$$XID RFA HL9203H HL-92-03-H P1O1 ************************************** MULTICENTER STUDIES OF DIET AND LIPOPROTEINS IN HUMANS RFA: HL-92-03-H P.T. 34; K.W. 0710095, 0755015, 0715040, 0755018, 0765020, 0710030 National Heart, Lung, and Blood Institute Letter of Intent Receipt Date: February 15, 1992 Application Receipt Date: April 23, 1992 PURPOSE OF PROGRAM The Division of Heart and Vascular Diseases, National Heart, Lung, and Blood Institute (NHLBI), invites cooperative agreement applications to conduct collaborative multicenter human nutrition studies on the effects of fats and other dietary constituents on blood lipids and lipoproteins, hemostatic factors, and other biologic intermediaries relevant to atherogenesis. This Request for Applications (RFA) program will have a structure similar to that of a multicenter clinical trial. A sequence of collaborative research protocols will be designed by the investigators. Field Centers will feed standardized experimental diets, use the same methods for data collection, and pool the data. A Coordinating Center will standardize management and data collection procedures, provide expertise in biostatistics to ensure sound approaches to study design and data analysis, and oversee a centralized quality control program for the measurement of outcome variables and the nutrient composition of experimental diets. The funding mechanism that will support this program is the Cooperative Agreement (U01), which is similar to the traditional NIH research grant (R01) but differs in the extent and nature of NHLBI staff involvement. Applications received in response to the RFA will participate in a single competition. An institution may apply to serve both as a Field Center and Coordinating Center, but separate applications are required. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This RFA, Multicenter Studies of Diet, and Lipoproteins in Humans, is related to the priority areas of heart disease and stroke and nutrition. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0 or Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-783-3238). ELIGIBILITY Applications may be submitted by for-profit and non-profit, public and private organizations, such as universities, colleges, hospitals, laboratories, units of State or local governments, and eligible agencies of the Federal Government. Applications from minority individuals and women are encouraged. For-profit organizations must waive their fee. Awards in connection with this announcement will be made to foreign institutions only for research of very unusual merit, need, and promise, and in accordance with Public Health Service policy governing such awards. DISCIPLINES AND EXPERTISE Expertise appropriate for the Field Centers includes, but is not restricted to, nutrition, dietetics, lipid and lipoprotein metabolism, biochemistry, protein and lipid chemistry, hematology, food chemistry, and biostatistics. An understanding of the public health, epidemiologic, and clinical aspects of cardiovascular disease is needed. Experience with multicenter collaborative studies is desirable. Experience with human feeding studies that have been well- controlled is essential. The expertise appropriate for researchers at the Coordinating Center includes, but is not restricted to, biostatistics, nutrition, food chemistry, and clinical chemistry, particularly regarding lipids and lipoproteins and hemostatic parameters. Investigators must have experience with research design, study coordination, data management and analysis (especially as related to human nutrition studies and other laboratory-based studies), and food composition analysis. Experience with multicenter collaborative studies is highly desirable. An experienced nutritionist with a substantial time commitment must be included. BACKGROUND A solid foundation of epidemiologic, clinical and laboratory evidence underlies the current dietary recommendations for population-based prevention of coronary heart disease. It is clear that average blood cholesterol levels will decline with the consumption of less saturated fat and cholesterol than has been traditional in the United States. It is not clear, however, whether or not reductions in total fat intake are necessary as well. More research also is needed to define how best to provide a national food supply whose composition will enhance efforts to reduce CHD risk. Fatty acid investigations are especially critical because this is an area in which the food industry has greater latitude in reformulating products according to current scientific evidence, dietary recommendations, and customer demand. Stearic acid, for example, may be suitable as a replacement for "hard" fatty acids because it has relatively little effect on total blood cholesterol levels, but it may be rendered less suitable for this purpose if it accelerates the tendency of blood to clot. Similarly, hydrogenated vegetable oils are used as substitutes for saturated animal fats, but they contain trans-fatty acids that may raise low-density lipoprotein levels in a manner similar to that of saturated fatty acids. In general, the mechanisms by which diet influences the eventual development of atherosclerosis through alterations in lipid and lipoprotein levels and metabolism, and through other factors such as hemostasis, still are not fully understood. Human clinical nutrition studies, when feasible, are among the best research approaches for addressing the links between diet and atherosclerosis. Moreover, because of their great relevance to everyday life, such findings are quickly publicized. Often, however, such studies do not yield consistent or reproducible results. The resulting transmission of mixed messages to the scientific and lay communities seriously undermines both the credibility of nutrition research and the public's confidence in the possibility of obtaining reliable and practicable advice on how to modify diet. Oat bran, with its rise and fall in the scientific and popular press ,as well as in the marketplace, is a good example of this phenomenon. The lack of consistency among designs of clinical nutrition studies seeking to answer the same scientific question (for example, the influence of dietary fiber on serum cholesterol levels) means that the results cannot be readily compared. Some study designs are flawed, lacking adequate hypotheses and control groups. In addition, compliance in dietary studies is frequently less than ideal. Studies that allow participants to select and prepare their own food, even when adhering to an "experimental" diet, frequently do not provide reliable results. Only in tightly controlled clinical settings, in which the participants receive all food from the experimental kitchen and are known to consume it, can the influence of poor compliance be minimized. A further complication is that the actual composition of study diets may not be as intended, due to natural variations in food sources and the vagaries of food composition data bases. Such discrepancies can be sufficient to alter the results of the study and lead to false conclusions, yet research budgets seldom allow for the high cost of food composition analyses. The typical small size of clinical nutrition studies has far-reaching effects. Because these studies are expensive and require great commitments of labor and space, it generally is very difficult for a single investigator funded by a traditional research grant to enroll, feed, and study more than 20-25 participants at one time. This imposes constraints on duration, design, and statistical power; consequently, many human nutrition studies lack sufficient power to detect biologically meaningful differences between groups or treatments. To avoid outside sources of variability that would further reduce study power, investigators usually make efforts to assemble a "homogeneous" study population and minimize the number of factors that might impinge on the experimental design; thus, studies are most often conducted in young Caucasian males with average or even low plasma cholesterol levels. Not much is known, therefore, about how response to diet is affected by sex, age, race, co-morbid conditions (such as obesity), lipoprotein phenotype and other factors that would make the results more generalizable to the population at large. Furthermore, the mechanisms underlying the so-called "hypo-responder" phenomenon, wherein individuals are presumed to be insensitive to the effects of diet on plasma lipid levels, cannot be elucidated unless individuals with a wide range of responses are studied in adequate numbers. The Cooperative Agreements funded through this RFA will draw upon the model of the multicenter clinical trial to undertake human nutrition studies with adequate sample size, rigorous quality control of experimental diets, and management practices aimed at ensuring excellent compliance with study protocols. OBJECTIVES AND SCOPE Overview The primary objective of this RFA is to support collaborative investigations into the effects of diet on human lipoprotein composition and concentration and to encourage simultaneous evaluation of dietary effects on other biological factors with potential etiologic roles in atherogenesis. To enhance the generalizability and reliability of data gathered by research funded through this RFA, the program will establish an administrative structure analogous to that used for multicenter clinical trials. Awards for this four-year program will be made to one Coordinating Center and four Field Centers. Data collection will take place in the Field Centers, each enrolling and retaining 20-25 participants per 4-6 month period. It is envisioned that the program will comprise a sequence of individual studies, each lasting approximately 4-6 months or one academic semester and involving a total of 80-100 participants per study; other designs may be proposed as well. At any one time, all Field Centers will be engaged in the same study. Using commonly agreed-upon procedures, the Field Centers will recruit, enroll, and feed study participants, conduct experiments, and make laboratory measurements. The Coordinating Center will participate in the development of the study design and the data collection procedures, provide a centralized facility for data management and analysis, and oversee quality control programs. The overriding unifying activity of the proposed program will be that, for every study, all Field Centers will feed experimental diets virtually identical for variables of interest (e.g., fatty acid composition and cholesterol content) so that data can be pooled. Food composition analyses will be used to ensure standardization of experimental diets. The sequence of collaborative studies will be designed mainly during the first year by a Steering Committee of all Principal Investigators and the NHLBI Project Scientist. The protocol for these studies will be derived from those proposed by the awardees in their applications, modified as necessary to accommodate the multicenter design of this program, and prioritized by the Steering Committee. Although the protocol will be established during the first year, ongoing review of results will allow flexibility during the latter years of the program to follow up on promising findings and adjust procedures to maintain quality control. The process of collaborative protocol development, although well-developed for multicenter clinical trials, is unusual for laboratory-oriented human nutrition studies. Investigators must be willing to compromise to ensure the success of the program. Furthermore, all centers must be willing to implement the strategies developed by the Steering Committee during protocol development and to supply data, diet aliquots, and biological specimens to the Coordinating Center or centralized laboratories as needed for analysis. The Steering Committee, or a publications subcommittee drawn from it, will define rules regarding access to and analysis of data from collaborative studies and publications and presentations resulting therefrom. The schedule of the Cooperative Diet Study will have three phases, estimated as: Phase I - Protocol development and pilot studies, 12 months Phase II - Recruitment, data collection and data analysis, 30 months Phase III - Final data analysis and closeout six months Phase I, which will last about 12 months, will be devoted predominantly to protocol development and pilot studies needed to establish the diet and laboratory quality control programs. During Phase I, the Coordinating Center must be ready to implement data collection and quality control systems for pilot studies. Progression to Phase II is dependent on the concurrence of the NHLBI, following advice from an expert group appointed by the NHLBI. The protocol will be implemented in Phase II. During this phase, Field Centers will recruit and feed participants, collect the outcome data specified in the protocol, and provide these data to the Coordinating Center. The Coordinating Center will collect, process, and analyze the data and provide reports to the Steering Committee. Phase III activities will comprise final data analysis, study closeout, and manuscript preparation. Study Design Each applicant for a Field Center award must propose the sequence of experiments thought to be most appropriate for this multicenter collaborative program. Applicants must discuss in detail the important design considerations, suggest solutions to perceived problems, and outline necessary pilot studies. Innovative approaches to reduce costs are strongly encouraged. Given the expense of conducting well-controlled human feeding studies, efficient use of funds will allow investigations of greater scientific sophistication and statistical power. Applications for Field Center awards must describe hypotheses and designs for collaborative studies and implementation methods in Phase II of the protocol. Hypotheses should address issues of major importance in public health nutrition, population-level modification of diet, and treatment of hyperlipidemia. Designs should take advantage of the program's relatively large sample size (80-100 participants among all centers per 4-6 month period). It is expected that individual Field Centers will enroll 20-25 participants per 4-6 month period, but those applicants for Field Center awards for whom it is feasible to enroll more participants are encouraged to do so. Small ancillary studies to be undertaken at individual Field Centers may also be proposed in the applications. Ancillary studies must not conflict with or compromise the collaborative research activities that comprise the main purpose of this RFA. Field Center investigators must describe assays to be undertaken in their own laboratories. The Steering Committee probably will choose to use centralized laboratories for some measurements for reasons of lower cost or higher quality, but assays for other study outcome measures may be conducted in individual Field Centers. For each proposed experiment, therefore, applications must indicate whether the investigators can perform specific assays for the entire study sample (n=80-100 per 6-month period). A particular goal of this program is the evaluation of plasma lipid response to diet in a variety of population sub-groups. Descriptions of study design thus must include appropriate populations for testing hypotheses, although it is not expected that every hypothesis will be evaluated in every possible subgroup. It is not necessary that every center recruit from every sub-group, but the application must describe the eligible study populations to which the investigators have access and from which participants can be recruited in sufficient numbers. Criteria for excluding individuals from participating must be described. Different participants could be enrolled in different studies; it is not anticipated that the same individuals would necessarily be studied for the entire length of the program. Applications must include calculations of statistical power for both collaborative studies and ancillary studies. Nutrition methodology must be described in detail. This includes the rationale for each experimental diet, the nutrient content, and quality assurance during preparation. Applicants may also consider whether or not experimental diets should incorporate any special foodstuffs that are not generally available (for example, table or cooking fats of particular fatty acid composition). The Coordinating Center, with the assistance of the NHLBI, would arrange for the provision of such foodstuffs upon adoption of the final protocol. Coordinating Center applications are not expected to propose specific investigations of diet and biologic parameters, but rather should address more general issues of study design and statistical considerations (see also Proposed Research, below). The nutrient data base proposed must be described and justified both in Coordinating Center and Field Center applications. The data base must have specificity for individual fatty acids, reflect the most recently available food composition data, and be updated on a regular basis. A single system will be chosen by the Steering Committee after award in order to expedite collaborative planning and evaluation of study diets. Program Components Field Centers In this RFA program, the Field Centers will be institutions actively involved in the recruitment, feeding, and investigation of study participants. They must consist of interdisciplinary teams of investigators and appropriate personnel, including research dietitians, participant coordinator(s), and kitchen, technical, and clerical staff. In order to participate fully in all aspects of the program, including protocol design and interpretation of data, the Principal Investigator in each Field Center must be an experienced researcher in nutrition and lipid metabolism. Applicants for a Field Center award must document the ability to recruit, feed and retain at least 20-25 participants per 6-month period. The application must address logistical aspects of conducting collaborative multicenter human feeding studies including familiarity and experience in recruiting and managing participants in human feeding studies, evaluating compliance, handling biological specimens, and maintaining masked designs. There must be a plan for expeditious transfer of data to the Coordinating Center and for shipment of food aliquots and biological samples to analytical laboratories outside the Field Center. There also must be documentation of strong institutional support for participation in the Cooperative Agreement and a stated willingness to follow the common protocol agreed upon in Phase I. An organizational structure for the Field Center must be set forth in the application, delineating lines of authority and responsibility for dealing with problems in all general areas. Discussions of planned analytical techniques must include an assessment of the capability of the Field Center laboratory to scale-up in the event of being chosen as a central study laboratory for any of the analysis, although this capability is not a prerequisite for a successful application. Applications must document the ability to perform standard lipid and lipoprotein measurements with high precision and reliability. Applications also must discuss methods for preparation of food composites that will be used in the diet quality control program. Coordinating Center The Coordinating Center funded by this RFA must be prepared to make a major contribution to the development of the study protocol and manual of operations. It will have primary responsibility for developing and implementing procedures to collect, edit, store, and analyze data generated by the Field Centers. The Coordinating Center also will play a lead role in developing plans for coordination of data and specimen transfer between each Field Center and the Coordinating Center or among the Field Centers. The Coordinating Center will have general responsibility for ensuring that data from the Field Centers can, with confidence, be pooled for analysis. In practical terms this means that the Coordinating Center will establish a quality control program for all necessary aspects of the research protocol, including the experimental diets and laboratory assays. The Coordinating Center will provide, through either its own or a co-investigator's resources or through subcontracting arrangements, food composition analyses of experimental diets. The purpose of this activity will be to document the actual content of diets as fed and to ensure comparability of diets among the various Field Centers. Standard Reference Materials will be provided through an arrangement with the Nutrient Composition Laboratory, Agricultural Research Center, U.S. Department of Agriculture. Depending upon the capabilities and interests of the Field Center awardees and on time, quality, and cost considerations, the Steering Committee may elect to have laboratory analysis of various parameters conducted by centralized laboratories or by an individual laboratory. The Coordinating Center will have the responsibility for any necessary subcontracting arrangements concerning laboratory assays and for quality control programs needed to ensure comparability and reliability of data. Should the study protocol require the use of special experimental foodstuffs, the Coordinating Center will, with the assistance of the Project Scientist, arrange for provision of these items to the Field Centers. The Coordinating Center also will have the responsibility of planning and arranging meetings of the Steering Committee and its subcommittees. The Coordinating Center would be expected to provide appropriately detailed statistical reports to these committees at regular intervals and to prepare the minutes of the meetings. Budget Applicants for a Field Center or Coordinating Center must submit an adequately justified budget for the entire anticipated project period of four years. The budgets for each Phase must be clearly delineated, in addition to the year-by-year organization of the budget pages. Detailed budgets will vary according to policies of the applicant and specific needs identified in response to this announcement. Applicants for Field Centers must include all key scientific, clerical and technical personnel including kitchen and dietary staff. Applicants for the Coordinating Center must include estimates of the time and effort of key personnel needed to participate in the planning and development of forms, a manual of operations and a data entry system. Costs for the diet quality control program, including necessary staff, must be included. Subcontracts, if planned, must be described in full. Coordinating Center budgets for the diet quality control program must include estimated costs for dietary Standard Reference Materials. Coordinating Center budgets also must include estimates for experimental foodstuffs that might be procured through subcontract. Costs of laboratory assays proposed as outcome measures and markers of compliance with diet, and as needed to characterize participants, would properly be included with budgets for Field Center applications, not Coordinating Center applications. During Phase I (protocol development and pilot study), it is expected that Steering Committee meetings will be held frequently. Travel budgets for year 01 (Phase I) should include six two-day trips for Principal Investigators and one to two other key personnel (round-trip costs to Bethesda, MD, may be used for purposes of estimation). Quarterly meetings are anticipated for years 02-04. Coordinating Center staff necessary for conducting training must be available for a training meeting to be held before the end of Phase I for approximately three days. Field Center travel costs must include this training meeting as well. STUDY RESPONSIBILITIES AND GOVERNANCE Steering Committee The primary governing body of the study will be the Steering Committee, composed of each of the Principal Investigators of the Field Centers and the Coordinating Center and the NHLBI Project Scientist. The Steering Committee will be responsible for developing the study protocol, making scientific decisions, facilitating the conduct of the study, and interpreting and reporting the study results. Unless otherwise explicitly provided, the Principal Investigators will have the lead role in the Steering Committee and its subcommittees. Subcommittees will be formed for such areas as study design and execution, quality control, and publications. The NHLBI Project Scientist (or if more appropriate, another NHLBI scientist) will serve on each subcommittee. The first meeting of the Steering Committee will be convened by the NHLBI Project Scientist. It is anticipated that the Steering Committee will meet on a bi-monthly basis during protocol development (Phase I) and on a quarterly basis thereafter Phases II and III). Investigators must agree to implement protocols designed by the Steering Committee and approved by NHLBI. PROPOSED RESEARCH Field Centers-Collaborative Studies The primary aim of this program is to support research on the effects of dietary components on lipid and lipoprotein levels and hemostatic parameters. This knowledge is needed to provide healthful dietary recommendations to different populations and to effectively treat hyperlipidemia. Applicants for Field Center awards are encouraged to describe their own ideas to meet the goals of the study, with applications for innovative research that takes advantage of the unique size and collaborative structure of this RFA program. Because the first half of year 01 of this RFA program will be devoted to protocol development and the second half of year 04 is planned for final data analysis, applicants must propose a sequence of experiments of approximately three years duration. Necessary pilot studies should be described with the assumption that they will take place during the second half of year 01. Listed below are examples, not in order of priority, of research topics that would be considered responsive to this RFA; investigators are encouraged to pursue other relevant topics as well. o Studies evaluating the effects of level and type of dietary fat on composition and concentration of specific lipoproteins and on other factors such as hemostasis. This might include studies that can separate the effects of fatty acid chain length from degree of unsaturation, and studies of specific fatty acids. o Studies examining the effects of specific types and amounts of dietary fiber on lipids, lipoproteins, hemostasis, and other factors related to atherosclerosis. o Studies of the efficacy of various recommended diets in altering LDL and HDL levels in various demographic or phenotypic subgroups. These might include studies evaluating optimal dietary treatments for hyperlipidemia in children, the elderly, and women. o Studies to elucidate the mechanisms responsible for the large apparently individual variability in response of plasma lipids and lipoproteins to dietary fatty acids and cholesterol. This might include studies of the ways that variation in cholesterol response is affected by factors such as age, sex, initial plasma cholesterol level, family history of CHD, race, apolipoprotein phenotype, or co-morbid conditions, as well as family studies involving parents and children. o Studies taking advantage of the tightly controlled research setting of this RFA to evaluate and improve techniques for dietary assessment. (Note: Such studies would be secondary to the principal aims of the project). Field Centers-Ancillary Studies In addition to the expected large-scale collaborative endeavors that will comprise the bulk of investigators' effort and budget, there may be opportunities to explore additional questions at individual Field Centers. Applicants are encouraged to submit plans for small ancillary studies that could be undertaken with the participants enrolled at the applicant's Field Center without interfering with the main collaborative endeavor. Such studies must be described in the usual fashion, including power calculations and budget. Potential ancillary investigations include: investigation of mechanisms by which diet influences lipid and lipoprotein concentration, composition, and metabolism; relationships between endocrine function and lipoprotein response to diet; and studies of free radicals and oxidized lipoproteins. Exclusions Epidemiologic surveys and interview-based nutrition research studies will not be considered responsive to this RFA. Outpatient dietary intervention protocols designed to effect changes in lipid profile through counseling of participants similarly will be considered non-responsive. Investigations in laboratory animals will not be supported by this program. Coordinating Center Applicants for the Coordinating Center award are encouraged to describe the design and implementation plan for the centralized activities of this RFA program. The Coordinating Center will play a crucial role in designing the protocol and the data collection methods, monitoring quality control of diets and study outcome measurements, and analyzing and interpreting results. One of the prime responsibilities of the Coordinating Center will be the diet quality control program, the purpose of which is to ensure that experimental diets fed at the various clinical centers are sufficiently comparable to be considered identical treatments. This constitutes a research project in its own right and provides unusual scientific opportunities in the area of food composition and analysis. Applicants for the Coordinating Center award are requested to propose research related to the diet quality control program, including hypotheses, analytical methodology, sampling schemes, power calculations, logistics, and cost. Necessary pilot studies during the second half of year 01 and full-scale activities during years 02-04 must be described. Although the range of constituents in food that could be assayed is vast, it is likely that the components of greatest interest will be proximate composition, specific fatty acids (including trans and omega-3 fatty acids), dietary fiber, cholesterol, and plant sterols. Other dietary components that applicants consider to be likely candidates, given the overall purpose of this RFA, should be discussed as well. FUNDS AVAILABLE It is anticipated that awards will be made for four Field Centers and one Coordinating Center. The total funds estimated for this program (direct plus indirect costs) are $1.95M, $2.96M, $3.08M and $2.45M in four successive years, and it is estimated that on the order of 50 percent, 67 percent, 67 percent and 55 percent of the funds in the respective years will go to Field Centers, the balance to the Coordinating Center. Funding is expected to begin in September 1992. There are no plans for re-issuance of this RFA. Competitive continuation applications may be submitted for review and competition through the traditional grant program of the NIH. MECHANISM OF SUPPORT The administrative and funding mechanism to be used to undertake this program will be the Cooperative Agreement (U01), an assistance mechanism. Under the Cooperative Agreement, the NHLBI Project Scientist assists and is substantially involved with recipients in conducting a study by facilitating performance of the effort in a "partner" role. Consistent with this concept, the tasks and activities in carrying out the studies will be shared among the awardees and the NHLBI Project Scientist. Thus, there will be substantial programmatic involvement of the designated NHLBI Project Scientist above and beyond the level characteristic for traditional program management of grants. The need for this involvement arises from the complexity introduced by the diverse protocols and study populations to be used and the array of centralized activities. Applicants from institutions that have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources may wish to identify the GCRC as a resource for conducting the proposed research. In such a case, a letter of agreement from either the GCRC program director or Principal Investigator must be included with the application. TERMS AND CONDITIONS OF AWARDS The tasks or activities in which the awardees will have substantial responsibilities include protocol development, participant recruitment and follow-up, data collection, quality control, interim data and safety monitoring, final data analysis and interpretation, preparation of publications, and collaboration with other awardees and the NHLBI Project Scientist. The NHLBI Project Scientist will have substantial responsibilities for protocol development, quality control, interim data and safety monitoring, final data analysis and interpretation, preparation of publications, collaboration with awardees, coordination, and performance monitoring. It is anticipated that awardees will have lead responsibilities whenever substantial roles are identified for both awardees and the NHLBI Project Scientist, except that the NHLBI Project Scientist may, consistent with publication policy to be adopted by the Steering Committee, have lead responsibilities in preparation of some publications. The NHLBI Project Scientist will serve as a member of the Steering Committee. The awardees will proceed from Phase I to Phase II only with the concurrence of the NHLBI. In addition, the appointment of any new or replacement key personnel is subject to the concurrence of the NHLBI. Awardees will retain custody of and have primary rights to the data developed under these awards, subject to Government, e.g., NHLBI, NIH, and PHS, rights of access consistent with current HHS, PHS, and NIH policies. Disagreements that may arise between award recipients and the NHLBI on programmatic decisions and scientific technical matters within the scope of the award may be brought to arbitration. An arbitration panel will be composed of three members: one selected by the Steering Committee (with NHLBI member not voting) or by the individual awardee in the event of an individual disagreement, a second member selected by the NHLBI, and the third member selected by the two prior members. This special arbitration procedure in no way affects the awardee's right to appeal an adverse action that is otherwise appealable in accordance with the PHS regulations at 42 CFR part 50, subpart C and HHS regulation at 45 CFR part 16. These special terms of award are in addition to and not in lieu of otherwise applicable OMB administrative guidelines, HHS Grant Administration Regulations at 45 CFR part 74, and other HHS, PHS and NIH grant administration policy statements. The NHLBI reserves the right to terminate or curtail the study (or an individual award) in the event of (a) substantial shortfall in participant recruitment, data reporting, quality control, or other major breech of the protocol; or (b) substantive deviations from the RFA objectives or agreed-upon protocol to which NHLBI does not agree; or (c) human subject ethical issues that may dictate a premature termination. SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH STUDY POPULATIONS NIH and ADAMHA policy is that applicants for NIH/ADAMHA clinical research grants and cooperative agreements will be required to include minorities and women in study populations so that research findings can be of benefit to all persons at risk of the disease, disorder or condition under study; special emphasis should be placed on the need for inclusion of minorities and women in studies of diseases, disorders and conditions which disproportionately affect them. This policy is intended to apply to males and females of all ages. If women or minorities are excluded or inadequately represented in clinical research, particularly in proposed population- based studies, a clear compelling rationale should be provided. The composition of the proposed study population must be described in terms of gender and racial/ethnic group. In addition, gender and racial/ethnic issues should be addressed in developing a research design and sample size appropriate for the scientific objectives of the study. This information should be included in the form PHS 398 in Section 2, A-D of the Research Plan AND summarized in Section 2, E, Human Subjects. Applicants/offerors are urged to assess carefully the feasibility of including the broadest possible representation of minority groups. However, NIH recognizes that it may not be feasible or appropriate in all research projects to include representation of the full array of United States racial/ethnic minority populations (i.e., Native Americans (including American Indians or Alaskan Natives), Asian/Pacific Islanders, Blacks, and Hispanics). For the purpose of this policy, clinical research includes human biomedical and behavioral studies of etiology, epidemiology, prevention (and preventive strategies), diagnosis, or treatment of diseases, disorders or conditions, including but not limited to clinical trials. The usual NIH policies concerning research on human subjects also apply. Basic research or clinical studies in which human tissues cannot be identified or linked to individuals are excluded. However, every effort should be made to include human tissues from women and racial/ethnic minorities when it is important to apply the results of the study broadly, and this should be addressed by applicants. For foreign awards, the policy on inclusion of women applies fully; since the definition of minority differs in other countries, the applicant must discuss the relevance of research involving foreign population groups to the United States' populations, including minorities. If the required information is not contained within the application, the application will be returned. Peer reviewers will address specifically whether the research plan in the application conforms to these policies. If the representation of women or minorities in a study design is inadequate to answer the scientific question(s) addressed AND the justification for the selected study population is inadequate, it will be considered a scientific weakness or deficiency in the study design and will be reflected in assigning the priority score to the application. All applications for clinical research submitted to NIH are required to address these policies. NIH funding components will not award grants or cooperative agreements that do not comply with policies. REVIEW PROCEDURES AND CRITERIA Review Procedures Upon receipt, applications will be reviewed by NHLBI staff for responsiveness to the objectives of this RFA. If an application is judged unresponsive, the applicant will be contacted and given the opportunity to withdraw the application or to have it considered for the NIH investigator-initiated grant program. If the application submitted in response to this RFA is substantially similar to a grant application already submitted to the NIH for review, but has not yet been reviewed, the applicant will be asked to withdraw either the pending application or the new one. Simultaneous submission of identical applications will not be allowed, nor will essentially identical applications be reviewed by different review committees. Therefore, an application cannot be submitted in response to this RFA that is essentially identical to one that has already been reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. Applications judged to be responsive will be reviewed for scientific and technical merit by an initial review group, that will be convened by the Division of Extramural Affairs, NHLBI, solely to review these applications. This initial review may include a preliminary evaluation to determine scientific merit relative to the other applications received in response to the RFA (triage); the NIH will withdraw from further consideration applications judged to be noncompetitive and promptly notify the Principal Investigator/program director and the official signing for the applicant organization. Those applications judged to be competitive will be further evaluated for scientific/technical merit by the usual peer review procedures, including, if deemed appropriate, a reverse site visit at the applicant's expense. Review Criteria Field Centers The major factors to be considered in the evaluation of each application will be similar to those used in the review of traditional research project grant applications and will include: (1) Originality of the scientific approach; the suitability of the experimental design for incorporation into a multicenter program; the appropriateness and quality of specialized measurements and nutrition methodology; and the quality and compatibility of proposed ancillary studies. (2) The feasibility of the proposed project, including access to appropriate study populations from which participants may be recruited and the adequacy of facilities and equipment for performance of the proposed research. (3) The expertise, training, and experience of the investigators and staff; the potential to accomplish the proposed research goals; the time to be devoted to the program; and the documented success in the conduct of well-controlled human feeding studies. (4) The administrative, supervisory and collaborative arrangements for achieving the goals of the program, particularly regarding the coordination of interdisciplinary components. Coordinating Center The major factors to be considered in the evaluation of Coordinating Center applications will include: (1) Understanding of the scientific, statistical, logistical, and technical issues underlying the planned multicenter study. (2) The adequacy of the proposed plans for data management, data analysis, and quality control of experimental diets, and the adequacy of the proposed facility, space, and equipment, particularly for computing. (3) The expertise, training, and experience of the investigator and staff, the potential to accomplish the proposed goals, and the time to be devoted to the program. (4) The administrative, supervisory, and collaborative arrangements for achieving the goals of the program, particularly regarding the coordination of interdisciplinary components, and the approach to and likelihood of soliciting cooperation from the participating Field Centers and exercising appropriate leadership in study design and direction and in data acquisition, management, and analysis. (5) The adequacy of proposed research related to the food composition analysis program. APPLICATION PROCEDURES Letter of Intent Prospective applicants are asked to submit a letter of intent that includes the name of the Principal and each Co-Investigator, the name of each cooperating institution, and an indication of whether the application will be for a Field Center, Coordinating Center or both. The NHLBI requests such letters only for the purpose of providing an indication of the number and scope of applications to be received and usually does not acknowledge the receipt. A letter of intent is not binding, will not enter into the review of any application subsequently submitted, nor a necessary requirement for applications. The letter of intent, is to be received no later than February 15, 1992, and is to be sent to: Dr. C. James Scheirer Review Branch, Division of Extramural Affairs National Heart, Lung and Blood Institute Westwood Building, Room 548B Bethesda, MD 20892 Telephone: (301) 496-7363 FAX: (301) 402-1660 Format for Applications Use form PHS 398 (rev. 10/88, reprinted 9/89), the application form for the traditional NIH research project grant. Copies of this form are available in the applicant institution's office of sponsored research and may be obtained from: Office of Grants Inquiries Division of Research Grants National Institutes of Health Westwood Building, Room 449 Bethesda, MD 20892 Telephone: (301) 496-7441 FAX: (301) 496-9975 Use the conventional format for research project grant applications and ensure that the points identified in the section "Review Procedures and Criteria" are fulfilled. To identify the application as being in response to the RFA, CHECK "YES" on item 2 of page 1 of the application, enter the title "Multicenter Studies of Diet and Lipoproteins in Humans" and enter the RFA number HL-92-03-H in the space provided. Investigators wishing to apply as both a Field Center and a Coordinating Center must submit separate applications. THE RFA LABEL FOUND IN THE FORM PHS 398 APPLICATION KIT MUST BE AFFIXED TO THE BOTTOM OF THE FACE PAGE OF THE ORIGINAL COMPLETED APPLICATION FORM PHS 398. FAILURE TO USE THIS LABEL COULD DELAY THE PROCESSING OF THE APPLICATION SUCH THAT IT MAY NOT REACH THE REVIEW COMMITTEE IN TIME FOR REVIEW. Application procedure Send or deliver the completed, signed application and four complete photocopies to the following, making sure that the original application with the RFA label attached is on top: Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892** SEND TWO ADDITIONAL COPIES OF THE APPLICATION TO DR. C. JAMES SCHEIRER AT THE ADDRESS LISTED UNDER "LETTER OF INTENT." THE NHLBI CANNOT GUARANTEE THAT THE APPLICATION WILL BE REVIEWED IN THE COMPETITION FOR THIS RFA UNLESS THE TWO COPIES ARE SENT AT THE SAME TIME AS THE ORIGINAL AND FOUR COPIES TO THE DIVISION OF RESEARCH GRANTS. Applications must be received by April 23, 1992. Applications not received by this date will be returned to the applicant. Timetable Letter of Intent Receipt Date (optional): February 15, 1992 Application Receipt Date: April 23, 1992 Review by the National Heart, Lung, and Blood Advisory Council: September 10-11, 1992 Anticipated award date: September 1992 INQUIRIES Inquiries regarding this announcement may be directed to: Dr. Abby G. Ershow Project Scientist, Lipid Metabolism-Atherogenesis Branch National Heart, Lung, and Blood Institute Federal Building, Room 401 7550 Wisconsin Avenue Bethesda, MD 20892 Telephone: (301) 496-1681 FAX: (301) 496-9882 Inquiries regarding review and application procedures may be directed to: Dr. C. James Scheirer Review Branch, Division of Extramural Affairs National Heart, Lung and Blood Institute Westwood Building, Room 548B Bethesda, MD 20892 Telephone: (301) 496-7363 FAX: (301) 402-1660 Inquiries regarding fiscal and administrative matters may be directed to: Ms. Marie A. Willett Chief, Heart and Vascular Diseases, Grants Operations Branch Division of Extramural Affairs National Heart, Lung, and Blood Institute Westwood Building, Room 4A11C Bethesda, MD 20892 Telephone: (301) 496-7536 FAX: (301) 402-1200 AUTHORITY AND REGULATIONS The programs of the Division of Heart and Vascular Diseases, National Heart, Lung, and Blood Institute, are identified in the Catalog of Federal Domestic Assistance, number 93.837. Awards will be made under the authority of the Public Health Service Act, Section 301 (42 USC 241) and administered under PHS grants policies and Federal regulations, most specifically 42 CFR Part 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or to Health Systems Agency Review.