It is important to note that all of these studies have undergone several levels of review by National Cancer Institute advisory and review committees. This It will be helpful to introduce the chronology of the diet and cancer intervention studies with a review of the advisory committee structure of the National Cancer Institute. structure provides critical guidance on program initiatives and the assessment of progress. - The advisory committee structure consists of the National Cancer Advisory Board (NCAB), four Boards of Scientific Counselors (BSCs) one board for each of the four research divisions of the NCI and the President's Cancer Panel. The men and women of the NCAB are appointed by the President and serve for six-year terms. The NCAB includes scientists from the broad spectrum of disciplines involved in cancer research as well as lay members who know and deeply care about cancer research and its application. The immediate past Board Chair was Dr. David Korn, Vice President for Medical Affairs and Dean of the Medical School, Stanford University. The NCAB advises the NCI Director on Institute priorities and resource allocation. In addition, according to statute, no grant may be funded without the approval of the NCAB. Approval of the NCAB does not automatically mean that a grant will be funded only that it can be funded. The Boards of Scientific Counselors advise the specific NCI research divisions on their programs. They review all grant and contract solicitations, provide advice on the reports of site visits to the intramural programs, and make recommendations about the overall functions of the relevant division. The President's Cancer Panel consists of three members who are appointed by, and report directly to, the President and advise on the progress of, and issues related to, the National Cancer Program. Members of the Panel serve for two-year terms and may be re-appointed at the pleasure of the President. The President's Cancer Panel was chaired by Dr. Armand Hammer from 1982 until his death in December 1990. Women's Health Trial: 1984 Feasibility Study The chronology begins in 1984 with a proposal by NCI's Division of Cancer Prevention and Control (DCPC) to test the feasibility of a large-scale dietary intervention trial to determine whether a low-fat diet could reduce breast cancer incidence. The proposal, termed the Women's Health Trial, was based, in part, on evidence accumulated during the 1970s suggesting that diet was strongly implicated in certain cancers. Reports released in the early 1980s from a number of distinguished scientists and scientific bodies reinforced these hypotheses. proposal to test the feasibility of a large-scale dietary intervention study was presented to the DCPC Board of Scientific Counselors (BSC) who approved the study. The study was designed as a cooperative agreement and involved three clinical centers. There were 303 women who participated in the study. The In 1987, study results were reviewed and found to be positive, to the extent that highly motivated women were able to adopt and maintain a low-fat diet with predicted reductions of blood levels of cholesterol and the intake of calories. On February 1, 1988, after much discussion of the feasibility of the study, coupled with a review of the scientific results to date in support of the diet and cancer hypothesis, the Division of Cancer Prevention and Control Board of Scientific Counselors recommended that the trial not move forward into full-scale implementation until more evidence of the relationship between fat and breast cancer was obtained. NCI accepted the recommendation of this BSC and did not move forward with the study, but did continue with its ongoing, broad program of cancer prevention research. The issues raised by the BSC, plus the fact that the study had not addressed methods for dietary change among minority, educationally disadvantaged and poor women, mirrored issues to be raised in future debates. Investigator-Initiated Proposal: DIET-FIT About a year later, an investigator-initiated research grant proposal was received (DIET-FIT) and evaluated through the NIH peer review process. The objective of this grant proposal was to conduct a low-fat dietary intervention study to test the effect of this diet on breast cancer, colorectal cancer, cardiovascular disease, and on all causes of mortality combined. As noted above, in order to fund this study under a grant, NCAB approval was required. During the period of the feasibility study the NCAB had been made aware of the Institute's steps toward the large-scale study due to its public health importance, the importance to the science of cancer prevention, and the expected scale and cost of the study. Estimates of the total cost ranged from $100-150 million, depending on the specific design of the trial which called for some 20,000-30,000 women to be enrolled. The cost of the investigator-initiated proposal was somewhat less, but still on the order of a total cost of $100 million involving 24,000 subjects. The result of the NCAB deliberations was to not concur with the recommendation of the initial review group to approve the grant for reasons that were not based on the grant proposal's scientific merit. In a letter from Dr. Korn to the National Cancer Institute, Dr. Korn noted that the Board action was taken in light of its responsibilities to ensure appropriate use of grant, cooperative agreement, and contract funds, and to assist NCI in establishing objectives and priorities. The letter states that the trial could add to our knowledge of the potential benefits of a low-fat diet, but the severe constraints on research resources, coupled with the many scientific opportunities available, made it inappropriate to fund a study of such magnitude from the investigator-initiated research grant pool. Workshop on Dietary Intervention Trials Among Women The DCPC continued to review data and studies related to the role of dietary fat in cancer and in the Spring 1990 concluded that the evidence had reached a point where further consideration should be given to a large-scale trial. To provide guidance on the design of such a trial, the NCI, in cooperation with the National Heart, Lung, and Blood Institute (NHLBI), convened a workshop on July 9-10, 1990 to consider the issue. The workshop recommended that NCI and NHLBI proceed to design a low-fat dietary intervention trial to reduce breast cancer, colorectal cancer and cardiovascular disease. The NCI, in collaboration with NHLBI, developed a proposal for funding through the contract mechanism that was brought to the DCPC BSC and approved in October 1990. In turn, the approved contract initiative was presented to the NCAB at its request in December 1990 for its information and counsel by Dr. Peter Greenwald, Director, DCPC. The NCAB recommended that prior to implementing a full-scale trial, NCI conduct a further feasibility study to test the methods for dietary change among poor women and women in minority populations. Indeed, one of the recommendations of the July 1990 workshop had been to include minority populations as a part of the intervention study. Poor and minority women are among our worst cancer statistics. The NCAB strongly recommended that there be a well-defined decision point at which the results of the feasibility study would be assessed along with the state of science and then-extant dietary patterns. The NCAB also recommended that no more than $2.5 million per year for three years be allocated to the feasibility study. Critical Issues The proposal to evaluate the impact of dietary change on cancer specifically a low-fat diet has engendered much debate. Both sides have strongly held views, and it is clear that reasonable people and responsible scientists can look at the same set of facts and disagree. Ironically, some who are against a study feel that the relationship has already been proven. They note that NCI and Department of Health and Human Services have already formulated sound dietary guidelines and that if followed by both the intervention and control groups the guidelines would preclude finding a significant difference in cancer rates between the two groups. A corollary of this view is that the resources committed for a dietary intervention study would be better spent on publicizing these dietary guidelines and finding ways of achieving their adoption by those who would benefit from nutritional modifications. Others believe that the key dietary causal factor is total calories, rather than fat, and that testing an intervention on both calories and fat simultaneously will not give a clear answer. Some are concerned about the type of fat and strongly favor a design that would test, for example, the effect of reducing fat derived from meat versus fat from dairy foods. Others are concerned that the dietary intervention methods have not been properly tested nor adapted to meet the needs of poor and minority women who have some of the Nation's worst statistics in breast and other cancers, a point of particular concern to NCI. Still others are very concerned by the total cost of the proposal in an era of restricted resources. The original proposal required a commitment of $10 million to $15 million per year for about 10 years. This funding is equivalent to about 60 to 70 traditional investigator-initiated research grants (RO1's) per year; or about six to ten core grants to Cancer Centers (P30's); or it is approximately equivalent to the funding of the entire Community Clinical Oncology Program (CCOP). By way of contrast, the CCOP supports over 50 community-based clinical and prevention and control research programs, participating jointly in some 400 research protocols involving over 5,000 cancer patients and 6,000 prevention and control subjects. NCI Position The National Cancer Institute has examined these issues and marked the following conclusions. First, with respect to the impact of following the nutrition guidelines on the trial, NCI staff have formulated the trial design to account for significant dietary behavior change on the part of the control group, who will receive full information on diet and cancer. The relationship between diet and cancer is not completely understood, and that is one of the main reasons NCI has considered launching this trial. The NCI feels, however, that following the dietary guidelines is a prudent choice at this point in time. NCI Secondly, whether the potential effect of a change in diet on cancer might be due to the change in calories consumed or due to a reduced intake of fat is an important scientific question. However, from a practical point of view, lowering fat in the diet reduces both fat and total calorie intake. NCI studies implicate both as having a critical role in mammary tumor development. believes that a large-scale study of such size, cost and complexity can only be conducted once, and therefore must be designed to maximize the utility of its results. A dietary modification that has both the greatest potential to reduce cancer and is broadly achievable by the American population is the best intervention strategy. Clearly, there are many tradeoffs that need to be made in the design of such a study and there may be reasonable people with differing views of the issue. This is part of science and the core of the scientific process. Thirdly, dietary intervention methods must be properly tested and adapted to meet the economic and cultural framework of poor and minority women, who suffer the most from breast cancer.. The recommendations from the NCAB and from the Workshop also stress this point. The prior feasibility study was not of the scale to develop interventions (strategies, techniques, and materials) specific to either the Hispanic or Black populations. NCI's studies should be sensitive to the cultural diversity of American women. A decade of cancer control research has made it abundantly clear that to achieve change, whether in smoking behavior, cancer screening behavior, or dietary behavior, it is essential to understand and tailor methods to the specific target population. It is also essential that no major population subgroup be disenfranchised from participation in our studies. A secondary but important goal of any large scale dietary intervention study is to facilitate clinical research and training opportunities at the various study-centers. Therefore, study-centers should be open to participation by health care professionals from minority and underserved communities. It is also important that the developmental aspect of the study take place even if the NCAB has not focused on the feasibility study in its recommendation. A feasibility study is necessary not only to address the development of techniques and materials, but also to identify the barriers to full participation in the study by these populations. These studies must include and be germane to those who suffer most from cancer. This is the rationale for our population-specific emphasis, and the reason NCI endorses the feasibility study to test methods for including Black and Hispanic women in the dietary intervention study. The recommendations of the NCAB, and the steps being taken by NCI permit the evaluation of intervention methods with respect to the broadest group possible who should benefit from the dietary intervention. In addition, they enable the identification of the best centers, those most suited to compete to perform this study. Every large-scale study includes the subsidiary but important goal of training clinical researchers and it is important to ensure minority participation in this opportunity. The NCI is committed to designing its research to be as applicable as possible to the broadest segment of the American people. Current Status NCI is now moving forward based on the recommendations of the DCPC BSC and the NCAB. Requests for Proposals (RFPs) are being issued to identify three clinical centers and a coordinating center to participate in the "Women's Health Trial: Feasibility Study in Minority Populations." One of the clinical centers will have 50 percent or greater representation of Black American women, one will have 50 percent or greater representation of Hispanic women and one will be representative of the U.S. population, including all minorities. The feasibility study will enroll 2,250 women representing all economic levels. It is anticipated that enrollment will begin in the Summer of 1992. The feasibility study is a three-year study and will be conducted by NCI in collaboration with NHLBI. Policy Advisory Committee: A Policy Advisory Committee will provide oversight of trial operations and scientific progress. Members to be appointed will consist of a subcommittee of the Division of Cancer Prevention and Control's Board of Scientific Counselors and outside experts in clinical trials, biostatistics, nutritional science, behavioral science, cardiovascular disease |