REGIONAL VARIATION IN BREAST CANCER RATES IN THE U.S. Release Date: May 14, 1998 RFA: CA-98-017 P.T. National Cancer Institute National Institute of Environmental Health Sciences Letter of Intent Receipt Date: June 30, 1998 Application Receipt Date: August 25, 1998 PURPOSE The Division of Cancer Control and Population Sciences of the National Cancer Institute (NCI) and the Division of Extramural Research and Training of the National Institute of Environmental Health Sciences (NIEHS) invite grant applications for interdisciplinary epidemiologic studies to better understand determinants of regional variations in breast cancer incidence and mortality rates in the U.S. Studies are to be designed to take known risk factors into consideration and to utilize biological markers or indicators, e.g., of exogenous exposures, individual susceptibility to environmental factors, intrinsic physiological processes or risk-related behavior, for elucidating the role of geographic-specific elements in the natural history and progression of breast cancer. The ultimate objective is to gain knowledge that could lead to effective prevention and cancer control strategies. The NCI is the principal Federal funding agency that supports laboratory and clinical investigations relating to the cause, prevention, diagnosis, and treatment of cancer. Of special interest are epidemiological studies incorporating quantitative methods or markers to identify and evaluate the role of etiological factors of cancer, including environmental and occupational agents. The NIEHS is the principal Federal funding agency to support research examining the human health consequences of exposure to physical and chemical toxicants in our environment. Epidemiologic studies that seek to identify exposed populations and understand the role of environmental and occupational risk factors in the development of breast cancer and other diseases are a major thrust of the NIEHS research program. 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 Request for Applications (RFA), Regional Variation in Breast Cancer Rates in the U.S., is related to the priority area of cancer. 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 202-512-1800). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic, for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Foreign institutions are not eligible for cooperative agreement awards. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators. MECHANISM OF SUPPORT The administrative and funding instrument to be used for this program will be the cooperative agreement (U01), an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH scientific and/or programmatic involvement with the awardee is anticipated during performance of the activity. Under the cooperative agreement, the NIH purpose is to support and/or stimulate the recipient's activity by involvement in and otherwise working jointly with the award recipient in a partner role, but it is not to assume direction, prime responsibility, or a dominant role in the activity. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. Details of the responsibilities, relationships and governance of the study to be funded under cooperative agreement(s) are discussed later in this document under the section "Terms and Conditions of Award." The total project period for an application submitted in response to this RFA may not exceed 4 years. The earliest feasible start date will be April 1, 1999. Because the nature and scope of the research proposed in response to this RFA may vary, it is anticipated that the sizes of awards will vary also. The average award is expected to be approximately $500,000 total (direct plus indirect) costs per year. This RFA is a one-time solicitation. Future unsolicited competing continuation applications will compete with all investigator-initiated R01 applications and be reviewed according to the customary peer review procedures. If the NCI and NIEHS determine that there is a sufficient continuing program need beyond the initially awarded period of performance, a request for new and renewal applications may be announced. FUNDS AVAILABLE Approximately $3.0 million per year in total costs for four years will be committed by the NCI and NIEHS to specifically fund applications submitted in response to this RFA. The expected number of awards is five to seven. This funding level is dependent on the receipt of a sufficient number of applications of high scientific merit. Although this program is provided for in the financial plans of the NCI and NIEHS, the award of cooperative agreements pursuant to this RFA are contingent upon the availability of funds for this purpose. RESEARCH OBJECTIVES Background Geographical variations in cancer rates have been observed for decades, and described spatial patterns and trends have provided clues for generating hypotheses about the etiology of cancer. In the case of breast cancer, investigators have demonstrated that some variation can be explained by differences in the population distribution of known breast cancer risk factors such as menstrual and reproductive variables (1-3). However, regional patterns may also reflect an aggregate of diverse factors including, for example, varying presence of hazards in the environment, demographics and lifestyle of a mobile population, subgroups of susceptible individuals, and changes and advances in medical practice and health care management. Disentanglement of these factors is necessary to assess associations, singly or jointly, with breast cancer risk in individuals and populations. It is unclear what the determinants of geographic differences in breast cancer rates may be and whether spatial variation of environmental factors is contributory in areas with elevated breast cancer incidence and mortality. Biologic data relating environmental pollutants to breast cancer risk are sparse, and epidemiologic studies have been challenged by methodological limitations, most often in determining past exposure levels. To date, the scientific literature on the association of measurable exposures, e.g., organochlorine pesticides, and breast cancer is conflicting. Based on the known importance of endogenous hormones in breast cancer development, a leading question remains whether environmental factors, such as xenoestrogens and other hormone-mimicking pollutants, may also exert an effect. A multidisciplinary workshop, "Hormones, Hormone Metabolism, Environment, and Breast Cancer," convened by the National Action Plan on Breast Cancer (NAPBC), the NCI, Tulane University, and the U.S. Public Health Service's Office of Women's Health, in September 1995 discussed the complexity of factors, unresolved controversial issues, and the need for improved methodology to measure hormones and their metabolites (4). The power of molecular and bioinformatic technology could potentially provide biologic probes and sensitive methods for epidemiologic studies to gain insights into the relationship between environment, the individual, and breast cancer. Research Scope and Goals The purpose of this RFA is to stimulate innovative epidemiologic studies that include assessment of markers or indicators of exposures, susceptibility or other factors relevant to human breast carcinogenesis. Major consideration will be directed to studies, including those that are transitional (from laboratory-based to population-based), that incorporate validation of utilizable markers, e.g., hormone-related, in human populations. Collaborations among multiple disciplines and research institutions are particularly encouraged, and research designs can make use of existing resources, such as specimen repositories. Supplementary research to expand an ongoing investigation (i.e., parent study) may be proposed, contingent upon the continuation of the parent study for at least two years. There is special interest in understudied populations, particularly those subgroups with unusually high breast cancer incidence and mortality rates, and in study populations of contrasting risk. Investigators are encouraged to involve appropriate community/advocacy groups interested in breast cancer research. These groups could be comprised, for example, of breast cancer survivors, health care professionals involved in breast cancer care or women at high risk of the disease. The type and degree of participation by the group members could vary depending upon the proposed research activities; e.g., members could serve as advisors to the investigative team or assist in research implementation such as informing and recruiting eligible study participants in the community. Studies responding to this initiative may propose, for example, research in areas listed below, but are not limited to: -- Evaluation of joint effects of environmental factors, intrinsic host characteristics or susceptibility, and behavioral patterns; -- Assessment of mechanisms by which exogenous exposures, e.g., occupational, could act in initiation and progression of breast cancer. This may include the evaluation of such exposures on hormonal or metabolic pathways, consideration of the timing of exposures during critical windows of development, and modulation of risk due to environmental exposures by genetic factors; --Comparison of populations with substantial regional differences in breast cancer incidence or mortality rates using parameters such as, for example: (1) host-specific factors related to health (e.g., comorbidity), socioeconomic status (e.g., income, residence in the inner city or rural geographic areas); (2) tumor-specific characteristics (e.g., histology types, tumor aggressiveness in susceptible subpopulations); or (3) related to medical care utilization; --Improvement and validation of methodology, e.g., for detecting steroid hormones, their metabolites, and xenohormones in biologic media, for use in large population studies; --Application of computer technology, e.g., geographic information systems, and development of innovative statistical methods for improving estimates of historical environmental exposures; --Investigation of environmental interaction and modulation of age-related markers of hormone activity related to normal and malignant breast physiology. SPECIAL REQUIREMENTS It is critical that each applicant include specific plans for responding to the Terms and Conditions of Award described below. Plans should describe how the applicant will comply with the program staff involvement as well as how all the responsibilities of awardees will be fulfilled. This initiative is designed to enhance cooperation between investigators and NCI. The role of NCI will be that of the provider of technical assistance and facilitator for cross-project collaborations. Applicants will be assessed for the ability to conduct research projects under the conditions of this cooperative agreement and must demonstrate an understanding of the research process and responsibilities as partners in the cooperative agreement. For example, each applicant should propose the study design most appropriate for the project and be responsible for selecting and recruiting appropriate patient/control populations. A description of the characteristics of the population should be included. Evidence should be presented indicating the likelihood of recruiting study participants and the feasibility of achieving significant participation rates. This should include data on the likelihood of subject availability for interview, if appropriate. Applicants should discuss any factors which they believe should exclude a participant from the study. Applicants should discuss: a) what data should be collected, b) how, when, where and by whom the data are to be collected, c) the numbers of study subjects to be enrolled, d) data management procedures, e) the procedures for assuring timeliness, completeness and accuracy of the data, and f) plans for data analyses. Failure of an awardee to meet the performance requirements, including these special terms and conditions of award, or significant changes in the level of performance, may result in a reduction of budget, withholding of support, suspension and/or termination of the award. The following TERMS AND CONDITIONS, pertaining to the scope and nature of the interaction between the NCI and the investigators, will be incorporated in the Notice of Award and are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines; HHS grant administration regulations at 45 CFR 74 and 92, and 42 CFR 52; other HHS, PHS, and NIH grant administration policy statements and other NCI administrative terms of award. TERMS AND CONDITIONS OF AWARD Nature of Participation of NCI and NIEHS Staff It is expected that the dominant role and primary responsibilities for the research activities will reside with the awardees, although specific tasks and activities in carrying out the studies may be shared among the awardees and NCI and NIEHS Program Coordinators. There will be a partnership among the awardees and NCI/NIEHS with the role of the NCI and NIEHS Program Coordinators being one of assisting, supporting, stimulating, and participating with the awardees in conducting the projects. The NCI and NIEHS Program Coordinators or Assignees will: -- Participate in Steering Committee meetings as voting members, assisting in development of operating guidelines and policies for dealing with recurrent situations that require coordinated action; -- Assist in development of ad hoc protocols which specify methods of research determined by the Steering Committee; -- Serve as liaison, helping to coordinate activities among the awardees; -- Assist, if applicable, in the monitoring of field data collection, helping to ensure standardization in methods across study sites; -- Participate in any group analyses as determined by the Steering Committee; -- Assist in the interpretation and reporting of information collected collaboratively; -- Monitor study progress. This may include periodic site visits for discussions with awardee research teams, observation of field data collection and management techniques, fiscal review, and other matters. Decisions for continued funding will be based on overall study progress, as well as sufficient participant and/or data accrual, cooperation in carrying out the research (e.g., attendance at Steering Committee meetings, implementation of group decisions, compliance with reporting requirements), and maintenance of a high quality of research which will allow pooling of data and comparisons across Cooperative Agreements for common data elements. The inability of a cooperative agreement recipient to meet the performance requirements, or significant changes in the level of performance, may result in an adjustment of funding, withholding of support, suspension or termination of the award; -- Assist by providing advice in the management and technical performance of the investigation; -- In conjunction with grants management, provide advice on administrative issues, including funding. Nature of Participation of Cooperative Agreement Recipients The recipients of Cooperative Agreement awards will cooperate with each other and the NCI and NIEHS in the conduct of this research. Each awardee will: -- Designate the Principal Investigator or assignee to participate in the Steering Committee. This committee will meet periodically during the course of the study. The first meeting will be called by the NCI Program Coordinator shortly after award of the agreements with subsequent annual meetings planned and scheduled at this meeting. Accordingly, sufficient funds must be included within the submitted budgets to accommodate travel expenses for one yearly trip to the Washington D.C. area for the principal investigator or designee. -- Retain primary authorities and responsibilities to define objectives and approaches, and to plan, conduct, analyze, and publish results, interpretations, and conclusions of the study as was originally proposed in the grant application and approved by the reviewers. -- Cooperate in development of any common research instruments (e.g., questionnaire) or study documents (e.g., medical record abstract forms, field procedures manuals) as determined by the Steering Committee. With the Steering Committee's approval, the awardee will utilize common instruments and documents, but additional elements could be appended by individual institutions to address issues of unique interest or capabilities; -- Establish and maintain quality control in all data and materials collection and management procedures. -- Submit periodic supplementary reports quarterly or semi-annually if requested by NCI and NIEHS Program Coordinators; -- Cooperate in the reporting of collaborative findings. The NIH will have rights of access to the data under this cooperative agreement. The awardees will retain custody and primary rights to the data consistent with current HHS, PHS, and NIH policies. Collaborative Responsibilities A Steering Committee will be the main oversight body and will be composed of the Principal Investigators or assignees from the awardee institutions and the NCI and NIEHS Program Staff or assignees. An organizational meeting of the Steering Committee will be convened by the NCI Program Staff early after award. A Chairperson, other than the NCI/NIEHS staff representatives, will be selected by a vote of the members. The Committee likely will meet annually and, if necessary, more frequently. Major scientific decisions regarding core data will be determined by the Steering Committee. All investigators selected will need to be able and willing to implement any core data collection method and strategy collaboratively decided upon by the Steering Committee. Research results will be disseminated by means of peer-reviewed publications that will be planned and prepared by award recipients, with assistance as needed from NCI and NIEHS program staff. Arbitration In the event of a major scientific/programmatic disagreement between NCI/NIEHS and the awardees that cannot be resolved by appropriate negotiations, an ad hoc arbitration panel will be assembled to consist of one awardee nominee, one NCI/NIEHS nominee, and a third member with appropriate expertise chosen by the other two. This NCI/NIEHS arbitration process in no way affects the awardees' right to appeal an adverse determination under the terms of 42 CFR Part 50, Subpart D, and 45 CFR Part 16. INCLUSION OF MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that members of minority groups and their subpopulations must be included in all NIH-supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B or Public Law 103-43). All investigators proposing research involving human subjects should read the "NIH Guidelines on the Inclusion of Women and Minorities as Subjects in Clinical Research," which was published in the Federal Register of March 28, 1994 (59 FR 14508-14513) and in the NIH GUIDE FOR GRANTS AND CONTRACTS of March 18, 1994, Volume 23, Number 11. Investigators may obtain copies from these sources or from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. LETTER OF INTENT Prospective applicants are requested to submit, by June 30, 1998, a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the names of other key personnel and participating institutions, and the number and title of the RFA in response to which the application may be submitted. Although a letter of intent is not required, is not binding, and does not enter into the review of subsequent applications, the information that it contains is helpful in planning for the review of applications. It allows NCI and NIEHS staff to estimate the potential review workload and to avoid conflict of interest in review. The letter of intent is to be sent to Dr. Kumiko Iwamoto at the address listed under INQUIRIES. APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 5/95) is to be used in applying for these grants. Applications kits are available at most institutional offices of sponsored research and may be obtained from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, Email: [email protected]. In accordance with the previously described Terms of Award for cooperative agreements: (1) applicants are to request sufficient funds in the budget to accommodate expenses for one to two participants to attend Steering Committee meetings (for approximation: round-trip travel to Bethesda, Maryland for one day annually during duration of the study), and (2) applicants must describe plans to fulfill requirements in the Terms and Conditions of Award. The RFA label available in the PHS 398 (rev.9/95) application form must be affixed to the bottom of the face page of the application. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. Submit a signed, typewritten original of the application, including the Checklist, and three signed photocopies, in one package to: CENTER FOR SCIENTIFIC REVIEW NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application must also be sent to: Ms. Toby Friedberg Division of Extramural Activities National Cancer Institute 6130 Executive Boulevard, Room 636 Bethesda, MD 20892-7399 Rockville, MD 20850 (for express/courier service) Applications must be received by August 25, 1998. If an application is received after that date, it will be returned to the applicant without review. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of a substantial revision of an application already reviewed, but such an application must follow the guidance in the PHS Form 398 application instructions for the preparation of revised applications, including an introduction addressing the previous critique. REVIEW CONSIDERATIONS Review Method Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by NCI and NIEHS. Incomplete and/or non-responsive applications will be returned to the applicant without further considerations. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by NCI in accordance with the review criteria stated below. As part of the initial merit review, a process may be used by the initial review group in which applications will be determined to be competitive or non-competitive based on their scientific merit relative to other applications received in response to this RFA. Applications judged to be competitive will be discussed and assigned a priority score. Applications determined to be non-competitive will be withdrawn from further consideration and the principal investigator/program director and the official signing for the applicant organization will be notified. The peer review will be followed by a second level of review by the National Cancer Advisory Board and National Advisory Environmental Health Sciences Council. Review Criteria The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. The reviewers will discuss the following aspects of the application to assess the likelihood that the proposed research will have a substantial impact on the pursuit of these goals, specific to the objectives of the RFA. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. The application does not need to be strong in all categories to be judged likely to have a major scientific impact. For instance, the proposed research may not be innovative but is essential to move a field forward. The review criteria are: 1. Significance: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? 2. Approach: Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative strategies? 3. Innovation: Does the project employ novel concepts, approaches or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? 4. Investigator: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? 5. Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? The initial review group will also examine: the appropriateness of proposed project budget and duration; the adequacy of plans to include both genders and minorities and their subgroups as appropriate for the scientific goals of the research and plans for the recruitment and retention of subjects; the provisions for the protection of human and animal subjects; and the safety of the research environment. Written summary statements of the review will be sent by NCI to the principal investigators. AWARD CRITERIA Applications recommended by the National Cancer Advisory Board and National Advisory Environmental Health Sciences Council will be considered for award based upon (a) scientific and technical merit; (b) program balance, including in this instance, sufficient compatibility of features to make a successful collaborative program a reasonable likelihood; and (c) availability of funds. SCHEDULE Letter of Intent Receipt Date: June 30, 1998 Application Receipt Date: August 25, 1998 Review by NCAB Advisory Board: February 9, 1999 Anticipated Award Date: April 1, 1999 INQUIRIES Written and telephone inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Dr. Kumiko Iwamoto Division of Cancer Control and Population Sciences National Cancer Institute 6130 Executive Boulevard, Suite 535, MSC 7395 Bethesda, MD 20892-7395 Telephone: (301) 496-9600 FAX: (301) 402-4279 Email: [email protected] Dr. Gwen Collman Chemical Exposures and Molecular Biology Branch National Institutes of Environmental Health Sciences P.O. Box 12233 Research Triangle Park, NC 27709 Telephone: (919) 541-5980 FAX: (919) 541-4937 Email: [email protected] Direct inquiries regarding fiscal matters to: Ms. Marie N. Moyer Grants Administration Branch National Cancer Institute 6120 Executive Boulevard, Suite 243, MSC 7150 Bethesda, MD 20892-7150 Telephone: (301) 496-7800, ext. 225 FAX: (301) 496-8601 Email: [email protected] Mr. David L. Mineo Grants Management Branch National Institutes of Environmental Health Sciences P.O. Box 12233 Research Triangle Park, NC 27709 Telephone: (919) 541-1373 FAX: (919) 541-2860 Email: [email protected] AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.393. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under HHS policies and grant regulations. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant and contract recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities ( or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people. References 1. Sturgeon SR, Schairer C, Gail M et al. Geographic variation in mortality from breast cancer among white women in the United States. J Natl Cancer Inst 1995;87:1846-53. 2. Robbins AS, Brescianini S, Kelsey JL. Regional differences in known risk factors and the higher incidence of breast cancer in San Francisco. J Natl Cancer Inst 1997;89:960-5. 3. Laden F, Spiegelman D, Neas LM et al. Geographic variation in breast cancer incidence rates in a cohort of US women. J Natl Cancer Inst 1997;89:1373-78. 4. Workshop on Hormones, Hormone Metabolism, Environment, and Breast Cancer, New Orleans, Louisiana, September 28-29, 1995. Monographs in Environ Hlth Perspect supp 1997; 105 (3):557-688.
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