MOUSE MODELS OF HUMAN CANCERS CONSORTIUM RELEASE DATE: October 10, 2002 RFA: CA-04-002 - (Reissued as RFA-CA-08-018) National Cancer Institute (NCI) (http://www.nci.nih.gov/) LETTER OF INTENT RECEIPT DATE: February 19, 2003 APPLICATION RECEIPT DATE: March 19, 2003 This RFA is a reissue of RFA CA-98-013, which was published in the NIH Guide on July 29, 1998 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism 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 NCI invites new and competing renewal cooperative agreement (U01) and NIH intramural applications from groups of investigators to continue the Mouse Models of Human Cancers Consortium (MMHCC). The scientific scope of this integrative human/mouse cancer research program may be expanded through incorporation of individuals or groups with additional new perspectives and expertise, such as chemistry, computational and mathematical modeling, and systems biology, to create trans-disciplinary approaches to the design, analysis, and applications of mouse cancer models. RESEARCH OBJECTIVES Background The original purpose of the MMHCC was "to accelerate the pace at which mice with heritable malignancies that are accurate, reproducible models of human cancers are made available to the research community for further investigation or application." Since its inception in October 1999, the component groups of the MMHCC have vigorously pursued this purpose. With the resources in their individual grants, the Consortium members evolve and test novel strategies to recapitulate the natural history and clinical course of human cancers in the laboratory mouse. Collectively, the MMHCC investigates the genetics and biology of the resulting strains for their ability to inform human research. They explore approaches to expand the role of mouse cancer models for translational research, using models to guide selection of, and credential, new targets for therapy, and test molecularly targeted agents, expose premalignant molecular genetic changes for early detection, disclose the genetic determinants of cancer susceptibility, test novel agents for tumor prevention and new concepts for prevention research, and incorporate imaging technologies to detect developing malignant lesions, follow their progression to invasive, metastatic tumors, and monitor response to therapy. In addition to advancing the original goals, the MMHCC is an active partner with the NCI to implement and continue to evolve the infrastructure that informs the research community about mouse cancer models and deploys them to the research community. The Consortium members organize numerous cancer models workshops and symposia, and participate in hands-on laboratory courses that are open to the greater research community. They also work with the NCI to establish and maintain a website (http://emice.nci.nih.gov) that provides disease-site–specific information about cancer models, and has links to the Cancer Models Database and the NCI-MMHCC mouse repository. The NCI anticipates that the MMHCC will continue to provide leadership in the future to sustain the mouse modeling research infrastructure already in place and to advise the NCI on emerging needs for additional infrastructure. The Cancer Models Database (http://cancermodels.nci.nih.gov) houses histopathologic, genetic, expression profiling, and other biological data about cell, tissue, and animal cancer models, and their use for therapy or prevention studies. The database, developed with help from the MMHCC, is a fundamental data source for the bioinformatics network deployed by the NCI Center for Bioinformatics (http://ncicb.nci.nih.gov). The network integrates genomic, expression profile, proteomic, histopathologic, preclinical, clinical, and image data from NCI preclinical models and human research programs sources. The MMHCC is a core component of this bioinformatics infrastructure, which creates the context for the Consortium at the present, and in the future. The NCI Cancer Molecular Analysis Project interface (http://cmap.nci.nih.gov) illustrates the exceptional potential for progress in cancer research that can result from merging information from human and cancer models investigations. The activities of the MMHCC include fresh approaches to mouse genetic engineering and phenotyping that have significantly advanced the field and stimulated interest in derivation and application of mouse cancer models to cancer research. Many challenges remain that will be pursued most effectively through continued support for the MMHCC; the challenges include the need for continued innovation to discern how widely and effectively cancer models can be applied to sustain discovery in human basic, translational, clinical, and population science. However, the routine application of mouse cancer models to translational research goals is not the intent of this RFA. Such applications are appropriate for a variety of support mechanisms, including investigator-initiated research projects and program project grants, competing supplements to existing research grants, and applications in response to other NCI special initiatives. As it was for the original RFA for the MMHCC, the intent of the NCI in this RFA is to foster research investigations, technological innovation, and extensive collaboration that cannot be pursued with traditional grant support. Applicants to this RFA are encouraged to propose risky approaches that incorporate broad knowledge of human cancer research into design, analysis, and applications of mouse cancer models, and to incorporate biocomputational, mathematical modeling, and systems biology strategies to inform design of genetic models and their cross-comparisons to human cancer. The newly implemented trans-disciplinary nature of the MMHCC will sustain discoveries that should stimulate mechanistic hypotheses for future research and generate additional tools in support of translational and clinical cancer science. Significant advances in the science of mouse cancer modeling reflect the rapid acquisition of mouse and human genome sequence information, the informatics tools to analyze and compare them, innovative technologies to derive molecular signatures of human and mouse cancer, and the evolution of new approaches to mouse engineering and phenotyping. The MMHCC has contributed to, and capitalized on, these advances. In-depth characterization of the latest mouse cancer models reveals that the diseases they develop more closely parallel the corresponding human cancers than did previous models. However, major challenges remain that will benefit considerably by increased incorporation of chemistry, bioinformatics, mathematical modeling, and other disciplines into this next phase of mouse cancer modeling research. At this time, molecular signatures of human tumors are one major starting point to define which genes to manipulate in mice. However, the pace at which new genes, pathways, and processes are identified as causally related to human cancers is accelerating, and understanding the phenotypes that result from altering expression of one or more genes in the mouse is increasingly complex. These realities suggest that future modeling efforts require better decisions about what to manipulate to produce novel, informative, and useful models. It may be possible to employ short-term phenotype alteration as an initial screen to guide selection of the parameter(s) to alter permanently in a model. Such technologies as siRNA, antisense, libraries of small molecules, or morpholinos may be useful to derive functional information about the role(s) of specific genes or proteins prior to germline modification. Incorporation of information about cancer-causing mutations in mice that are produced in large- scale mutagenesis screens or arise spontaneously could be instructive. It will also be valuable to integrate knowledge from models of other human disease processes, such as inflammation and obesity, and from developmental biology and its anomalies, environmental exposures, reproductive biology, and normal immunity. However, for these diverse areas of investigation to be effective information resources for cancer research, there must be inventive new bioinformatics strategies to integrate the data. Increasingly, human tumors of a single disease site are analyzed by expression profiling, and the results enable segregation of the tumors into discrete subtypes. Use of comparable genomic technologies for mouse tumors, although not yet widely applied, suggests that one particular model is more likely to reflect the features of a single human tumor subtype rather than represent the heterogeneity of human disease. For cross-comparisons, bioinformatics will assist in ensuring that appropriate conclusions are reached and then used to guide derivation of additional models or refinement of existing ones to fill gaps in the collection of models for a particular disease site. Although gene expression and protein profiling of tumors is a good starting point to assess how closely a given engineered mouse strain models a specific cancer subtype, it substantially limits what may be learned about human disease by focusing on the end stage of cancer only. An inherent strength of mouse cancer models is that researchers can interrogate the diseases along the continuum of stages and not just at the point at which there is clinical manifestation. The ability to collect data on changes in cancers at many pre- malignant and malignant disease stages – the biology, gene expression and protein profiles, histopathology, response to various interventions, and appearance by non-invasive imaging techniques – is a powerful approach with significant potential for impact on human disease outcomes. Another strength of mouse cancer models is that they enable researchers to test hypotheses about the natural history and clinical course of human diseases in a genetically tractable experimental system, exploring questions that cannot be approached experimentally in human populations or patients. Other aspects of the cancer phenotype, such as host immune response, endocrinology, and physiological and metabolic profiling, are much less well characterized in the mouse cancer models than are the tumors themselves. In this regard, the relative ease with which such data can be gathered from cancer models compared to human subjects along the continuum of cancer initiation, tumor establishment, and progression to invasion and metastasis is an important application of mouse cancer models as research tools. No doubt there are measurable parameters of mouse physiology and biology that are important to catalog to expose changes that may relate to cancer initiation and progression. However, the technologies needed to analyze physiological changes easily and reproducibly are likely to require additional development or refinement. To recognize potential cancer-related deviations will require effective incorporation of information from collections of research data on normal mouse development and biology. As new observations about human cancer biology emerge, additional mouse germline or other engineering approaches may be needed to recapitulate them in mice. Recently, genomic scans of tumors and the underlying stroma reveal that cells in the microenvironment of the tumor have different patterns of chromosomal aberrations. Changes in patterns of signal cross-talk among the various cell types in a tissue occur during cancer progression. These and similar observations in many human cancers suggest the need for additional experimentation in genetic engineering to recapitulate such phenomena and to interrogate the processes for their relevance to cancer progression and clinical course. Inspecting all mouse cancer models for differences in the molecular signatures of tumor cells and the diverse types of cells in the stroma may be an important phenotyping strategy as well. One key emerging use for mouse cancer models is as tools for research on interventions – to define molecular targets and to test molecularly targeted agents for therapy and prevention. Models can be used to illuminate the mechanisms for less than optimal clinical experience of a given agent. In a number of instances, mouse cancer models have been used with considerable effect for therapy-related research because they display much of the natural history and response to standard therapy of the related human cancer. To explore how to improve clinical outcome, researchers can test new combination therapies in mice; with this strategy, they often find that the mutated genes drive cancer progression by a different mechanism than first hypothesized. Such discoveries can lead to the development of new classes of agents that reflect better knowledge about the function of particular genes in tumors. Published results of this kind suggest that there are many potential avenues yet to investigate. It will be an essential goal of the MMHCC to apply the most promising cancer models to identify the range of clinical questions for which they are useful. For example, there are questions about the prognostic value of costly or invasive post-therapy analysis of residual tumors that can easily be addressed using comparable models exposed to the same therapy. There are many opportunities to invent and test new delivery systems, including those enabled by recent advances in nanotechnology. In addition, mouse cancer models can be used to define the genetic determinants of response or resistance to interventions. Incorporation of functional and structural imaging permits researchers to identify animals that are developing tumors or metastases without invasive procedures, visualize delivery of agents to a tumor and measure rate of uptake, show the temporal and regional response of a tumor to therapy, and follow development of recurrences. However, as the means to phenotype cancer models from the initiation of disease, through tumor establishment, progression to an invasive malignancy, and metastasis to distant sites, there are unprecedented opportunities for invention, refinement, and application of imaging techniques. To expand imaging as a routine part of the characterization and translational application of mouse cancer models requires new methods for animal handling and data collection, developing novel imaging agents, mathematical modeling, and data reconstruction and visualization. Significant advances in this area of research will enable investigators to incorporate imaging in early detection and prevention applications of cancer models. As is true for other aspects of cancer modeling, the questions about human disease processes that can be tested by integrating innovative imaging strategies in mouse model design and application transcend the limitations of imaging as used in clinical settings. Rare, high penetrance genes account for only a small proportion of human cancers, which are regarded as complex traits. However, the very common genes of low penetrance that collectively contribute to human susceptibility are difficult to identify from population studies. Mouse models and normal inbred mouse strains are invaluable for finding low penetrance susceptibility genes and genes that modify aspects of disease progression or clinical course, and for exploring cancers as complex traits. Recent studies illustrate that it is feasible to use cancer models to identify general susceptibility genes for major epithelial cancers, as well as tissue-specific genetic modifiers of malignancies. It is also important to determine how genes or genetic loci identified with other complex traits, such as immune function, or chronic inflammatory diseases, obesity, and other traits that are low-level risk factors for cancer etiology, are involved in human malignancies. The expanding base of genomic information from mouse and human sequencing, increasingly well characterized normal inbred mouse strains, and an abundance of appropriate cancer models provide substantial opportunities for comparative human/mouse approaches to discover the genetic basis of human cancer susceptibility and interactions among genetic and environmental factors. However, although the associations among genes may be comparable between mouse and human, the mechanisms that underlie association of particular genes or loci with risk in human populations may differ from those in the mouse. It will be important to incorporate suitable study designs, statistical analyses, and data mining tools to integrate this aspect of mouse modeling with human translational science goals. The NCI anticipates that augmenting the mouse cancer modeling expertise of the MMHCC with a broader base of perspectives in the future will enable the Consortium to design and generate additional mouse cancer models and modeling strategies, invent new ways and employ existing methods to characterize the models much more fully for cross-comparisons to human cancer, substantially expand the repertoire of applications to many more aspects of human cancer research, and employ bioinformatics to an unprecedented degree to ensure full integration of human and mouse model cancer research. Objectives and Scope In the original RFA, the NCI invited applications from groups with the scientific and technical expertise "to derive mouse models, characterize them thoroughly, and validate them for various aspects of basic, developmental, and applied cancer research." The significant advances in the science of mouse cancer models and their increasing integration into translational cancer research, coupled with the accumulation of exceptional amounts of human and mouse cancer data for comparison, reinforces the need to augment the original scope of the MMHCC with expertise in new domains of science. In this RFA, the NCI encourages applications from groups with broad expertise that may include, but is not limited to: Mouse-related research, such as genetics, genetic engineering, biology, physiology, and phenotyping; application of cancer models to human basic, translational, clinical, and population science; application of computational, statistical sciences, mathematical modeling, and bioinformatics to integrate human and mouse cancer research; use of chemistry, genomics, proteomics, imaging, and image analysis to inform model design, characterization, and application; development of innovative technologies to support derivation, phenotyping, and translational applications of new or existing mouse cancer models. To implement the MMHCC, the NCI will select as components up to 18 new and competing renewal U01 applications, and up to 4 NIH intramural projects, each supporting a multi- disciplinary team. Each component will be a self-assembled team of investigators who contributes to the MMHCC effort a unique blend of complementary research experience. The NCI anticipates that an applicant team will incorporate the appropriate mix of expertise that team believes they need to achieve their own goals and to contribute substantially to achieving the overall MMHCC goals. Teams of investigators composed of researchers in NIH intramural laboratories may submit applications to be components of the MMHCC; however, they may not receive salary, equipment, supplies, or other remuneration from the extramural RFA set-aside funds for this program. An NIH intramural PI must obtain the approval of her/his NIH Institute Scientific or Division Director to allocate resources to the project, and must follow both the general application format instructions and the additional guidelines for NIH intramural project applications under "APPLICATION PROCEDURES". NIH intramural project applications will be reviewed and scored with the U01 applications. The NIH intramural projects selected by the NCI to be components of the MMHCC will participate in a manner that is analogous to the U01 awardees. There are many outstanding research questions and opportunities related to mouse cancer models that applicants to this RFA may propose in their programs. The following paragraphs are intended to illustrate, but certainly not to limit, the possibilities. o To reflect the natural history of human cancers in laboratory mice generally requires genetic engineering or other strategies to modify the mouse germline. Applicants are encouraged to consider whether the current mouse genetic engineering tools are adequate to enable future models to encompass more aspects of the biology of human cancers than do the present models. For example, mice that model or investigate the distinct and diverse roles of all of the component cell types of specific tissue microenvironments are under- represented in the current mouse cancer models. Such models may present a substantial challenge to derive, and are an important opportunity to incorporate what is known about developmental and normal adult biology of a specific tissue or organ context. Applicants are encouraged to consider if there are other biologic, genomic, or epigenetic phenomena or observations unique to cancer for which the present modeling approaches are inadequate, and to propose to modify the current techniques or to devise and test new ones. o There are some excellent examples of how well mouse cancer models apply to human translational cancer research, but the full range of potential applications is untapped. Applicants are encouraged to explore the translational uses for which models that reflect the natural history and clinical course of human cancers are appropriate. There are likely to be significant opportunities to propose novel strategies to address any gaps in model design to enlarge the scope of translational application. Widespread incorporation of imaging is also encouraged, because the potential for non- invasive approaches to observe disease processes, to understand cancer etiology, progression, metastasis, response to interventions, and recurrence, and to correlate image properties with histopathology and expression profiles is significant. o The starting point for many cancer models is what is documented about aberrations in crucial genes, pathways, or processes and their roles at particular stages in specific human malignancies. However, perhaps due to species differences, the equivalent mutation in a mouse gene may not produce a cancer model that resembles the human cancer associated with that mutant gene, although perturbations in other nodes of the same pathway or process may. Applicants are encouraged to consider whether there are approaches to model derivation in addition to those that employ known human tumor molecular signatures that will support discovery about human cancer etiology and progression. For example, there may be new strategies for short-term or permanent phenotype alteration (e.g., siRNA, anti-sense, drug-sensitive alleles, etc.) that can help to define which genes or pathways to manipulate, and there are likely to be bioinformatics or modeling tools that can be employed to refine the priorities about which pathways or processes to alter in a model. Applicants are encouraged to integrate information about key cell pathways and processes derived from research in other model systems into related data from mouse and human cancer studies. o One important use for mouse cancer models is for research related to cancer therapy. Applicants are encouraged to propose optimal ways to use cancer models to inform research on human cancer treatment. For example, there may be experimental approaches using mice that can guide clinicians in determining what are the most valuable assays to perform or information to collect from patients and patient specimens. Applicants are encouraged to consider the most important and pressing clinical questions for which use of preclinical cancer models are best suited, and to propose how to integrate cancer models into research to define and test interventions, to understand why clinical experience with particular agents is sub-optimal, and to increase the effectiveness of preclinical models. o There are important opportunities to apply mouse models to define the host and environmental determinants of cancer susceptibility and progression, as well as the genetic factors that influence response or resistance to therapy. There is ample evidence that quantitative traits in mice can inform studies of cancer risk in human populations. It is possible that the associations among the genes that define a quantitative trait in the mouse are true for human populations despite significant mechanistic differences between mouse and human. Applicants are encouraged to consider approaches to define and exploit mechanistic variation in association among cancer-related genes in human and mouse. It may be possible to apply both quantitative and qualitative approaches to analyze mouse models to identify and stratify human risk factors. Applicants are encouraged to consider approaches that better define the priorities for development of mouse cancer susceptibility models. In addition, there may be value in integrating analysis strategies used for gene association studies in mice with those used for human population research. There are doubtless many opportunities to propose new computational, statistical, and modeling tools. As with the previous RFA for the MMHCC, the NCI does not anticipate that the expertise in any single applicant group will encompass all, or be restricted to, the research areas cited above. The NCI intends this RFA as an opportunity for the cancer research community to propose innovative approaches and unique perspectives to the challenges of mouse cancer modeling and integration of models with human science. Applicant groups are not required to focus on a single disease site; however, groups should include any required experience if they propose to explore a broad range of malignancies. The NCI expects that the assembled MMHCC will encompass the necessary and relevant expertise to accomplish the overall goals of the program. The NCI will ensure that the goals of the Consortium reflect the highest priorities of the Institute. Because the MMHCC is an on-going activity, the NCI expects that new investigators included in the Consortium through funding from this RFA will participate in any MMHCC-related projects that are underway and are carried over from the previous project period. Each applicant group should provide evidence of institutional and on-going research resources that augment and sustain the research strengths of the team. Applicant institutions are encouraged to commit additional resources, or leverage existing ones, in support of any application from their institution. Applicants are encouraged to incorporate partners or collaborators from the private sector where their participation is appropriate. In structuring these partnerships or collaborations, applicants should take into account pre-existing intellectual property rights associated with the use of these models and make appropriate licensing arrangements. Applicants and their technology licensing offices are encouraged to seek assistance as needed from the NCI Technology Transfer Branch (http://www-otd.nci.nih.gov/) in determining whether arrangements are adequate. In assembling their teams, applicants are encouraged to consider the availability of research expertise, technologic innovations, and potential collaborations from NCI-funded networks and consortia. The Director's Challenge (http://dc.nci.nih.gov), SPORE (Specialized Programs of Research Excellence) programs (http://spores.nci.nih.gov), Early Detection Research Network (http://www3.cancer.gov/prevention/cbrg/edrn), Small Animal Imaging Resource Program (http://www3.cancer.gov/dip/sairp.htm), the Cancer Genetics Network (http://epi.grants.cancer.gov/CGN), the Cancer Family Registries programs (http://epi.grants.cancer.gov/CFR), and others are listed on the NCI website (http://cancer.gov/research_programs/extramural). U01 applicant groups may identify researchers who are intramural staff of NIH Institutes or Centers as potential collaborators or consultants. The intended roles and contributions that the intramural investigator might have in the project should be delineated in the application in APPLICATION PROCEDURES Section 3, "Internal and External Collaborations". However, for purposes of this RFA, no NIH intramural scientist may be a formal collaborator or consultant, commit time and effort to, or be a co-PI of, any U01 application. When the MMHCC is assembled from the component projects, if there are NIH intramural investigators whose expertise is identified in the funded U01 applications as desirable to achieve the applications' goals, the NIH intramural investigators, with approval of their Institutes' Scientific Directors, will collaborate with one or more of the MMHCC U01 components in specified roles, including time and effort. NIH intramural investigators who are designated in this manner to collaborate in the Consortium may not serve on the MMHCC Steering Committee. The participation of any NIH intramural scientist, including those on the Steering Committee who represent the NIH intramural project components of the MMHCC, is independent of, and unrelated to, the roles of the NCI Project Coordinator and NCI Program Director as described under "Cooperative Agreement Terms and Conditions of Award." The NCI anticipates that NIH intramural investigators will contribute substantially to the breadth of scientific and technical expertise of the MMHCC. MECHANISM OF SUPPORT This RFA will use NIH U01 award mechanism. Applicants are solely responsible for planning, directing, and executing the proposed project. The anticipated award date is April 01, 2004. The NIH U01 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 source of support for NIH intramural components will be from existing intramural resources. Extramural grant funds will not be expended to support the intramural components that are selected as part of the MMHCC, or extramural collaborations that are part of intramural applications. FUNDS AVAILABLE NCI intends to commit approximately $18,000,000 in FY2004 extramural funds to support up to 18 new and competing renewal U01 grants in response to this RFA. Any new or competing renewal applicant may request a project period of up to five years and a budget of total costs of $1,000,000 (including third party facility and administrative costs) in the first year; budgets for out-years may not exceed the usual incremental increase of 3%. Because the nature and scope of the proposed research will vary from application to application, the NCI anticipates that the size of each award may also vary. In addition, the NCI anticipates incorporating up to 4 NIH intramural projects as components of the Consortium. No funds from the amount set aside for this RFA will be used to support intramural projects. For further budget information pertaining specifically to NIH intramural applications, see the SUBMITTING AN APPLICATION section below regarding "Additional Instructions for NIH Intramural Project Applicants." Although the financial plans of NCI provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds for this purpose in fiscal year 2004, and the receipt of a sufficient number of meritorious applications. The anticipated award date is April 1, 2004. At the present time, the NCI has not determined whether or how this solicitation will be continued beyond the present RFA. 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 or foreign o Intramural components of the Institutes of the National Institutes of Health 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 her/his institution to develop an application for support. Individuals from under-represented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs. NIH intramural applicants must be designated by their Institutes as Principal Investigators; however, they may not receive salary, equipment, supplies, or other remuneration from the RFA set-aside funds for this program. An NIH intramural PI must obtain the approval of her/his NIH Institute Scientific Director to allocate resources to the project, and must follow both the general application format instructions and the additional guidelines for NIH intramural project applications under "APPLICATION PROCEDURES." An intramural applicant group may include extramural collaborators as subcontracts, but the resources to support any subcontract must be available from intramural sources and not from any set-aside funds for this RFA. SPECIAL REQUIREMENTS Cooperative Agreement Terms and Conditions of Award These special Terms of Award are in addition to and not in lieu of otherwise applicable OMB administrative guidelines, HHS Grant Administration Regulations at 45 CFR Parts 74 and 92, and other HHS, PHS, and NIH Grant Administration policy statements. (Part 92 applies when state and local governments are eligible to apply as a "domestic organization.") The administrative and funding instrument used for this program is a cooperative agreement (U01), an "assistance" mechanism (rather than an "acquisition" mechanism) in which substantial NCI scientific and/or programmatic involvement with the awardee is anticipated during performance of the activity. Under the cooperative agreement, the NCI 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. Consistent with this concept, the dominant role and prime responsibility for the activity resides with the awardee(s) for the project as a whole, although specific tasks and activities in carrying out the studies will be shared among the awardees and the NCI Project Coordinator. 1. Awardee Rights and Responsibilities o The PI of a U01 or NIH intramural project has primary authority and responsibility to define objectives and approaches, and to plan, conduct, analyze, and publish results, interpretations, and conclusions of studies conducted under this program. o The PI of a U01 or NIH intramural project will assume responsibility and accountability to the applicant organization officials and to the NCI for the performance and proper conduct of the research supported by the U01 or NIH intramural project in accordance with the terms and conditions of the award. o The PI and an additional senior investigator from each U01 or NIH intramural project serve as voting members of the MMHCC Steering Committee and are required to attend the twice-yearly Steering Committee meetings. o The PI of a U01 or NIH intramural project will be responsible for accepting and implementing the goals, priorities, procedures, and policies agreed upon by the Steering Committee. o The PI of a U01 or NIH intramural project will be responsible for close coordination and cooperation with the other components of the MMHCC and with NCI staff. o Awardees will retain custody of, and have primary rights to, the data developed under these awards, subject to Government rights of access consistent with what are the current HHS, PHS, and NIH policies throughout the length of awards under the auspices of this RFA. Awardees will be responsible for implementing the approved data sharing plan for their project. o The NCI anticipates that awardees under the auspices of this RFA will develop unique research resources. The policy of the NIH is to make available to the public the results and accomplishments of the activities that it funds. Awardees will be responsible for implementing the approved research resource sharing plan and intellectual property plan for their project. o The NCI reserves the right to require the transfer of appropriate mouse stocks, related reagents, and pertinent data that are generated as the result of participation in research supported under these awards to an eligible third party, in order to preserve the mouse models and data about them and/or to continue the research. Third parties supported under these awards must be informed of this right. o Awardees under the auspices of this RFA should obtain appropriate licenses for technologies that are necessary for the conduct of the proposed research. o Effective continuation of the MMHCC requires that any bioinformatics, computational, and statistical, data modeling, or data visualization projects that are funded as a result of this RFA are compatible with the on-going bioinformatics schema that is designed and implemented by the NCI Center for Bioinformatics (http://ncicb.nci.nih.gov). 2. NCI Staff Responsibilities The NCI Project Coordinator will have substantial scientific-programmatic involvement during conduct of this activity, through technical assistance, advice, and coordination beyond normal program stewardship for grants. o The NCI Project Coordinator will coordinate and facilitate the MMHCC programs, will attend and participate as a voting member in all meetings of the MMHCC Steering Committee, and will provide liaison between the Steering Committee, the MMHCC, and the NCI. o The NCI Project Coordinator, in cooperation with the NCI Center for Bioinformatics, will ensure that there are effective mechanisms to enable electronic communication among the MMHCC components, and between the MMHCC and the NCI. o The NCI Project Coordinator will assist the Steering Committee in developing and drafting operating policies and policies for dealing with recurring situations that require coordinated action. o The Director, NCI Center for Bioinformatics, will ensure that there are appropriate core services for the integration of mouse data emerging from the MMHCC with data from other NCI programs of human cancer research. Any bioinformatics activities funded on the individual U01 grants or NIH intramural projects will be required to be conducted coordinately with the activities of the NCI Center for Bioinformatics. An NCI Program Director will be responsible for the normal stewardship of the awards, including: o The NCI Program Director will review the scientific progress of individual U01 grants and NIH intramural projects, and review them for compliance with the operating policies developed by the Steering Committee. o The NCI Program Director may recommend withholding of support, suspension, or termination of a U01 award for lack of scientific progress or failure to adhere to policies established by the Steering Committee. o The NCI Program Director will transmit to the appropriate NIH Institute Scientific Director any recommendation from the Steering Committee concerning failure of an NIH intramural component of the MMHCC to adhere to policies established by the Steering Committee. The NCI Program Director may also serve as the NCI Project Coordinator. 3. Collaborative Responsibilities Steering Committee The NCI Project Coordinator and the Principal Investigators of the U01 grants and the NIH intramural projects that comprise the MMHCC will be responsible for forming a Steering Committee, the main governing board of the MMHCC, as defined below. An arbitration system, as detailed below, will be available to resolve disagreements between the NCI Project Coordinator and the members of the Steering Committee. o The Steering Committee will be composed of the Principal Investigator and another senior scientist from each MMHCC U01 or NIH intramural project, the NCI Project Coordinator, one representative from each extramural NCI Division, a representative from the NCI Center for Bioinformatics, and an MMHCC Consumer Liaison. Each member will have one vote. o The Steering Committee chairperson(s) may not be an NCI staff member(s). The Steering Committee may establish committees, as it deems appropriate; the NCI Project Coordinator will serve on committees, as s/he deems appropriate. o The Steering Committee may, when it deems it to be necessary, invite additional, non-voting scientific advisors to the meetings. The NCI reserves the right to augment the scientific or consumer expertise of the MMHCC when necessary. o The Steering Committee will meet twice every year, at locations selected by the Steering Committee in consultation with the NCI. The PI and another senior investigator from each U01 or NIH intramural project must attend every Steering Committee meeting. 4. Arbitration Any disagreement that may arise on scientific/programmatic matters (within the scope of the award), between award recipients and the NCI may be brought to arbitration. An arbitration panel will be composed of three members - one selected by the Steering Committee (with the NCI member not voting) or by the individual awardee in the event of an individual disagreement, a second member selected by NCI, and the third member selected by the two prior selected members. This special arbitration procedure in no way affects the awardee's right to appeal an adverse action that is otherwise appealable in accordance with the PHS regulations at 42 CFR Part 50, Subpart D and HHS regulation at 45 CFR Part 16. WHERE TO SEND INQUIRIES The NCI encourages inquiries concerning this RFA and welcomes the opportunity to answer questions from potential applicants. Inquiries fall into four areas: scientific/research, intellectual property, peer review, and financial or grants management issues: o Direct questions about scientific/research issues to: Cheryl L. Marks, Ph.D. National Cancer Institute Division of Cancer Biology Executive Plaza North, Room 5000 Bethesda, MD 20892-7380 Telephone: (301) 594-8778 FAX: (301) 496-8656 Email: marksc@mail.nih.gov Because of the multi-disciplinary scientific content of the RFA, potential applicants may be referred to additional NCI extramural program staff for further advice and clarification of the intent of the RFA, or for consultation regarding the design and implementation of bioinformatics projects that are intended to coordinate with those developed by the NCI Center for Bioinformatics. o Direct questions about intellectual property, technology licensing, data sharing, and research tools issues to: Wendy E. Patterson, Esq. National Cancer Institute Technology Transfer Branch Executive Plaza South, Suite 450 Bethesda, MD 20892-7182 Telephone: (301) 435-3110 FAX: (301) 402-2117 Email: pattersw@mail.nih.gov o Direct questions about peer review issues to: Referral Officer National Cancer Institute Division of Extramural Activities 6116 Executive Boulevard, Room 8041, MSC 8329 Bethesda, MD 20892-8329 Telephone: (301) 496-3428 FAX: (301) 402-0275 Email: ncidearefof@mail.nih.gov o Direct questions about financial or grants management matters to: William Wells Grants Administration Branch National Cancer Institute Executive Plaza South, Room 243 Bethesda, MD 20892 Telephone: (301) 496-8796 FAX: (301) 496-8601 Email: ww14j@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, email address, and telephone number of the Principal Investigator o Names of other key personnel o Names of all participating institutions and key personnel at those 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 a subsequent application, 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 February 19, 2003 by mail, FAX, or email to: Cheryl L. Marks, Ph.D. National Cancer Institute Division of Cancer Biology Executive Plaza North, Room 5000 Bethesda, MD 20892-7380 Telephone: (301) 594-8778 FAX: (301) 496-8656 Email: marksc@mail.nih.gov 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 http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 435-0714, Email: GrantsInfo@nih.gov. SUPPLEMENTAL INSTRUCTIONS: For U01 and NIH intramural applicants to this RFA, only the "Research Plan" section of the PHS 398 grant application is changed. The remainder of the PHS 398 application form remains the same. The "Research Plan", sections a. to d. (the subsequent sections e. to i. remain the same), is altered as follows: o The number of pages is increased from 25 to 35 pages; the 35-page limitation applies to the replacement for sections a. to d. only, and does not include the pages for sections e. to i. o The 35 pages should be apportioned as desired by the applicant to cover new sections 1. to 3. that replace sections a. to d. The three sections are: 1. Applicant Group; 2. Scope of Research; and, 3. Collaborations. Section 1 – Applicant Group. Applicants should briefly state the major objectives of the project and describe what expertise the group encompasses, as well as specialized or unique facilities, core resources, and services that are available to support these objectives. In this section, applicants should describe any ongoing grant-supported, institutional, or private sector resources that augment or complement resources for which funding from this RFA is sought. The roles of all key personnel, collaborators, and consultants who are associated with the application may be briefly described; however, the full extent of activities for each participant should be covered in Section 2. Section 2 – Scope of Research. For competing renewal applicants, Section 2 should have a description of the goals of the previous grant and include the scientific progress from the previous project period. For all applicants, depending on the composition and structure of the group, this section may be organized as distinct projects or as one integrated plan; in either case, the page limitation is the same. There is no requirement for applicants to use the format of an R01 application. Instead, applicants should define the major research questions and opportunities related to mouse cancer modeling that their group effort proposes to undertake, and the importance of those questions to human cancer research. Applicants should describe the approaches to be taken by the group in the aggregate or as inter-dependent projects, and should describe the rationale for approaches to be used or planned for development. Applicants are encouraged to use this section of the application to highlight how the diverse expertise of the group members contributes to the innovation of which the group is capable, the flexibility they possess to redirect research when scientific progress warrants it, and their ability to anticipate new directions, based on their individual experience and ability to contribute to a collective effort. The roles and expertise of all key personnel, collaborators, and consultants who are associated with the application should be documented; letters from collaborators and consultants should be included in Section i. of the research plan format as specified in the instructions for the Form 398 application. Section 3 – Collaborations. For competing renewal applications, applicants should describe their participation in the MMHCC and involvement in its activities, and the contribution of collaborations within, and outside, the Consortium to the successes of their projects. For new applications, applicants should describe the experience of their group in collaborative programs and activities. Specific issues related to cooperative agreements must also be addressed in the application as follows. o In Section 3, applicants must include their specific plans for responding to the "Cooperative Agreement Terms and Conditions of Award" section. Applicants should state their willingness to collaborate and share data freely with the other MMHCC components, to participate in planning and attending workshops and symposia, to serve on the Steering Committee and be bound by its decisions, and to be able and willing to share data and research resources with each other and the NCI. o At the end of Section 3, applicants must append a letter from the applicant institution describing how that institution intends to meet the NIH policies for sharing of data or why data sharing is not possible. In this regard, attention is drawn to the NIH Draft Statement on Sharing Research Data (http://grants1.nih.gov/grants/policy/data_sharing/index.htm). Investigators submitting an NIH application will be required to include a plan for data sharing or to state why data sharing is not possible. NIH has invited comments on the draft statement cited above, and, following consideration of public comments and appropriate revisions, it is expected that NIH will announce a new policy. o Applicants to this RFA must also append a research tools and resources sharing plan at the end of Section 3. Investigators conducting biomedical research frequently develop unique research resources. The policy of the NIH is to make available to the public the results and accomplishments of the activities that it funds. To address the interest in assuring that research resources are accessible, NIH requires applicants who respond to this RFA to submit a plan (1) for sharing the research resources generated through the grant, including engineered mice and genetic and phenotype data for all mouse strains; and (2) addressing how they will exercise intellectual property rights, should any be generated through this grant, while making such research resources available to the broader scientific community. The sharing of research resources plan and intellectual property plan must make unique research resources readily available for research purposes to qualified individuals within the scientific community in accordance with the NIH Grants Policy Statement (http://grants.nih.gov/grants/policy/nihgps/) and the Principles and Guidelines for Recipients of NIH Research Grants and Contracts on Obtaining and Disseminating Biomedical Research Resources: Final Notice, December 1999 (http://www.ott.nih.gov/policy/rt_guide_final.html and http://ott.od.nih.gov/NewPages/64FR72090.pdf ). These documents also define terms, parties, responsibilities, prescribe the order of disposition of rights, prescribe a chronology of reporting requirements, and delineate the basis for and extent of government actions to retain rights. Patent rights clauses may be found at 37 CFR Part 401.14 and are accessible from the Interagency Edison web page, http://www.iedison.gov. If applicant investigators plan to collaborate with third parties, the research tools sharing plan must explain how such collaborations will not restrict their ability to share research materials produced with PHS funding. o Awardees under the auspices of this RFA should obtain appropriate licenses for technologies that are necessary for the conduct of the proposed research so that the goals that are proposed in Section 2 of the "Research Plan" can be accomplished. A statement from the applicant institution regarding their intent to obtain any necessary licenses must be appended to Section 3. o The NCI reserves the right to require the transfer of appropriate mouse stocks, related reagents, and pertinent data that are generated as the result of participation in research supported under these awards to an eligible third party, in order to preserve the mouse models and data about them and/or to continue the research. Third parties supported under these awards must be informed of this right. A statement from the applicant institution to that effect must be appended to Section 3. o Applicants must budget for travel and per diem expenses for the semi-annual Steering Committee meetings. In all years, applicants must budget for two investigators, the principal investigator and another senior investigator, to attend two Steering Committee meetings. o In addition, applicants must budget for travel and per diem expenses for participation by at least five members of their group (other than the PI and a senior investigator) in either MMHCC Steering Committee meetings or other MMHCC-organized workshops and symposia. USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) application form must be affixed to the bottom of the face page of the application. Type the RFA number, CA-04-002 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, MOUSE MODELS OF HUMAN CANCERS CONSORTIUM, and number, RFA CA-04-002, 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: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf. SENDING AN APPLICATION TO THE NIH: For U01 applicants only (NIH intramural applicants must use the address in the Section below entitled "ADDITIONAL INSTRUCTIONS FOR NIH INTRAMURAL PROJECT APPLICANTS"), 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 be sent to: Referral Officer Division of Extramural Activities National Cancer Institute 6116 Executive Blvd., Room 8041, MSC-8329 Rockville, MD 20852 (express courier) Bethesda MD 20892-8329 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.) (http://grants.nih.gov/grants/guide/notice-files/NOT-CA-02-002.html) 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 http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-012.html. APPLICATION PROCESSING: Applications must be received by the application receipt date, March 19, 2003, listed in the heading of this RFA. If an application is received after March 19, 2003, 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. ADDITIONAL INSTRUCTIONS FOR NIH INTRAMURAL PROJECT APPLICANTS: NIH intramural project applicants must use the PHS 398 application form and the modified format and content described above with the following additional modifications. o On the Face Page, fill out only items 1., 2., 3. (leave item 3c. blank), 4., and 5. The remainder of the items should be left blank, AND THE APPLICATION MUST NOT BE SIGNED BY EITHER THE PI OR AN NIH INSTITUTE OFFICIAL. The RFA label must be affixed to the bottom of the Face Page, as described above in the section entitled "USING THE RFA LABEL". o Do not submit "Other Support", Checklist", "Personnel Report", or "Personal Data" pages. o The PI must obtain the approval of her/his NIH Institute Scientific Director for applying, for collaboration, for participating as a component of the MMHCC under the terms and conditions of the RFA, and for complying with the policies of the Steering Committee. A copy of that letter of approval must be provided as part of a cover letter, addressed to the NCI Referral Officer, for the application. o The budget pages should supply the time and effort for each project participant, but no other budget figures should be included. The resources available for the project and the research environment should be carefully described, but no budget figures should be included. The NIH Institute Scientific Director, as part of the letter of approval for participation, must verify that appropriate intramural resources will be allocated to the project described in the application if it merits funding, and provide assurance that the conduct of the project will comply with the PHS regulations for research involving human subjects (if applicable), with the PHS policy on vertebrate animal research, and with the PHS policies for data sharing and access to research tools. o Submit an unsigned, typewritten original of the application, and five photocopies to: Referral Officer Division of Extramural Activities National Cancer Institute 6116 Executive Blvd., Room 8041, MSC-8329 Rockville, MD 20852 (express courier) Bethesda MD 20892-8329 Do not send the application or any copies to the Center for Scientific Review. NIH intramural project applications must be received by March 19, 2003. If an application is received after that date, it will be returned to the applicant without review. PEER REVIEW PROCESS Upon receipt, U01 applications will be reviewed for completeness by the CSR and for responsiveness by NCI program staff. NIH intramural project applications will be reviewed for completeness by the NCI Division of Extramural Activities, and for responsiveness by NCI program staff. U01 and NIH intramural project applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group in accordance with the review criteria stated below. As part of the initial merit review, all applications: o will receive a written critique o may 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 that receive a priority score will undergo a second level review by the National Cancer Advisory Board at their September 2003 meeting. 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. (1) SIGNIFICANCE: Does your study address important problems in human cancer research that will benefit from innovation in cancer mouse modeling? Are there translational aspects of cancer research that will benefit from how you plan to apply the models? If the goals of your project are achieved, how will they support discovery in human cancer research or overcome challenges in human cancer research? What will be the effect of these studies on the concepts or methods that drive the field of cancer modeling and its integration with human cancer research? Is there evidence that your applicant group is capable of anticipating new directions in research and of channeling resources to new opportunities? (2) APPROACH: Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the goals of the project? Do you acknowledge potential problem areas and consider alternative tactics? (3) INNOVATION: Does your project employ novel concepts, approaches, methods, or combinations of expertise? Are the goals original and innovative? Does your project challenge existing paradigms, develop new methodologies or technologies, or provide unique perspectives on cancer research through derivation, in-depth characterization, or application of mouse cancer models? (4) INVESTIGATORS: Are you and your team appropriately trained and well suited to carry out this work? Is the work proposed appropriate to your experience as the principal investigator and to that of other researchers? To what extent does your group of investigators have the necessary complementary skills? Have collaborations been established or consultants identified to provide the appropriate depth and breadth of scientific expertise required for the project? Will your team of investigators contribute unique skills to the overall Consortium? (5) ENVIRONMENT: Does the scientific environment in which your work, and that of your group, will be conducted 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 in the applicant institution and all cooperating institutions? 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 SHARING OF DATA AND RESEARCH TOOLS: The adequacy of the proposed plan to share data or the rationale for not doing so. The appropriateness of the research tools sharing plan and the explanation of how third part collaborations will not restrict the ability to share research materials produced with PHS funding. o INTELLECTUAL PROPERTY: An appropriate statement that the applicant institution is willing to obtain appropriate licenses for technologies that are necessary for the conduct of the proposed research. o BUDGET: For U01 applications, the reasonableness of the proposed budget and the requested period of support in relation to the proposed research. For NIH intramural project applications, the commitment of effort and the adequacy of the resources and environment. o COLLABORATIONS: For competing renewal applications, the nature and extent of collaborations within and outside the MMHCC, participation in internal MMHCC activities, and contributions to the NCI efforts to establish and maintain cancer research infrastructure for the entire community. For new applicants, evidence of significant experience with collaborations within and outside the applicant institution. For all applicants, evidence of willingness to collaborate extensively and share information fully and to abide by the priorities and policies agreed upon by the Steering Committee. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: February 19, 2003 Application Receipt Date: March 19, 2003 Peer Review Date: June – July, 2003 Council Review: September, 2003 Earliest Anticipated Start Date: April 01, 2004 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 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 http://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/. Although the primary objective of this RFA is to derive mouse models for cancer research that will be analogous to human malignancies, there may be instances in which applicants must collect or use pathology specimens derived from human subjects, or clinical or epidemiological data from projects involving human subjects, to inform the design of the models or their characterization with respect to human cancer. In those instances, the NIH policies apply and must be addressed in the application. 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 http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this RFA 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. 93.396, 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 http://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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