COOPERATIVE GRANTS FOR NUTRITIONAL MODULATION OF GENETIC PATHWAYS LEADING TO CANCER RELEASE DATE: January 22, 2002 RFA: RFA-CA-03-001 PARTICIPATING INSTITUTES AND CENTERS (ICs): National Cancer Institute (NCI) (http://cancer.gov/) LETTER OF INTENT RECEIPT DATE: June 14, 2002 APPLICATION RECEIPT DATE: July 12, 2002 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism(s) of Support o Funds Available o Eligible Institutions o Individuals Eligible to become Principal Investigators o Special Requirements o Where to send Inquiries o Letter of Intent o Submitting an Application o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations PURPOSE The National Cancer Institute (NCI) invites applications (U54) to develop Cooperative Specialized Centers for both basic and clinical research in areas related to dietary nutrients as modifiers of genetic pathways leading to cancer. The overall goal of this initiative is to advance the science of nutrition by capitalizing on recent advances in molecular biology and genetics and by addressing three extraordinary opportunities identified in The National Cancer Institute's 2002 Bypass Budget, i.e. Genes and the Environment, Defining the Signatures of Cancer Cells, and Molecular Targets. (http://www.cancer.gov/initiatives/). This Request For Applications (RFA) invites investigators to form Interdisciplinary Research Teams to resolve complex gene-nutrient interrelationships that relate to cancer prevention. All research approaches are encouraged, as long as they address the following essential features: a cancer focus, institutional commitment, organizational capabilities, facilities, and interdisciplinary coordination and collaboration. Receipt of a Planning Grant award (P20) is not a prerequisite to apply for this RFA. A team must include investigators from one or more institutions with expertise in nutrition and molecular biology/ genetics and may contain others as required to address the role(s) of nutrient(s) on genetic pathways leading to cancer. Regardless of the genetic pathway selected the Team must indicate how the proposed studies will advance knowledge of the pertinent biology, define what events are likely informative in meeting this initiative's goals, focus on the development of relevant and practical assays, probes, and other tools to assess the effects of the nutrient(s) on that genetic pathway in vivo and foster the translation of their research findings into a patient or population setting. Examples of areas of interest include, but are not limited to carcinogen bioactivation, cell-cycle control, signal transduction; intercellular communication, apoptosis; immune effectors, and angiogenesis. Public Briefing Date: February 19, 2002 An initial informational session for those investigators planning to submit applications in response to this RFA will be held Tuesday, February 19, 2002 from 1:00 PM to 3:00 PM at the Bethesda Marriott, 5151 Pooks Hill Road, Bethesda, MD 20814. Representatives from the NCI's extramural research programs, Grants Administration Branch, and Division of Extramural Activities will be available to provide information and to answer questions relevant to applications responding to this RFA. Investigators who are unable to attend should request transcripts. Investigators are encouraged to contact Nutritional Science Research Group Office at the address listed under INQUIRIES to obtain further information about the meeting, confirm their attendance or to request a transcript of the meeting. RESEARCH OBJECTIVES Background The impetus for this overall program comes from increasing observations that link diet with cancer risk. Data from a multitude of sources, including epidemiological and controlled preclinical experiments, indicate that several dietary components may have a role in the cancer process. While the risks of breast, prostate, colon, lung and liver cancers have been associated with dietary patterns, frequent inconsistencies are noted. These inconsistencies may reflect the multi-factorial and complex nature of cancer and/or the specificity that individual dietary constituents have in modifying genetic pathways. Since variation occurs in cancer incidence among and within populations with similar dietary patterns, the absolute response may reflect complex interactions occurring among nutrients and with other extrinsic environmental factors, or with intrinsic gender, ethnic and genetic factors. Traditional reduction approaches used by some to examine gene-chemical interactions may be inadequate for the study of nutrition and cancer because of the likelihood that multiple nutrients interact with multiple genes to create a phenotypic effect. Thus, applications that include components to examine nutrient-nutrient interactions and response to whole foods are encouraged. The National Cancer Institute's 2001 Bypass Budget (http://2001.cancer.gov/opps.htm) identified six extraordinary research opportunities that offer exciting possibilities for accelerating progress against cancer. Opportunities for moving nutrition research into a new era in cancer prevention are identifiable in several of these extraordinary opportunities including: Genes and the Environment, Defining the Signatures of Cancer Cells, and Molecular Targets. The diet consumed is an environmental exposure that may either enhance or suppress cancer risk and tumor behavior depending on its composition. By addressing the role that diet and dietary components have in each of these areas, better insights will emerge about who might benefit from selected dietary intervention strategies. Astonishing strides have been made in understanding how molecules and pathways in pre- and malignant cells differ from their normal counterparts. The discovery and exploitation of molecular targets for cancer prevention have arisen from the convergence of scientific advances in several areas but have not been totally embraced by the nutrition research community. Preclinical evidence demonstrating that several dietary components can influence Phase I and II enzymes involved with carcinogen metabolism, as well as alter pathways involved with cell proliferation and differentiation, serve as justification for expanding this area of investigation while simultaneously satisfying NCI's goal to identify Molecular Targets of Prevention and Treatment. All cells have unique "signatures" that are characterized by active and inactive genes and cellular products. Evidence already exists that both essential and non-essential nutrients can influence cell cycle regulation, processes involved with replication/transcription, and factors involved with apoptosis. Part of this protection may relate to their ability to prevent oxidative damage. Compounds suppressing oxidative stress have been reported to produce changes in c-fos, c-jun, and c-myc and the tumor suppressor gene p53, as well as genes coding for the syntheses of protective molecules such as metallothioneins, glutathione, and stress proteins. Preclinical evidence exists that such diverse dietary components as folate, allyl sulfur, genistein and resveratrol can alter genes and pathways associated with tumor cell proliferation and apoptosis. This evidence raises the possibility that the expanded use of molecular signatures will assist in developing effective dietary intervention strategies. Defining interactions between genetic pathways and dietary constituents should assist in clarifying discrepancies among pre-clinical, epidemiological, and intervention studies. For example, knowledge about genetic pathways that are, and are not, influenced by carotenoids may clarify why beta-carotene intake emerged in several prospective epidemiological investigations as inversely related to lung cancer risk, while it is contraindicated in controlled trials with smokers. By simultaneously examining other extrinsic factors such as tobacco exposures and the occurrence of genetic changes accompanying pre- neoplastic lesions, it may be possible to clarify why a nutrient might be an antagonist (antioxidant) in one situation yet an agonist (pro-oxidant) in another. Resolving complex issues about intrinsic and extrinsic determinants of cancer are often hampered by the limited scientific breadth of single investigators and institutions and/or access to study populations. The development of research teams from multiple units and/or locations offers exciting opportunities for addressing several overarching nutrition and cancer issues. Among the benefits are the establishment of meaningful integrated and multidisciplinary collaborations among scientists at the interface between the biological domain and medical practice. Objective and Scope The explosive increase in the understanding of new genes and pathways for regulating cell growth and development, and evaluating the response to hormones and other chemicals synthesized by the body offers exciting opportunities for understanding how the diet influences cancer prevention. Cohort studies that can define key interrelationships between genes and dietary exposures, including the content of specific nutrients in target tissues, are sometimes beyond the capabilities of individual institutions. By fostering collaborations between investigators and institutions that use new genetic approaches, this RFA seeks to improve opportunities to address critical research questions that define the mechanism by which nutrients modify the cancer process, characterize how gene variation in key molecular pathways modulate the response, and how to assess/monitor the biological response to foods and their isolated constituents. This RFA is meant to foster interdisciplinary teams to resolve issues about the physiological significance of dietary components as regulators of genetic and epigenetic pathways involved with cancer. Significant advances will require that the approaches taken by these Teams go beyond customary thinking and organizations to the creation of new cross-disciplinary and multi- institutional collaborations. Thus, in this RFA, the Principal Investigator may draw innovative expertise from wherever it may exist; investigators need not be limited to a single institution. Collaborating investigators may be from academic, industrial, or government institutions (including NIH intramural scientists and non-US sites). This RFA, however, does not provide support/funding for synthesis/production of therapeutic agents. Below is a list of some of the areas of research that are viewed as relevant for this U54 RFA. This list is not meant to be all-inclusive and prospective applicants are encouraged to discuss program relevance issues with program staff cited under INQUIRIES. These topics also identify areas where research at the basic/clinical interface is deemed essential to understanding the role of bioactive food components and cancer prevention: o Use of natural genetic variations to elucidate how nutritional exposures are linked to phenotype; o Characterization of molecular events that govern the ability of specific nutrients to alter cell cycle checkpoints; o Credentialing of target receptors for cancer prevention that are modified by dietary constituents; o Methylation patterns that are influenced by dietary manipulations that influence gene expressions and cellular phenotypes; o Antioxidant scavenging and oxygen stress modulation by nutrients; o DNA repair mechanisms influenced by dietary constituents; o Intercellular communications that are influenced by bioactive food components o Signaling pathways that regulate cancer growth, development, differentiation and apoptosis as regulated by dietary components; and o Features of DNA damage, DNA repair or cell cycle progression that makes them particularly susceptible to dietary intervention strategies Specific Objectives The central objective of the Teams supported by this initiative is to identify and characterize the biological consequences of specific nutrients on key genetic pathways involved in cancer processes. The required components are as follows: o Selecting one or more cancer-relevant genetic pathways for which evidence exists that it may be modified by nutrients. o Establishing effective and synergistic collaborations that enhance the capabilities of individuals and leverage available resources for the Team. o Evaluating and validating assays, probes, and other techniques in preclinical models, for assessing genetic effects, changes in biochemical processes downstream from the main target; pharmacokinetics or pharmacodynamics of bioactive food components and for the establishment of quantity-temporal relationships. o Identifying how nutrients directed at high-priority genetic pathways/targets affect endpoints/biomarkers that may be used as indicators in a clinical setting. A Team may choose to achieve translational goal of their research by including (a) acquisition of relevant cells (e.g., from cancers, preinvasive neoplastic lesions, or fields at risk for cancer) by biopsy, aspiration or plasmapheresis, (b) Techniques for imaging molecular and cellular processes such as techniques based on radiotracers or ultrasound or optical imaging, or (c) other indicators as appropriate. o Exploring new scientific insights into mechanisms and determinants of response o Exploring new approaches to early clinical trials methodology; for example, the use of alternate trial designs and endpoints, or exploring designs based on molecular classifications of tumor rather than histology per se. o Responsiveness to share information via publications, meetings and support of training activities and to disseminate new reagents and techniques discovered under this initiative to other investigators. When appropriate, the NCI may facilitate the dissemination of bioactive components and/or approaches to other groups funded by this initiate by providing additional support to the originating laboratory. Team investigators are expected to participate in NCI-sponsored working groups focused on high-priority genetic pathways. Awardees are encouraged to file patent applications in a timely manner in order to permit timely presentation and publication of results. Organizational Structure In order to provide the greatest flexibility for organizing research efforts in these cooperative agreements, the PI must organize the investigators and resources into the following required elements: 1. Overall Research Theme This RFA is to support any part of the full range of research and development from very basic to clinical; involving interdisciplinary teams to resolve issues about the physiological significance of dietary components as regulators of genetic and epigenetic pathways involved with cancer. 2. Research Projects Each application must include at least three meritorious Research Projects, which together represent experimental approaches to define and characterize the mechanisms by which bioactive food components modulate genetic pathways leading to cancer. The discovery and/or development of assays, probes, and other tools suitable for use in preclinical models and clinical research are germane to these investigations. Research Projects may also conduct research on the biologic and pharmacodynamic aspects of nutrient interactions to enable assessment of how dynamics among nutrient(s) may modify specific genetic pathway(s). All of the Research Projects must be related to one or more specific genetic pathways associated with cancer and the benefits/risks associated with a specific nutrient or class of nutrients. Teams must plan to continually select the most promising research approaches that are likely to have impact on the development of clinically useful probes. The flexibility of the Team is intended to promote the discontinuance of research projects demonstrating little or no translational significance and to promote initiation of new projects with greater potential. Translational research is defined as the movement of a laboratory discovery into a patient or population setting or the movement of an observation in a patient or population setting into a laboratory research environment. 3. Core Services The Team is encouraged to develop and maintain core resources that are essential for the conduct of this research. Core Services may include resources that may already be available at the institution and do not need further development/research. Examples of potential Core Services include animal cores, pharmacology, pathology, clinical data monitoring services, and statistical support. An Administrative Core is required and is responsible for administrative management and coordination of meetings and other activities within the Team and with other potential collaborators such as industry and NCI and other funded Teams. The Principal Investigator of the Team must serve as the Principal Investigator of the Administrative Core. The Administrative Core may encompass the other service cores, or, if they are separately organized, each service core must provide resources to at least two Research Projects and/or Pilot Projects. 4. Pilot (Developmental) Projects Every Team must facilitate and support Pilot Projects that take maximum advantage of new technological and research opportunities. These projects may be collaborative among scientists within one or more Teams, or with scientists outside the Team. If a clinical trial is not proposed as one of the Research Projects, at least one Pilot Project must outline the general plan for a (future) clinical trial that incorporates the methodologies, techniques, and probes to be developed in the research projects. Each application must propose an institutional review process for selecting Pilot Projects for funding that generate feasibility data and have the most promising translational research potential. While the specific number of pilot projects to be proposed is at the discretion of the applicant, requested funding for pilot studies may not exceed $125,000 or 10 percent (whichever is larger) of the direct cost budget proposed for any 1 year. All proposed pilot projects need not be ongoing at any one time, but may be phased in during the life of the award. It is recognized that the relative priority or need for specific pilot projects may change during the course of the award. For the first 2 years that funds are requested for pilot projects, the application must provide descriptions of the projects to be supported. For years 03-05, the application must provide the specific number of pilots planned in each year and a brief description of the anticipated direction of these pilots. Pilot studies should not have individual budgets. The PI can request a single line item in the administrative core for pilot studies. These funds are intended to remain flexible and to support studies of a limited duration, e.g., two years or less. Successful feasibility studies may be used to replace full projects that are no longer contributing significantly to the objectives of the Team. Therefore scientific members of the Team may change during the course of the award. Framing experiments as pilot projects permits maximal flexibility to proceed in the directions that seem most scientifically fruitful. Individual Pilot Projects are expected to have small budgets since the majority of the personnel and equipment involved will likely be supported by the Research Projects and Cores and thus funds would only be needed for supplies, animals, etc. While the framework for management of pilot funds and the mechanism for operating the program are left to the discretion of the PI, the application must provide specific information to enable adequate scientific evaluation by a peer review committee. The application should include: o A full description of the management of the pilot project component, including a description of the process to be followed in selecting new pilot projects and replacing projects proposed in the application, should it become necessary. o A full description of each pilot study proposed in the first 2 years, including its rationale, objectives, approach, investigators, and significance to the overall undertaking. A description of the number and anticipated direction of pilot projects in the 03-05 years, including their significance to the Program. The research description of any individual pilot project may not exceed five pages; the entire narrative for this Pilot Project Component may not exceed 25 pages regardless of the number of pilot projects proposed. o For competing renewal applications, information should be provided in the pilot project component description on the past experience in utilizing pilot funds to further the goals. The narrative should include an assessment of the overall benefits derived from the availability of pilot resources. o A budget should be submitted for the pilot project component as a whole for each year in which pilots are proposed as a line item within the Administrative Core. For years 01 and 02, this budget will reflect costs of pilots proposed in the application. For years 03-05, the budget will estimate cost based on the number and kind of studies to be pursued. 5. Planning Committee. A Planning Committee with representation from the Principal Investigator from each Team and from NCI Program Staff (NSRG Project Scientist see below) will be established to help coordinate the activities and exchange information and techniques among the Teams (see below). The expectation is that successful feasibility studies will be developed by the Planning Committee that will allow new technologies and approaches to become a core function and/or be distributed more widely to other investigators funded by this RFA. The research activities included in these cooperative agreements are explicitly translational and are, of necessity, highly interdisciplinary. Each Team must be able to deal expertly with nutritional biochemistry and cancer biology, and with such matters as chemistry, pharmacokinetics, cellular and molecular imaging, in vivo animal models, and early clinical trials as needed. MECHANISM OF SUPPORT This RFA will use NIH U54 award mechanism. As an applicant you will be solely responsible for planning, directing, and executing the proposed project. This RFA is a one-time solicitation. Future unsolicited, competing-continuation applications based on this project will compete with all investigator- initiated applications and will be reviewed according to the customary peer review procedures. The anticipated award date is April, 2003. The NIH U54 is a cooperative agreement award mechanism in which the Principal Investigator retains the primary responsibility and dominant role for planning, directing, and executing the proposed project, with NIH staff being substantially involved as a partner with the Principal Investigator, as described under the section "Cooperative Agreement Terms and Conditions of Award". The U54 mechanism may support any part of a full range of research development from very basic to clinical. The U54 is a cooperative agreement, an assistance mechanism (rather than an acquisition mechanism) in which substantial NIH scientific and/or programmatic involvement with the awardee is anticipated during the performance of the activities. Under a cooperative agreement, the NIH's purpose is to support and stimulate the recipient's activities by involvement in and otherwise working jointly with the award recipient in a partner role. NIH staff work cooperatively with the award recipients in a partner role and do not assume direction, prime responsibility, or a dominant role in the activity. Details of the responsibilities, relationships, and governance of the activities to be funded under the cooperative agreements awarded for this Program are discussed below under "Terms and Conditions of Award." At this time the NCI has not determined whether or how this solicitation will be continued beyond the present RFA. If it is determined that there is a continuing program need, the NCI will either invite recipients of awards under this RFA to submit competitive continuation cooperative agreement applications for review or re-issue the RFA for re-competition. If the NCI does not continue the program, awardees will be able to submit grant applications through existing investigator-initiated grant programs that will be reviewed according to the customary peer review procedures. FUNDS AVAILABLE The NCI intends to commit approximately $5.3 million in FY 2003 to fund 3 to 4 Teams in response to this RFA. An applicant may request a project period of up to five years. Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of the NCI provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. At this time, it is not known if this RFA will be reissued. ELIGIBLE INSTITUTIONS You may submit (an) application(s) if your institution has any of the following characteristics: o For-profit or non-profit organizations o Public or private institutions, such as universities, colleges, hospitals, and laboratories o Units of State and local governments o Eligible agencies of the Federal government o Domestic o Faith-based organizations Foreign organizations are not eligible to serve as grantees but may be part of domestic applications. PIs must be United States citizens, non-citizen alien nationals, or permanent residents of the United States. An application must contain three or more related and interactive research projects that provide an interdisciplinary, yet thematic, approach to a nutrient-genetic pathway issue involved with cancer prevention. Applications will not be accepted that include research activities focused exclusively on clinical research or exclusively on basic research, or that are limited to epidemiological or large scale clinical trials. INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs. SPECIAL REQUIREMENTS Cooperative Agreement Terms and Conditions of Award Cooperative agreements are assistance mechanisms and are subject to the same administrative requirements as grants. The following Terms and Conditions of Award are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, HHS grant administration regulations in 45 CFR Part 74 and 92 and administered under the NIH Grants Policy Statement. The administrative and funding instrument used for this program is a cooperative centers agreement (U54), an "assistance" mechanism (rather than an "acquisition" mechanism) in which substantial NIH scientific and programmatic involvement with the awardee is anticipated during the grant award. The NIH purpose is to support and stimulate the activity by working jointly with the recipient in a partner role, but it is not to assume direction, prime responsibility or a dominant role in the activity. The prime responsibility for the research resides with the awardees, although some activities may be carried out as a collaboration among the awardees with coordination and facilitation by the NCI-NSRG Project Scientist as described below. 1. Awardee Rights and Responsibilities: a. Awardees will have primary responsibility for the project as a whole, including research design and conduct, data collection, data quality control, data analysis and interpretation and preparation of publications, as well as collaborations with other awardees. Awardees will retain primary custody of and have primary rights to the data developed under these awards, subject to government rights of access consistent with current HHS, PHS, and NIH policies. However, awardees must be committed to making the assays and probes and other research tools and research materials they develop available to the cancer research community. b. The Principal Investigator must plan to participate in regular meetings of a Planning Committee to discuss progress and directions of research and to insure that the necessary interdisciplinary interactions are taking place. c. Awardees agree to participate on common projects identified by the Planning Committee on common research interests that address a specific basic and/or clinical research problem. d. The Principal Investigator must plan to participate in regular meetings with the Team to discuss progress and directions of research and to insure that the necessary interdisciplinary interactions are taking place. Plans to extend meetings via teleconferencing, videoconferencing or web conferencing, as well as fact to face meetings, are appropriate. e. The Principal Investigator and/or another designated investigators will attend an Annual Meeting to be organized by NCI staff in Washington D.C. In addition, the PI will be a voting member of the Planning Committee which meets twice a year (one meeting will be coordinated with the Annual Meeting). f. Each Team will submit biannual progress reports to the NCI that describe activities and accomplishments during the previous funding period. g. An NIH intramural scientist (IMS) may not serve as the Principal Investigator but may participate as part of the Awardee Team. The participation of an IMS is independent of and unrelated to the role of the NSRG Project Scientist as described below. An IMS who is part of the award's project team will have the same programmatic rights and responsibilities as other investigators. h. Intellectual Property Plan. In order to encourage timely presentation and publication of results, the Awardees are encouraged to file patent applications in a timely manner, according to approved implementation plan. i. All Awardees must adhere to the Principles and Guidelines for Recipients of NIH Research Grants and Contracts on Obtaining and Disseminating Biomedical Research Resources (64 Federal Register 72090). The Principles and Guidelines can be accessed electronically at: (http://ott.od.nih.gov/). j. Awardees shall include the following terms concerning intellectual property rights, or provide an alternative plan. In no event will an award be made absent incorporation of either the terms below, or Institution's own plan. "Institution agrees to grant to commercial collaborator: (i) a paid-up nonexclusive, nontransferable, royalty-free, world-wide license to all Institution Inventions for research purposes only; and (ii) a time-limited first option to negotiate an exclusive, world-wide royalty-bearing license for all commercial purposes, including the right to sub-license, to all Institution Inventions on terms to be negotiated in good faith by the collaborator and Institution. The collaborator shall notify Institution, in writing, of its interest in obtaining such an exclusive license to any Institution Invention within six (6) months of the collaborator's receipt of notice of such Institution Invention(s). In the event that a collaborator fails to so notify Institution, or elects not to obtain an exclusive license, then the collaborator's option shall expire with respect to that Institution Invention, and Institution will be free to dispose of its interests in such Institution Invention in accordance with Institution's policies. If Institution and collaborator fail to reach agreement within ninety (90) days, (or such additional period as collaborator and Institution may agree) on the terms for an exclusive license for a particular Institution Invention, then for a period of six (6) months thereafter Institution shall not offer to license the Institution Invention to any third party on materially better terms than those last offered to collaborator without first offering such terms to collaborator, in which case collaborator shall have a period of thirty (30) days in which to accept or reject the offer. Institution agrees that notwithstanding anything contained herein to the contrary, any inventions, discoveries or innovations, whether patentable or not, which are not Subject Inventions as defined in 35 USC 201(e), arising out of any unauthorized use of the collaborator's agent and/or any modifications to the agent, shall be the property of the collaborator (hereinafter "Collaborator Inventions"). Institution will promptly notify the collaborator in writing of any such Collaborator Inventions and, at collaborator's request and expense, Institution will cause to be assigned to collaborator all right, title and interest in and to any such collaborator inventions and provide collaborator with assignment or other documents). Institution may also be conducting other research using the agent under the authority of a separate Material transfer Agreement (MTA) with the collaborator. Inventions arising there under shall be subject to the terms of the MTA, and not to this clause." 35 USC. k. Protection of Proprietary Data Raw and primary data may be provided exclusively to the NCI, industrial collaborators, and the FDA, as appropriate. This provision shall not affect the investigators' right to disseminate their research findings through publications or presentations. 2. NCI Staff responsibilities: a. The NCI Program Director from the Division of Cancer Prevention, Nutritional Science Research Group (NSRG) and other staff members within the NSRG will work closely with individual investigators (including NIH intramural scientists) to facilitate collaborations with other NCI-funded research groups and to leverage the resources available for this effort. An assigned NCI program official will be responsible for normal program stewardship and monitoring of the award. b. A NSRG Project Scientist will assist in the coordination of activities that involve all the awardees, such as annual meetings and Planning Committee meetings. This individual will also assist the research efforts of the Team by facilitating access to fiscal and intellectual resources provided by industry, private foundations and NIH intramural scientists. The NSRG Project Scientist will serve as a voting member of the Planning Committee. As required, when projects are not making headway, the NSRG Project Scientist, will help reprogram research efforts within the peer-reviewed scope of work, including options to modify or terminate projects, by mutual consent between a Team and NCI. c. The NSRG Project Scientist will interact with each Team, evaluating the progress of that particular Team, help coordinate research approaches between Teams, and contribute to the adjustment of research projects or approaches as warranted. The NSRG Project Scientist will assist and facilitate this process and not direct it. This individual will also provide assistance in reviewing and commenting on all major transitional changes of an individual Team's activities prior to implementation to assure consistency with the goals of this RFA-CA-03-001. d. The NSRG Project Scientist will coordinate this activity with other ongoing studies supported by NCI to avoid duplication of effort and to encourage sharing and collaboration in the development of new clinically useful reagents and methodologies for assessing nutrient-gene interactions. The NSRG Project Scientist will coordinate access to other resources from NCI including NCI sponsored agents for preclinical and clinical testing, drug screening, preclinical toxicology testing, assistance in IND filing, etc. e. The NSRG Project Scientist will organize an annual meeting of all funded PIs or their designees to share progress and research insights that may benefit all of the projects. In addition, he/she will be responsible for organizing biannual meetings of the Planning Committee. f. The NSRG Project Scientist will assist, where warranted, in data analyses, interpretations, and the dissemination of study findings to the research community and health care recipients including co-authorship of the publication of results of studies conducted by the Teams, subject to NIH publication policies. 3. Collaborative responsibilities: The Planning Committee will provide overall coordination of the Teams; voting members will consist of the Team Principal Investigators, and 1 NCI Program Staff (NSRG Project Scientist). Additional Program Staff and scientists other than PIs may attend as non-voting members of the Planning Committee where additional expertise may be required. A non-NIH chairperson for the Planning Committee will be chosen by a majority vote of the Principal Investigators. The Planning Committee will identify the need for collaborations either within or outside the Teams and the need to redirect certain efforts as mandated by establishment of sufficient data to reach conclusions, data supporting alternative approaches, or experience proving that the proposed research is no longer feasible. Some Teams will have common research interests that address a specific basic and/or clinical research problem; research focus groups may be formed to conduct coordinated research activities identified by the Planning Committee. The Planning Committee will make recommendations regarding genetic targets and possible research tools. It will also seek input from the scientific research communities and consider how to have an impact on nutritional recommendations to the larger community. The Team investigators must be willing to consider addressing future scientific needs discussed by the Planning Committee. The Planning Committee will meet twice yearly. The purpose of these meetings is to share scientific information, assess scientific progress, identify new research opportunities and potential avenues of collaborations such as with industry, private foundations and/or NIH intramural scientists, establish priorities that will accelerate the translation of preclinical findings into clinical applications, reallocate resources and conduct the business of the cooperative research program. 4. Arbitration: When agreement between an awardee and NCI staff cannot be reached on scientific/programmatic issues that may arise after the award, an arbitration panel will be formed. The panel will consist of one person selected by the awardee, one person selected by NCI staff, and a third person selected by these two members. The decision of the arbitration panel, by majority vote, will be binding. This special arbitration procedure in no way affects the right of an awardee to appeal an adverse action in accordance with PHS regulations at 42 CFR Part 50, Subpart D, and HHS regulations at 45 CFR Part 16. WHERE TO SEND 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 and address the letter of intent to: John A. Milner Chief, Nutritional Science Research Group, DCP, National Cancer Institute Executive Plaza North 6130 Executive Blvd, EPN Suite 3164 Rockville, MD 20852 Email: milnerj@mail.nih.gov Telephone: (301) 496-0108 FAX: (301) 480-3925 Direct inquiries regarding review issues to: NCI Referral Officer Division of Extramural Activities National Cancer Institute 6116 Executive Boulevard, Room 8041, MSC 8329 Rockville, MD 20852 (express service) Bethesda, MD 20892-8329 Telephone (301) 496-3428 Fax: (301) 402-0275 Email: ncidearefof-r@mail.nih.gov Direct inquiries regarding fiscal matters to: Ms. Priscilla Grant Grants Administration Branch National Cancer Institute 6120 Executive Boulevard, EPX Suite 243 Bethesda, MD 20892-7150 Rockville, MD 20852 (for express/courier service) Telephone: (301)496-3160 Fax: (301) 496-8601 Email: cm113g@nih.gov LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes the following information: o Descriptive title of the proposed research o Name, address, and telephone number of the Principal Investigator o Names of other key personnel o Participating institutions o Number and title of this RFA 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 allows NCI staff to estimate the potential review workload and plan the review. The letter of intent is to be sent by the date listed at the beginning of this document. The letter of intent should be sent to: John A. Milner Chief, Nutritional Science Research Group, DCP, National Cancer Institute Executive Plaza North 6130 Executive Blvd, EPN Suite 3164 Rockville, MD 20852 SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). The PHS 398 is available at https://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: GrantsInfo@nih.gov. USE P01/U54 Grant Guidelines and Descriptions located at (http://deainfo.nci.nih.gov/flash/awards.htm). SUPPLEMENTAL INSTRUCTIONS: A collaborating NIH Intramural Scientist (IMS) may not receive salary, equipment, supplies, or other remuneration from this RFA. The IMS must obtain approval of his/her NIH Institute Scientific Director to allocate resources to the project. This letter must specify that no more than $300,000 direct costs of intramural resources will be allocated to the project and provide assurance that the conduct of the project will comply with the DHHS regulations for research involving human subjects (if applicable) and with the PHS policy of vertebrate animal research.). Each applicant Team must provide in the application a detailed description of the approach to be used for obtaining patent coverage and for licensing where appropriate, in particular where the invention may involve investigators from more than one institution. Procedures must be described for resolution of legal problems should they arise. Your attention is drawn to P.L. 96-517 as amended by P.L. 98-620 and 37 CFR Part 401. Instructions were also published in the NIH Guide for Grants and Contracts (NIH Guide, Vol. 19, No. 23, June 22, 1990).) NCI acknowledges that some commercial collaborators that are members of applicant Teams, or who provide agents to applicant Teams, may require that Institution agree to grant to them certain intellectual property rights, as described by the terms above. If Institution voluntarily agrees to the described terms, then they should appear in the Institution's Team application. NCI recognizes that Institutions' ability to access agents from commercial collaborators for this effort may be limited absent such a voluntary agreement, or a substantially similar independent agreement between Institution and commercial collaborators providing agents. However, in no event will the award of cooperative agreement be dependent upon the described terms' being part of an Institution's Team application. Rather, Institution's Team application may provide Institution's own plan for accessing agents from commercial collaborators. USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/01) application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. 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. The RFA label is also available at: https://grants.nih.gov/grants/funding/phs398/label-bk.pdf. SENDING AN APPLICATION TO THE NIH: 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 (20817 FOR EXPRESS SERVICE) At the time of submission, two additional copies and all appendix material of the application must also be sent to: NCI Referral Officer Division of Extramural Activities National Cancer Institute 6116 Executive Boulevard, Room 8041, MSC 8239 Rockville, MD 20852 (express service) Bethesda, MD 20892-8329 APPLICATION PROCESSING: Applications must be received by July 12, 2002. 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 substantial revisions of applications already reviewed, but such applications must include an Introduction addressing the previous critique. Applications must meet all eligibility requirements as described above and must address all programmatic requirements (see SPECIAL REQUIREMENTS above) in the RFA. APPLICATIONS HAND-DELIVERED BY INDIVIDUALS TO THE NATIONAL CANCER INSTITUTE WILL NO LONGER BE ACCEPTED. This policy does not apply to courier deliveries (i.e. FEDEX, UPS, DHL, etc.) (https://grants.nih.gov/grants/guide/notice-files/NOT-CA-02-002.html) This change in practice is effective immediately. This policy is similar to and consistent with the policy for applications addressed to Centers for Scientific Review as published in the NIH Guide Notice https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-012.html. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NCI. Incomplete applications will be returned to the applicant without further consideration. And, if the application is not responsive to the RFA, CSR staff may contact the applicant to determine whether to return the application to the applicant or submit it for review in competition with unsolicited applications at the next appropriate NIH review cycle. 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 the Division of Extramural Affairs (DEA) at NCI in accordance with the review criteria stated below. As part of the initial merit review, all applications will: o Receive a written critique o Undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed and assigned a priority score o Receive a second level review by the National Cancer Advisory Board. REVIEW CRITERIA The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments, reviewers will be asked to discuss the following aspects of your application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals: o Significance o Approach o Innovation o Investigator o Environment The scientific review group will address and consider each of these criteria in assigning your application's overall score, weighting them as appropriate for each application. Your application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, you may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. The factors to be considered in the evaluation of all applications are given below. A. INDIVIDUAL RESEARCH PROJECTS: 1. SIGNIFICANCE: How important are the selected target(s)/pathway(s)/mechanism(s)? Are the selected targets considered high priority for the development of intervention strategies? Will development of the proposed assays, probes, and other tools improve the identification of individuals who might benefit from dietary intervention strategies? 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? If there is a foreign component within the application has it been adequately justified. How effective is the strategy for selecting assessment tools? Have preclinical models been proposed in which the nutrients or classes of nutrients been shown to have activity? Have the investigators considered the appropriate negative and positive controls? Will the design of preclinical experiments permit conclusions that will be ultimately applicable to dietary intervention strategies? Does the investigator identify potential limitations in currently available models and possible approaches to rectifying them? 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: Does the training, experience, qualifications, accomplishments and availability of the proposed Investigators and evidence of ability, organizational structure and availability to function as a team meet requirements to carryout the proposed project? 5. ENVIRONMENT: Is there evidence of prior experience with preclinical and clinical evaluation of nutrients and genetic pathways? Is there an explanation of how the organization will provide support and expertise to this project and the proposed PI? Is there prior experience of the PI/Organization with multi-institutional research projects, or is there a clear plan to organize multi-institutional research projects if they are proposed? Does the preparation of the projects indicate that experts from different backgrounds communicated with each other in writing the grant application? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your application will also be reviewed with respect to the following: o PROTECTIONS: The adequacy of the proposed protection for humans, animals, or the environment, to the extent they may be adversely affected by the project proposed in the application. o INCLUSION: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria included in the section on Federal Citations, below) o DATA SHARING: The adequacy of the proposed plan to share data. o BUDGET: The initial review group will also examine the reasonableness of the proposed budget and the requested period of support in relation to the proposed research. The support for attendance at Planning Committee meetings can be provided through the Team's award as part of the travel budget. B. CORES 1. Qualifications, experience and commitment of key personnel in the services provided by the core unit, as well as their ability to devote the required time and effort in providing services to the Team. 2. Appropriateness of the use of the core services by the proposed projects 3. Adequate plans for charge back and priority management procedures for service/technical core units C. DEVELOPMENTAL/PILOT PROJECTS 1. Are the specific plans for use of developmental funds consistent with the Team's overall goals and priorities? Do the Pilot Projects interact with the Research Projects and Cores? 2. Does the quality of the pilot projects proposed by the Team demonstrate the effectiveness of the selection process?3. Are proposed studies adequately considering women and minorities in the design? 4. Is the budget appropriate for what has been proposed for investigation? D. OVERALL PROGRAM ORGANIZATION AND CAPABILITY: a. SIGNIFICANCE: Does the proposed work address an important genetic pathway in the cancer process? If the aims of the application are accomplished, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive these types of investigations? b. 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 tactics? c. 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? d. INVESTIGATORS: Are the Principal Investigator and collaborators appropriately trained and well suited to carry out this work? Does the research experience of the PI demonstrate expertise in nutrition or cancer prevention? Is the work proposed appropriate to the experience level of the key investigator and other researchers? Is the Principal Investigator committed to devote the required time and effort to the Team? Does the PI demonstrate willingness to work and collaborate with other Team Programs as appropriate and with NCI assistance in the manner summarized in this RFA. e. ENVIRONMENT: Does the scientific environment in which the work will be performed contribute to the probability of success? Are resources such as space, equipment, preclinical models, technical and clinical capabilities described that are needed for the success of the research? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? f. In addition, the criteria for reviewing the integrated effort are: o Overall strength of the Investigators in terms of the combined strength of the research projects, pilot projects and core units, and the significance of the application to the objectives of the Program outlined in this RFA; o Leadership ability and scientific stature of the Principal Investigator, particularly, but not exclusively in the area of the proposed research, and his/her ability to meet the demands of time and effort; o An appropriate organizational and administrative structure for effective attainment of the objectives that considers arrangements for internal quality control of ongoing research, the allocation of funds, day-to-day management, contractual agreements, if applicable, and internal communication among investigators; o Demonstrated institutional commitment to the investigators and their objectives in terms of providing research facilities and management support. OVERALL EVALUATION AND SCORING OF APPLICATIONS The individual Research Projects will be assigned numerical priority scores while the Cores will be rated superior, satisfactory, or NRFC, without numeric scores. The Pilot Projects will be rates as a group reflective the ability of investigators to select quality preliminary studies. The Pilot studies as a unit will be rated superior, satisfactory or not recommended for further consideration (NRFC). A single numerical priority score will then be assigned to the Team application as a whole after discussing all of the review elements listed above. The score will be based on the overall quality of the Research Projects, the Developmental/ Pilot Projects, the overall effectiveness and adequacy of shared resources, the overall program organization and capability, the plans for interactions with the Team, and the potential for adding critical knowledge about the role of bioactive food components in modulating the cancer process. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: June 14, 2002 Application Receipt Date: July 12, 2002 Peer Review: November, 2002 Review by NCAB: February, 2003 Earliest Anticipated Award Date: April, 2003 AWARD CRITERIA Award criteria that will be used to make award decisions include: o Scientific merit (as determined by peer review) o Availability of funds o Programmatic priorities REQUIRED FEDERAL CITATIONS MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research components involving Phase I and II clinical trials must include provisions for assessment of patient eligibility and status, rigorous data management, quality assurance, and auditing procedures. In addition, it is NIH policy that all clinical trials require data and safety monitoring, with the method and degree of monitoring being commensurate with the risks (NIH Policy for Data Safety and Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: https://grants.nih.gov/grants/guide/notice-files/not98-084.html). Clinical trials supported or performed by NCI require special considerations.. The method and degree of monitoring should be commensurate with the degree of risk involved in participation and the size and complexity of the clinical trial. Monitoring exists on a continuum from monitoring by the principal investigator/project manager or NCI program staff or a Data and Safety Monitoring Board (DSMB). These monitoring activities are distinct from the requirement for study review and approval by an Institutional review Board (IRB). For details about the Policy for the NCI for Data and Safety Monitoring of Clinical trials see: http://deainfo.nci.nih.gov/grantspolicies/datasafety.htm. For Phase I and II clinical trials, investigators must submit a general description of the data and safety monitoring plan as part of the research application. See NIH Guide Notice on "Further Guidance on a Data and Safety Monitoring for Phase I and II Trials" for additional information: https://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html. Information concerning essential elements of data safety monitoring plans for clinical trials funded by the NCI is available: http://nci.nih.gov/clinicaltrials/conducting/dsm-guidelines. INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating 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 of Public Law 103-43). All investigators proposing clinical research should read the AMENDMENT "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines are available at https://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects that is available at https://grants.nih.gov/grants/funding/children/children.htm. REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. You will find this policy announcement in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at https://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. A continuing education program in the protection of human participants in research in now available online at: http://cme.nci.nih.gov/. HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on hESCs can be found at https://grants.nih.gov/grants/stem_cells.htm and at https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (see http://escr.nih.gov). It is the responsibility of the applicant to provide the official NIH identifier(s)for the hESC line(s)to be used in the proposed research. Applications that do not provide this information will be returned without review. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at https://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this PA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site. HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This RFA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople. AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance No. 93.3393 and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH grants policies described at https://grants.nih.gov/grants/policy/policy.htm and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the 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.
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