumstances than not at all. GENE THERAPY EXPERIMENT Question. Last September at the Clinical Center, an historic gene therapy experiment was begun on a little girl with a previously incurable and deadly disease that shuts down the immune system. I understand that the experiment has gone well, and the little girl now has a nearly normal immune system. Could you describe the therapy for the Committee and its potential for curing other diseases? Answer. In 1989, NIH researchers from the National Cancer Institute and the National Heart, Lung, and Blood Institute obtained permission from 13 different review committees, including the Food and Drug Administration, to perform one of the most important clinical studies of our time, the first human trial of gene transfer therapy. The gene introduced into the cells was the neomycin resistance gene, chosen mainly to provide a marker by which tumor infiltrating lymphocyte (TIL) cells could be tracked throughout the body. This trial has been completed and has demonstrated the safety and feasibility of this technique. The genetically modified TIL cells were tracked in the blood stream for up to 120 days and isolated from the tumor as long as 60 days following infusion. Gene transfer therapy is now being pursued simultaneously on two fronts: insertion of genes into TIL cells to enhance their tumor killing capabilities as well as insertion of normally functioning genes into cells obtained from individuals with diseases caused by specific genetic deficiencies or abnormalities. Beginning in January of this year, cancer patients have been treated with TIL cells altered in the laboratory to include the gene for tumor necrosis factor (TNF), a naturally occurring substance that stimulates the tumor fighting capabilities of TIL cells. These patients are being closely monitored to see if these genetically modified TIL cells are effective at eradicating their tumors. In the Spring of 1990, a young girl with an immunodeficiency disease called severe combined immunodeficiency caused by an inherited lack of the adenosine deaminase (ADA) enzyme received normal lymphocytes that had been taken from her body, genetically altered in the laboratory to contain a normal ADA gene, and given back intravenously to the girl. The girl has been followed for more than nine months and now has normal ADA levels as well as a normal immune system. Gene transfer therapy has tremendous implications for diseases caused by specific genetic abnormalities, many of which are currently fatal. These include inborn errors of metabolism, which cause significant disability and death in infancy, as well as acquired genetic defects which cause diseases such as diabetes in adolescence or adulthood. Although treatments exist for many of these disorders, these treatments are aimed mainly at the control of the end manifestations of the disease. Gene transfer therapy has the potential to address the very cause of these diseases, providing the hope that, for the first time, we may be able to cure individuals stricken with these devastating diseases. Gene transfer therapy holds great potential for diseases such as sickle cell anemia, cystic fibrosis, thalassemia, and glycogen storage diseases, which exact a tremendous toll on the health of Americans every year. ETHICAL CONSIDERATIONS OF GENE THERAPY EXPERIMENTS Question. Dr. Broder, as you know better than I do, gene therapy is manipulating the fundamental blueprint of a human being which of course could and does raise ethical questions. What level of review do you believe is necessary for gene therapy experiments? Answer. An extensive review process has been set up to review gene therapy experiments. All efforts at gene therapy must receive approval from the following review groups before they can begin: Institutional Clinical Research Committee Institutional Biosafety Committee (that deals with |