RFA-CA-08-018: Integration of Mouse Models into Human Cancer Research (U01)

Part I Overview Information

Department of Health and Human Services

Participating Organizations
National Institutes of Health (NIH), (http://www.nih.gov)

Components of Participating Organizations
National Cancer Institute (NCI), (http://cancer.gov)

Title: Integration of Mouse Models into Human Cancer Research (U01)

Announcement Type
This is a reissue of RFA-CA-04-002.

Request For Applications (RFA) Number: RFA-CA-08-018

Catalog of Federal Domestic Assistance Numbers
93.393, 93.394, 93.395, 93.396, 93.399

Key Dates
Release Date: August 18, 2008
Letters of Intent Receipt Date: October 14, 2008
Application Receipt Date: November 14, 2008
Peer Review Date(s): February-March, 2009
Council Review Date: May 2009
Earliest Anticipated Start Date: July 2009
Additional Information To Be Available Date (Url Activation Date): Not Applicable
Expiration Date: November 15, 2008

Due Dates for E.O. 12372

Not Applicable

Additional Overview Content

Executive Summary

Purpose. This Funding Opportunity Announcement (FOA), issued by the National Cancer Institute (NCI), extends the NCI-Mouse Models of Human Cancers Consortium (NCI-MMHCC) for a third project period. The previous periods resulted in generation, validation, and utilization of many novel mouse cancer models. Having successfully attained the original specific program goals, the NCI-MMHCC is poised to enter the next stage that stresses the use of biologically relevant mouse models as effective tools for human research. The overall objective of the NCI-MMHCC is integration of mouse models into basic, translational, epidemiological, and clinical cancer research. Goal 1 of the NCI-MMHCC is to support individual research projects that promote innovation in use of mouse models to address crucial questions in human cancer research. All applicants who respond to this FOA must submit applications for regular research project awards that address Goal 1. To facilitate the overall research and integration goals, the NCI-MMHCC will also support up to four Science Leadership components to coordinate activities in defined scientific areas (”research clusters”) under Goal 2 “Science Leadership and Integration”. Goal 2 includes (a) coordinating intra-NCI-MMHCC projects in specific research clusters; (b) enhancing collaborations throughout the NCI-MMHCC and with NCI networks and consortia; and (c) expanding the NCI cancer models bioinformatics infrastructure and integrating it with human cancer bioinformatics. The Science Leadership components must be based on the science of appropriate research projects. Therefore, only applicants who submit research project applications may also submit separate applications for Science Leadership components to serve Goal 2. .
Mechanism of Support. This FOA utilizes the NIH Cooperative Agreement (U01) award mechanism for both regular research project applications and Science Leadership component applications.
Funds Available and Anticipated Number of Awards. The NCI expects to commit up to $19 million in FY2009 to support 14-16 U01 regular research project awards, and up to 4 Science Leadership component U01 awards.
Budget and Project Period. The total project period for applications submitted in response to this FOA may not exceed five years. The budget for a research project U01application may range (as appropriate for a given project) from $250,00 up to $850,000 Total Costs per year; applicants are encouraged to consider smaller budgets. The budget for a Science Leadership component U01 application may be up to $750,000 Total Costs per year.
Eligible Institutions/Organizations. Institutions/organizations listed in Section III, 1.A. are eligible to apply.
Eligible Project Directors/Principal Investigators (PDs/PIs). Individuals with the skills, knowledge, and resources necessary to carry out the proposed research are invited to work with their institution/organization 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 support.
Number of PDs/PIs. More than one PD/PI (i.e., multiple PDs/PIs), may be designated on the application.
Number of Applications. Applicants may submit more than one application, provided they are scientifically distinct.
Resubmissions. Resubmission applications are not permitted in response to this FOA.
Renewals. Renewal applications are permitted in response to this FOA
Special Date(s). This FOA uses non-standard due dates. See Receipt, Review and Anticipated Start Dates
Application Materials. See Section IV.1 for application materials.
Hearing Impaired. Telecommunications for the hearing impaired are available at: TTY 301-451-5936.

Table of Contents

Part I Overview Information

Part II Full Text of Announcement

Section I. Funding Opportunity Description
1. Research Objectives

Section II. Award Information
1. Mechanism(s) of Support
2. Funds Available

Section III. Eligibility Information
1. Eligible Applicants
    A. Eligible Institutions
    B. Eligible Individuals
2.Cost Sharing or Matching
3. Other - Special Eligibility Criteria

Section IV. Application and Submission Information
1. Address to Request Application Information
2. Content and Form of Application Submission
3. Submission Dates and Times
    A. Receipt, Review and Anticipated Start Dates
         1. Letter of Intent
    B. Sending an Application to the NIH
    C. Application Processing
   D. Application Assignment
4. Intergovernmental Review
5. Funding Restrictions
6. Other Submission Requirements and Information

Section V. Application Review Information
1. Criteria
2. Review and Selection Process
    A. Additional Review Criteria
    B. Additional Review Considerations
    C. Resource Sharing Plan(s)
3. Anticipated Announcement and Award Dates

Section VI. Award Administration Information
1. Award Notices
2. Administrative and National Policy Requirements
     A. Cooperative Agreement Terms and Conditions of Award
         1. Principal Investigator Rights and Responsibilities
        2. NIH Responsibilities
         3. Collaborative Responsibilities
         4. Arbitration Process
3. Reporting

Section VII. Agency Contact(s)
1. Scientific/Research Contact(s)
2. Peer Review Contact(s)
3. Financial/ Grants Management Contact(s)

Section VIII. Other Information - Required Federal Citations

Part II - Full Text of Announcement

Section I. Funding Opportunity Description

1. Research Objectives

Purpose

With this FOA, the National Cancer Institute (NCI) plans to extend for another five years an on-going program, the Mouse Models of Human Cancers Consortium (NCI-MMHCC). During the previous funding periods, the NCI-MMHCC successfully generated and validated many novel mouse cancer models. The NCI-MMHCC also successfully conducted research to explore the many opportunities of applying mouse models to inform human cancer research. Significant progress in both of these areas now allows the program to advance to the next stage, which is designed to capitalize on the broad application of biologically relevant mouse models as effective tools for human research. This FOA is designed to stimulate efforts on the integration of mouse models into basic, translational, epidemiological, and clinical cancer research. This overall objective is served by the following two main goals for the NCI-MMHCC.

Goal 1: Individual Research Projects - Integration of Mouse Models into Human Cancer Research. The principal goal of the NCI-MMHCC is research that focuses on high-risk innovations to transform how mouse models are used in human cancer research. Research projects proposed in response to this FOA should use mouse models to address crucial questions in human cancer genetics, basic discovery, translational, prevention, and clinical cancer research. Projects that propose only the development and validation of new mouse models, which were the original scientific goals of the NCI–MMHCC in 2000, will not be supported.

Goal 2: Science Leadership and Integration. To facilitate the research and integration goals, the NCI-MMHCC will support, in addition to the research projects that address Goal 1, up to four Science Leadership components to coordinate program activities in defined scientific areas (”research clusters”). The objectives of this goal are to (a) coordinate intra-NCI-MMHCC projects in specific research clusters; (b) foster collaborations throughout the NCI-MMHCC and with other NCI networks and consortia; and (c) enhance the existing NCI cancer models bioinformatics infrastructure and integrate it with relevant human bioinformatics systems in collaboration with the NCI Center for Biomedical Informatics and Information Technology, NCI CBIIT.

In line with two main goals, this FOA solicits two types of applications:

(i) All applicants responding to this FOA must submit applications for regular research project awards. ;

(ii) Separate applications for Science Leadership component awards may be submitted only by applicants who also submit regular U01 research project applications.

Background

In the decade since the NCI conceived the original rationale for the NCI-MMHCC and its structure, the landscape of cancer research has changed dramatically. Advances on all cancer science and technology fronts, including in the cancer animal modeling arena, provide the impetus for re-conceiving the science opportunities and structure of this program. Today’s mouse cancer models are demonstrably superior tools for human cancer discovery and application to research questions in clinical, translational, and epidemiological science. As the NCI-MMHCC program has matured, the science has expanded beyond cancer biology into susceptibility, prevention, and therapy studies.

Along with new scientific challenges, there are increasing needs for coordination of efforts of the NCI-MMHCC that go beyond the individual research projects. For the foreseeable future, the research of the NCI-MMHCC is expected to cluster into the following four main areas: (1) cancer susceptibility and resistance; (2) cancer biology; (3) preventive interventions; and (4) experimental therapeutics. These main “research clusters” are the logical organizing and outreach principles for the NCI-MMHCC. However, it is also important to encourage collaborations among the individual projects within the research clusters in the NCI-MMHCC, and foster cross-cutting interactions among all research clusters. The research clusters should also serve as the means to evolve additional links for the NCI-MMHCC to other NCI and NIH programs and the greater cancer research community.

Since 2000, the NCI-MMHCC has cooperated with the NCI CBIIT to evolve an informatics and enterprise vocabulary infrastructure that captures information about the biology, genetics, and pre-clinical use of mouse and other cancer models. This infrastructure is crucial to NCI’s intensified emphasis for the NCI-MMHCC on integration of model organisms into human cancer research.

Ad Goal 1: Objectives, Requirements, and Scope of Individual Research Project Applications (required application)

All applicants responding to this FOA must submit applications for individual research project awards adhering to the following guidelines. For the principal NCI-MMHCC goal in this FOA, the NCI encourages applicants to build upon the state-of-the-science mouse models, advances in knowledge about human cancer, other diseases, and normal human biology, and established and emerging technologies to confront the most challenging questions in cancer research that are addressable with mouse models. At present, one major challenge in cancer research is to model human cancers effectively so that the models are predictive of susceptibility, early malignancy, progression, metastasis, and treatment outcomes. The revolutions in “omics”, other types of molecular analyses, and data mining and modeling techniques permit rapid identification of the key individual parts of a particular human disease. However, knowledge of the parts alone is insufficient to achieve the important goal of predicting all of these outcomes. Mouse models of cancer are valuable because they enable researchers to explore cancers as dynamic systemic processes. Cancers are emerging, adaptive, complex systems; to understand their behaviors requires insight into these dynamic processes by systematic perturbation and detailed characterization of the changes from the molecular to the organism levels. The observed consequences of various perturbations—germline and somatic mutations, gene copy number changes, RNAi-based knock-down, sequence variation, small molecules, and other approaches—prompt development of additional or refined models to delve deeper into the underlying mechanisms. This iterative process, informed by, and informing, human cancer biology is a powerful way to use the tractable genetics of laboratory mice to further our understanding of the natural history and clinical course of human cancers.

The NCI expects that some of the outcomes of these cross-species approaches will be: substantial new knowledge about human cancer biology; new means to intervene in the initiation, progression, and clinical course of cancer; improved ability to detect emerging cancers at their earliest stages and as recurring or metastasizing tumors; and, novel biological attributes that define populations at risk of developing cancer, patients at risk of continued progression to invasive, metastatic disease, and patients who are likely or not likely to respond to preventive interventions or therapy.

Mouse Models. The NCI encourages applicants to use existing models whenever possible in projects proposed in response to this FOA. Projects focused solely on developing and validating new genetically engineered cancer models, which were the original scientific goals of the NCI–MMHCC in 2000, are no longer appropriate for this FOA. However, the NCI recognizes that there are research questions and emerging directions pertinent for the current objectives for which applicants should propose to develop new models or modeling approaches. Many cancer models, and strains to generate new models, are available from the NCI Mouse Repository, which is a member of the Federation of International Mouse Resources. This worldwide collaborative network among mouse repositories archives and provides to the research community strains of mice as cryo-preserved embryos and gametes, ES cell lines, and live breeding stock. In addition to the NCI Mouse Repository, the International Mouse Strain Resource and The Jackson Laboratory are sources of cancer models.

As in the two previous FOAs for the NCI-MMHCC, in this FOA the NCI strongly encourages applicants to propose high-risk, high-payoff research that they cannot pursue with traditional grant support. Mouse models are tools that enable researchers to explore questions about human cancer that are enabled by, or require, an intact experimental system. The approaches that applicants propose should explore how best to use mouse models and their genetics to understand human cancer susceptibility, biology, prevention, and therapy.

This FOA is a trans-NCI initiative that incorporates viewpoints about the needs of human cancer research from many perspectives. Some of the research opportunities that each of the NCI Divisions considers to be important are described below. These are but a few of the many research opportunities. By citing them, the NCI does not intend to circumscribe the topics that applicants may incorporate in their project plans, nor suggest that an application may address only one research area.

Cancer Biology: Increasingly, the research literature contains examples of how mouse cancer models accelerate discovery about human disease biology and genetics. Information from analyses of the natural history of the cancers that arise in mouse models discloses molecular signatures that classify human tumors, identifies the features of putative stem cell populations that inform identification of human stem cells, and exposes the role of the immune system in cancer etiology. Investigations of the models delineate the molecular and functional tissue changes in the earliest cancer lesions, permit testing of novel, exceptionally sensitive in vivo imaging, reveal the interplay among perturbed signal pathways and networks in cancer progression, expose the contributions of the tissue micro-environment to disease progression, and provide potential candidate biomarkers for early detection. However, the effective range of questions in human cancer biology that mouse model research has already uncovered is not exhaustive and many new directions for discovery are emerging.

A significant advantage of GEM models and inbred mouse strains is their normal immune system. Very sensitive functional imaging techniques, novel cell-specific tagging reagents, and nanotechnology enable investigation of how immune surveillance factors: (a) respond to initiation of cancer in different organs and tissues; (b) contribute to cancer regression or disease progression and metastasis; and (c) augment or complicate therapeutic outcomes. Numerous questions about tumor immunity and the contributions of specific immune cell types can be addressed in mouse models. The results will give valuable insight into how to exploit activities of the immune system for interventions. There is mounting evidence that microRNAs are important in cancer; research into their function in mouse models will expose how miRNAs contribute to the etiology and progression of human cancers. The resulting information can reveal novel biomarkers, diagnostic and prognostic tools, and new therapies. Genomic instability is a prominent feature of many human tumors; newer GEM cancer models also display this trait. Investigation of the models indicates that there is substantial variation in the tissue-specific features of instability in early lesions and in advanced tumors and metastases. Knowing how these differences affect outcomes will inform choices of preventive interventions and therapy. In addition to genomic instability, there are other interesting genome-level questions that can be approached in models, such as how copy number variants, large deletions and amplifications, changes in the epigenome, imprinting, and chromatin remodeling factor into cancer etiology. These alterations are potential markers of risk of disease progression or predictors of therapeutic response. The NCI supports a number of projects that primarily use in vitro systems to explore the altered activities of DNA repair enzyme complexes and their potential mechanisms in cancer. But the molecular mechanisms that underlie the local and systemic effects of radiation and other DNA-repair–stimulating exposures are under-studied in vivo. This affords an exceptional opportunity to forge collaborations across a number of research communities to enable in vivo exploration of cell-based hypotheses about DNA repair. An NCI-MMHCC–sponsored meeting focused on the numerous opportunities for studying the earliest manifestations of cancer in mouse models to provide insights into the molecular and tissue architecture and other features of similar human lesions. For a number of organ sites, the functional properties of early lesions in mice are informative of human early disease. Further research that employs a variety of tactics could yield potential candidate biomarkers for early detection or for development of novel medical diagnostic imaging techniques, and new prevention approaches. An increase in reactive oxygen species (ROS) often accompanies neoplastic transformation; ROS damages the mitochondrial genome, accelerating the somatic mutation rate of mitochondrial DNA. These mutations may be biomarkers of potential cancer development and tumor progression. Although mitochondrial mutations and dysfunction are hallmarks of cancer cells, whether mitochondrial genomic status affects nuclear genome stability or whether there is correlation between nuclear and mitochondrial DNA alterations during cancer progression is unknown. Metastases to distant organs are the unfortunate consequences of most late-stage human cancers. Many of the newer GEM models do exhibit metastases, particularly to lymph nodes and lungs, and occasionally to bone. Using novel imaging approaches in mouse models may expose the mechanisms of organ-specific metastasis, an important question for human tumor biology. The knowledge gained from studies on animals with metastatic tumors may expose aspects of the biology of early lesions that computational biologists will use to develop predictors of risk of progression. From human specimens and mouse models comes evidence for cancer and tumor stem cells. Cross-species comparisons will be invaluable to understand how cancer stem cells differ from normal tissue stem cells, how cancer and tumor stem cells contribute to disease etiology, and how, or if, tumor stem cells contribute to response or resistance to therapy or tumor recurrence.

Cancer Susceptibility and Resistance: Human tumor analyses implicate many altered genes as potentially causal for cancer etiology. Much of GEM modeling involves introducing various alterations to one or more genes in the mouse; these changes result in diseases that afford many opportunities to understand cause and effect relationships in cancer development for a small number of genes at a time. However, cancer genes act in concert and with many other cancer and normal genes, and interact with endogenous and exogenous factors to confer susceptibility or resistance to cancer development, and to disease progression. Gene and environmental factors also govern the ability of a tumor to invade locally and metastasize to distant organs, to respond to therapy, and to develop resistance to therapy and systemic toxicities. The wealth of well-characterized mouse strain resources—inbred, recombinant inbred, consomic, congenic, heterogeneous stock, and advanced intercross lines, and others—contributes exceptional opportunities to tackle the subtleties of interactions among genes and between genes and the environment that contribute to the natural history and clinical course of human cancers. Thus, it is crucial to apply the genetics of laboratory mice systematically to questions about human cancer genetics to improve understanding of the individual context in which the cancer process evolves and how that context influences outcomes.

Human population studies have exposed evidence of multi-factorial contributors to cancer risk; aging, chronic stress, inflammation, environmental exposures, lack of exercise, diet, smoking, alcohol abuse, asthma, obesity, infectious agents, and endocrine disorders are but a few examples. The mechanisms that underlie these observations are largely unknown, particularly at the organism level. The genetics of mouse models allow the exploration of the coordinate effects of these contributions at all levels of analysis: cell, tissue, organ, and organism. Novel bioinformatics approaches and multi-scale modeling are required to integrate the data about effects of perturbations across all levels; new data visualization tools will facilitate discovery based on this data integration. Many factors about which there is limited knowledge are postulated to govern the phenotypic manifestations of human cancer genetics. One example is epistasis, which is defined as interactions among genes. Studies in mouse models and other organisms are required to ascertain the extent to which epistasis contributes to human biological heterogeneity. To understand the complexity of multiple contributors to cancer risk will require the combined expertise of mouse and other model organism geneticists, medical and clinical geneticists, mathematical and computational modelers, statistical geneticists, genetic and molecular epidemiologists, and bioinformaticians. Systems genetics is one way to expose the combinations of which, and to what extent, genetic and environmental factors contribute to the variation of cancer susceptibility and resistance. At the present time, assessing changes in gene expression is the primary tool of systems genetics. Many new opportunities exist to develop and apply exceptionally sensitive chemistries, functional imaging, nanotechnology, “omics”, and other methods to define previously unknown hallmarks of susceptibility. Biological systems are emergent, adaptive systems; they are highly complex and often nonlinear, and studies on the individual parts often do not explain their overall behavior. Fuller knowledge of gene network structure, function, dynamics, and perturbations of the networks is required to understand the role of adaptation and other processes on susceptibility, and to explain the mechanisms of trans-generational observations. There is recent evidence that implicates mutations in the mitochondrial genome in cancer etiology. Somatic mitochondrial mutations are common in human cancers, and are useful as biomarkers for early detection of cancer. However, there are many unanswered questions about whether combining mitochondrial markers with nuclear genome markers to refine human risk assessment will improve sensitivity and specificity.

Preventive Interventions: No area of human cancer research provides more potential for effective integration of GEM models and their genetics than does cancer prevention. Many existing GEM models exhibit very slow disease progression, thereby providing exceptional test-beds for discovering the earliest changes that could be targets for early detection and interventions. Furthermore, the availability of the many reliable mouse genetic resources to decipher the key factors and their relative contributions to the natural history of cancer affords a wealth of opportunities to develop and test effective preventive interventions.

A major challenge in prevention research is determining who is at risk for developing cancer; attributing the degree of risk can help to define the individuals most likely to benefit from interventions. Advances in integrated use of mouse models and inbred mice to understand human cancer susceptibility can help to stratify populations for prevention trials. The background genetics of inbred strains can also help to expose effective intervention targets for specific populations. Mouse models with well-defined early lesions are suitable test-beds for varying schedules of interventions, an approach to evaluate efficacy and the need for chronic use of interventions. In vivo imaging and nanotechnology present important opportunities in evaluating efficacy while testing interventions, exposing new biomarkers for early detection, and delivering new highly targeted interventions. The genetics of mice are valuable to identify subtle local and systemic toxic responses that develop slowly, and to expose the underlying mechanisms that affect the safety of long-term use for specific patient sub-populations. The cell, tissue, and gene expression alterations in early stages of human cancer may be minor and provide only inconclusive evidence about the critical, cancer-promoting pathways. Mouse models that are engineered with subtle or adjustable perturbations in several pathways can be used to validate and credential specific pathways as potential targets for interventions. Functional imaging, or analysis of tissues and body fluids in mice can expose potential candidate biomarkers of pathway activation, surrogate endpoints, early evidence of efficacy or toxicity, and mechanisms of action. Cross-species comparisons of these candidates are important tools for human biomarker discovery.

Experimental Therapeutics: The value of GEM models for testing new therapeutic agents and their combinations with standard chemotherapy and examining the potential of specific early interventions is well established. The use of these newer models to inform the choice of agents and appropriate patients is an emerging approach that should improve outcomes. The use of mice as testing vehicles is an important element of translational and clinical research at the present time. As important as these endeavors and the information obtained from them are for the near term, they are insufficient for discovery and evolution of the next generation of therapies. Many additional strategies, for example those that employ the background genetics of mouse models, are required to understand tumor progression in an intact organism and to evolve safe, effective therapies.

Radiation and targeted chemotherapies invoke apoptosis and other known cell death mechanisms. However, there are inadequate molecular details about which of the possible mechanisms, or the balance among them, underlie response to most therapies. Although GEM models are used to test therapies, an in-depth appreciation of how to use GEM models most effectively to inform human clinical trials requires extensive and continuing collaborations among modelers, imaging scientists, and the clinical trials and prevention communities. The design of GEM models for experimental therapeutics also requires considerable input from many research communities. Mouse and medical geneticists can collaborate to define approaches that exploit mouse background genetics to understand drug response, recurrence, toxicity, and safety in humans. It is crucial to examine the differences between mice and humans to understand the mechanisms of species-specific absorption, distribution, metabolism, and excretion (ADME). To overcome some species differences, there are several tactics, including “humanizing” drug-metabolizing enzymes or grafting human immune system stem cells into immune-compromised mice as recipient animals for human tumor or cell line grafts. Another approach is to perform comparative systems analyses to select the most relevant genes or cell types that are the cause of differences in drug responses or disease pathogenesis. It is also essential to understand the relative contributions to metabolism of agents by liver and other tissue enzymes, and gut commensal bacteria. Another opportunity involves using mouse tumor models to decipher the nature and function of tumor stem cells as confounders of response to therapy or as the cells that lead to recurrent disease. Exceptional opportunities exist to develop and apply novel imaging methods to ask mechanistic questions based on emerging knowledge and to promote discovery. There are many small molecule and biological agents that target specific proteins implicated in tumor biology; their use alone and in combination with established cytotoxic or other targeted chemotherapy agents is the basis for many on-going clinical trials. However, to provide significant future clinical successes, it is critical to discover new approaches that advance cancer therapy beyond the modalities that are now available, are in the pipeline, or are under development.

Ad Goal 2: Objectives, Requirements, and Scope of NCI-MMHCC Science Leadership Applications (optional separate application).

Science Leadership awards will provide separate funding for the activities pertinent to Goal 2 in addition to support for an individual research project. Submitting an application for a Science Leadership award is optional. However, this option is available only to applicants submitting the required application for an individual research project.

Note: Submitting (or not submitting) an application for Science Leadership award will not affect in any way the evaluation of the corresponding application for an individual research project.

Applications for Science Leadership awards must adhere to the following guidelines.

The proposed Science Leadership components must be planned to integrate the efforts of the NCI-MMHCC in defined key research areas. These areas are expected to span cancer biology, cancer susceptibility and resistance, preventive interventions, and experimental therapeutics. The NCI-MMHCC will be organized as clusters of individual awarded research projects grouped by the appropriate key research areas . After the U01 research project awards and Science Leadership awards are funded, each research project awardee will affiliate with one or more research clusters that are coordinated by the successful Science Leadership awardees. Specific affiliations are expected to depend upon the research interests of the individual awardees and the nature of their research projects.

A. The Functions of Science Leadership and Integration Components. The basic coordinating roles of the NCI-MMHCC Science Leadership awards are expected to include:

(a) fostering collaborations among the U01 awardees who are affiliated with their research cluster;

(b) collaborating with the U01 awardees affiliated with a given Science Leadership component to delineate research resources or pilot projects that promote the cluster collaborations; and

The NCI-MMHCC Science Leadership U01 awards will also be focal points for outreach to the major research networks and consortia supported by the NCI and similar programs supported by other NIH Institutes. The proposed Science Leadership components are expected to take advantage of a range of productive collaborations with individual components of other NCI programs developed by individual NCI-MMHCC groups since the inception of the program. These linkages exemplify the variety of cross-cutting translational research opportunities on which the NCI can now capitalize. The NCI programs to which the NCI-MMHCC already links or that afford potential collaborations include the Specialized Programs of Research Excellence (SPOREs), the Early Detection Research Network (EDRN), the Integrative Cancer Biology Program (ICBP), the Tumor Microenvironment Network (TMEN), The Cancer Genome Atlas (TCGA), the Small Animal Imaging Resource Program (SAIRP), the Strategic Partnering to Evaluate Cancer Signatures (SPECS) Program, the Transdisciplinary Research on Energetics and Cancer Centers (TREC) program, the Centers of Cancer Nanotechnology Excellence (CCNEs), the Cancer Family Registries (CFRs), the Cancer Genetics Network (CGN), and others. The NCI website has additional links to the programs of, and resources from, all NCI Centers and Divisions.

B. Integrated Human/Model Organism Bioinformatics. Another area of activities for Science Leadership awardees will include the coordination of efforts to integrate bioinformatics systems. The NCI-MMHCC will continue to collaborate with the NCI Center for Biomedical Informatics and Information Technology (NCI CBIIT) and participate in the cancer Biomedical Informatics Grid (caBIG™) project. The collaboration of the NCI-MMHCC with the NCI CBIIT has already produced the eMICE Website, the Cancer Models Database, the Cancer Images Database, and the Cancer Electronic Laboratory Management Information Resource, which is a Laboratory Information Management System for housing data generated during preclinical testing of agents of present or potential use in the clinic. The intent is to enhance further the bioinformatics infrastructure that is vital for cross-species comparisons for basic, translational, clinical, and epidemiological cancer research. Applicants for NCI-MMHCC Science Leadership U01 awards must include dedicated support for bioinformatics in their budgets, as detailed in Section IV.2. Content and Form of Application Submission. Investigators responsible for the bioinformatics activities under the NCI-MMHCC Science Leadership U01 awards will collaborate with the NCI for continued development of the on-going NCI-MMHCC–NCI CBIIT and caBIG™ informatics projects. They will also collaborate with the NCI to coordinate the generation of any new information resources that are required to ensure the integration of animal model information with the corresponding data from human cancer research endeavors.

See Section VIII, Other Information - Required Federal Citations, for policies related to this announcement.

Section II. Award Information

1. Mechanism of Support

This funding opportunity will use the NIH Cooperative Agreement (U01) award mechanism. The Project Director/Principal Investigator (PD/PI) will be solely responsible for planning, directing, and executing the proposed project.

This FOA uses “Just-in-Time” information concepts. It also uses non-modular budget formats described in the PHS 398 application instructions (see https://grants.nih.gov/grants/funding/phs398/phs398.html).

This funding opportunity will use a cooperative agreement award mechanism. In the cooperative agreement mechanism, the Project Director/Principal Investigator (PD/PI) 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 VI. 2. Administrative Requirements, "Cooperative Agreement Terms and Conditions of Award". At this time, the NCI’s plans beyond this current funding opportunity are indefinite.

2. Funds Available

The National Cancer Institute (NCI) intends to commit approximately $19 million in FY2009 and approximately $95 million over five years to support 18 - 20 projects. There will be two types of U01 awards: 14-16 regular research project awards, and up to 4 Science Leadership component awards. Future year amounts will depend on annual appropriations. Although applicants for research U01 awards may request budgets up to $850,000 total costs per year, applications that request much lower budgets are also encouraged. Applicants who submit a research U01 application may also submit an NCI-MMHCC Science Leadership U01 application for a budget of up to $750,000 total costs. Applicants may request a project period of five years for both kinds of U01 applications.

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 funding opportunity are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications.

Facilities and administrative costs requested by consortium (sub-contract) participants are not included in the direct cost limitation, see NOT-OD-05-004.

NIH grants policies as described in the http://era.nih.gov/ElectronicReceipt/preparing.htm for instructions).

The decision of whether to apply for a grant with a single PD/PI or multiple PD/PIs is the responsibility of the investigators and applicant organizations, and should be determined by the scientific goals of the project. Applications for grants with multiple PD/PIs will require additional information, as outlined in the instructions below. The NIH review criteria for approach, investigators, and environment have been modified to accommodate applications involving either a single PD/PI or multiple PD/PIs. When considering multiple PD/PIs, please be aware that the structure and governance of the PD/PI leadership team as well as the knowledge, skills and experience of the individual PD/PIs will be factored into the assessment of the overall scientific merit of the application. Multiple PD/PIs on a project share the authority and responsibility for leading and directing the project, intellectually and logistically. Each PD/PI is responsible and accountable to the grantee organization, or, as appropriate, to a collaborating organization, for the proper conduct of the project or program, including the submission of required reports. For further information on multiple PD/PIs, please see https://grants.nih.gov/grants/multi_pi.

Applications Involving Federal Agencies

NIH Intramural investigators may be collaborators or consultants on applications submitted by extramural institutions. .

The requests involving federal agencies, including the NIH intramural program, will not include any salary and related fringe benefits for career, career conditional or other federal employees (civilian or uniformed service) with permanent appointments under existing position ceilings or any costs related to administrative or facilities support (equivalent to Facilities and Administrative costs).

In general, the budget requests will be limited to the incremental costs required for carrying out the proposed work. These costs may include salary for staff to be specifically hired under a temporary appointment for the project, consultant costs, equipment, supplies, travel, and other items typically listed under Other Expenses. While support for extramural collaborators may be requested in a separate grant application, funds can be requested for services by an external investigator or contractor as a subcontract/consortium including the applicable indirect (F&A costs) of the contractor/collaborating institution.

Justification must be provided for all requested support and for the Federal employees who will be committed to the project although no funds are requested in the application.

Applicants should indicate the number of person-months devoted to the project, even if no funds are requested for salary and fringe benefits.

2. Cost Sharing or Matching

This program does not require cost sharing as defined in the current NIH Grants Policy Statement.

3. Other-Special Eligibility Criteria

Applicants may not submit re-submission applications in response to this FOA.

Applicants may submit competing renewal applications for this FOA.

Applicants may submit more than one U01 individual research project application, provided each application is scientifically distinct.

Only applicants submitting applications for individual research projects may submit applications for Science Leadership awards.

Applicants may submit more than one U01 Science Leadership application, provided each application is scientifically distinct. In addition, such multiple Science Leadership U01 applications from the same institution will be expected to pertain to different “research clusters” as defined in Section II. Research Objectives.

Section IV. Application and Submission Information

1. Address to Request Application Information

The PHS 398 application instructions are available at https://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. Applicants must use the currently approved version of the PHS 398. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: GrantsInfo@nih.gov.

Telecommunications for the hearing impaired: TTY 301-451-5936.

2. Content and Form of Application Submission

Applications must be prepared using the most current PHS 398 research grant application instructions and forms. Applications must have a D&B Data Universal Numbering System (DUNS) number as the universal identifier when applying for Federal grants or cooperative agreements. The D&B number can be obtained by calling (866) 705-5711 or through the web site at http://www.dnb.com/us/. The D&B number should be entered on line 11 of the face page of the PHS 398 form.

The title and number of this funding opportunity must be typed in item (box) 2 only of the face page of the application form and the YES box must be checked.

Applicants must demonstrate in the application the ability to meet the Research Objectives in Section I of the FOA and to meet the investigator responsibilities described in Section VI.2.A Cooperative Agreement Terms and Conditions of Award.

Two types of applications may be submitted in response to this FOA:

U01 applications (required for all applicants) that address the research objectives of Goal 1 (also referred to as “U01 research project applications”); and
NCI-MMHCC Science Leadership U01 applications (optional) that address Goal 2, as described in Section I.1. Research Objectives.

Only applicants who submit regular applications for U01 research project awards may apply for NCI-MMHCC Science Leadership U01 awards. Both applications must be individually complete.

Organization of U01 Research Project Applications

For U01 research project applications submitted in response to this FOA, the standard PHS398 Research Plan (Items 2-5 as per Revision 11/07 of the PHS 398 Table of Contents, previously known as “Sections A-D”) is altered as follows:

The number of pages for the Research Plan is increased from 25 to 35. Applicants are encouraged to use the minimum number of pages necessary to describe the research plan clearly and succinctly. The 35 pages (or fewer, if possible) should be apportioned as desired by the applicants to cover new Sections 1 – 3 as outlined below.
Other items of the PHS398 Research Plan remain unmodified.

Section 1: Research Team and Environment. Applicants should describe the expertise of each key member of the research team as that person’s expertise relates to the research objectives. Applicants should also describe how the parent and collaborating institutional environments are strengths for the conduct of the research.

Section 2: Research Problem(s), Rationale(s), and Strategy(ies). In this section, applicants should detail the research questions on which they and their teams propose to focus. Applicants should describe the rationale, including any supporting evidence, for undertaking each research question as that question relates to human outcomes. Applicants should describe primary strategies, as well as alternative approaches.

Section 3: Progress Report/Preliminary Data. Competing renewal applicants must provide a brief progress report in this section and a list of all publications that are attributable to the previous funding support for the project. New and competing renewal applicants may provide preliminary data and relevant citations in this section.

In the budget for the U01 research application, applicants must budget for travel to the two semi-annual Steering Committee meetings that are mandatory for the two representatives from each U01. They also must budget for attendance by two more key personnel from the applicant group to attend either both Steering Committee meetings or one Steering Committee meeting and another NCI-MMHCC meeting annually.

Organization of NCI-MMHCC Science Leadership U01 Applications (optional)

For NCI-MMHCC Science Leadership U01 applications submitted in response to this FOA, the standard PHS 398 Research Plan (Items 2-5 as per Revision 11/07 of the PHS 398 Table of Contents, previously known as “Sections A-D”) is altered as follows:

The number of pages for the Research Plan is 25; applicants are encouraged to use the minimum number of pages necessary. The 25 pages (or fewer, if possible) should be apportioned as desired by applicants to cover new Sections 1 – 5 as outlined below.
Other items of the PHS398 Research Plan remain unmodified.

Section 1: Summary of the U01 Research Application. Applicants should briefly describe the research objectives of their U01 research applications and the expertise and experience of the leadership team of the U01 research application as the context for their ability to provide Science Leadership for the NCI-MMHCC in the research area specified.

Section 2: NCI-MMHCC Science Leadership Plan. Applicants should apply to provide science leadership for the NCI-MMHCC in one of four research clusters: Cancer Susceptibility and Resistance; Cancer Biology; Preventive Interventions; and Experimental Therapeutics. The Science Leadership plan should describe the applicants’ vision of what strategies they believe will provide science leadership for the NCI-MMHCC in the specified area. The plan should include information that relates the leadership strategies to potential positive outcomes for human health if the plan were implemented. In this section, applicants should describe the role of any key personnel who are not included in the U01 Research Application, and the environment of the applicant and collaborating institutions as contributors to the applicants’ ability to provide science leadership in a specific area.

Section 3: NCI-MMHCC Communication and Coordination. The Science Leadership U01 awardees will stimulate and coordinate the development of concepts for the NCI-MMHCC pilot studies, collaborative projects, and common resources with the NCI-MMHCC U01 groups that form their particular research cluster. The Science Leadership U01 awardees will cooperate with the NCI to coordinate communications within and among the NCI-MMHCC clusters. Therefore, the Science Leadership plan should describe possible strategies for how the Science Leadership U01 could facilitate communications among the NCI-MMHCC U01 groups that form the research cluster, and between that cluster and the other research clusters in the NCI-MMHCC. The plan should include brief descriptions of concepts for some possible NCI-MMHCC activities or projects that the applicants believe would significantly enhance the impact of mouse models research on human cancer research in the specified area. The plan should include brief descriptions of common resources for the NCI-MMHCC that the applicants believe would be necessary for advancing research in the specific research area. The plan should include brief descriptions of concepts for projects or activities or resources that the applicants believe would stimulate collaborations with other NCI-MMHCC research clusters.

Section 4: NCI-MMHCC Outreach. The Science Leadership U01 awardees will collaborate with the NCI to promote communications between the NCI-MMHCC and other programs of the NCI and the NIH and the greater cancer research community. The plan should briefly describe some activities that the applicants believe would facilitate the thorough exchange of ideas about what human research challenges would benefit substantially from integration of mouse cancer models and modeling. The plan should outline possible mechanisms to incorporate the viewpoints of the greater cancer research community into the NCI-MMHCC program, and to connect the NCI-MMHCC to other NCI and NIH programs. The plan should suggest some potential ways to promote the development of interdisciplinary research to integrate mouse modeling with human cancer research.

Section 5: NCI-MMHCC Pre-Clinical Models Informatics. The Science Leadership U01 awardees will collaborate with the NCI CBIIT to continue to evolve the caBIG™-compatible cancer model organism informatics infrastructure that the NCI-MMHCC initiated and developed during the previous two project periods. The plan should include information about the prior or planned participation by the applicant or collaborating institutions in the caBIG™ program, and describe the experience of the applicants in use of bioinformatics to support pre-clinical models or human research.

Although the PD/PI(s) of the NCI-MMHCC Science Leadership U01 team is/are expected to be the same person(s) as the PD/PI(s) of the U01 research award, the other key personnel identified in the Science Leadership U01 application need not be the same individuals as those who are key personnel in the U01 research award application. The ability to provide NCI-MMHCC Science Leadership in one of the four areas may result from unique capabilities or specific research programs at the applicant or collaborating institutions.

In the budget for the NCI-MMHCC Science Leadership U01, applicants must include support for bioinformatics personnel to ensure that the informatics for the NCI-MMHCC research clusters are coordinated with the caBIG™ program. Applicants may request support for administrative assistance to coordinate the regular interactions among the U01 groups in the research cluster with the NCI, and with the other three Science Leadership U01 awards. Applicants must budget for travel of the key members of the Science Leadership team to attend the two semi-annual meetings of the NCI-MMHCC Steering Committee. This is a separate requirement from the travel requirement of the U01 research application.

The NCI will restrict $250,000 Total Costs of the budget for each of the four Science Leadership U01 awards to support NCI-MMHCC pilot and collaborative projects and common resources as considered and recommended by the NCI-MMHCC Steering Committee and approved for funding by the NCI.

SPECIAL INSTRUCTIONS

Applications with Multiple PD/PIs

When multiple PD/PIs are proposed, use the Face Page-Continued page to provide items 3a – 3h for all PD/PIs. NIH requires one PD/PI be designated as the “contact PD/PI” for all communications between the PD/PIs and the agency. The contact PD/PI must meet all eligibility requirements for PD/PI status in the same way as other PD/PIs, but has no special roles or responsibilities within the project team beyond those mentioned above. The contact PD/PI may be changed during the project period. The contact PD/PI should be listed in block 3 of Form Page 1 (the Face Page), with all additional PD/PIs listed on Form Page 1-Continued. When inserting the name of the PD/PI in the header of each application page, use the name of the “Contact PD/PI, et.al.” The contact PD/PI must be from the applicant organization if PD/PIs are from more than one institution.

All individuals designated as PD/PI must be registered in the eRA Commons and must be assigned the PD/PI role in that system (other roles such as SO or IAR will not give the PD/PI the appropriate access to the application records). Each PD/PI must include their respective eRA Commons ID in the eRA Commons User Name field.

All projects proposing Multiple PD/PIs will be required to include a new section describing the leadership plan approach for the proposed project.

Multiple PD/PI Leadership Plan: For applications designating multiple PD/PIs, include section 14, entitled “Multiple PD/PI Leadership Plan”, in the Research Plan of the PHS 398 form. A rationale for choosing a multiple PD/PI approach should be described. The governance and organizational structure of the leadership team and the research project should be described, and should include communication plans, process for making decisions on scientific direction, and procedures for resolving conflicts. The roles and administrative, technical, and scientific responsibilities for the project or program should be delineated for the PD/PIs and other collaborators.

If budget allocation is planned, the distribution of resources to specific components of the project or the individual PD/PIs should be delineated in the Leadership Plan. In the event of an award, the requested allocations may be reflected in a footnote on the Notice of Award.

Additional information is available in the PHS 398 grant application instructions.

3. Submission Dates and Times

Applications must be received on or before the receipt date described below (Section IV.3.A). Submission times N/A.

3.A. Receipt, Review and Anticipated Start Dates
Letters of Intent Receipt Date: October 14, 2008
Application Receipt Date: November 14, 2008
Review Date: February-March 2009
Council Review Date(s): May 2009
Earliest Anticipated Start Date: July 2009

3.A.1. Letter of Intent

Prospective applicants are asked to submit a letter of intent that includes the following information:

Descriptive title of proposed research
Name, address, and telephone number of the PD/PI(s)Principal Investigator
Names of other key personnel
Participating institutions
Number and title of this funding opportunity

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 IC staff to estimate the potential review workload and plan the review.

The letter of intent is to be sent by the date listed in Section IV.3.A.

The letter of intent should be sent to:

Cheryl L. Marks, Ph.D.
Division of Cancer Biology
National Cancer Institute
6130 Executive Boulevard, Suite 5000
Bethesda, MD 20892-7387 (for U.S. Postal service Express or regular mail)
Rockville, MD 20852 (for non-USPS delivery)
Telephone: (301) 594-8778
Fax: (301) 496-8656
Email: marksc@mail.nih.gov

3.B. Sending an Application to the NIH

Applications must be prepared using the forms found in the PHS 398 instructions for preparing a research grant application. 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 (U.S. Postal Service Express or regular mail)
Bethesda, MD 20817 (for express/courier service; non-USPS service)

Personal deliveries of applications are no longer permitted (see https://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-040.html).

At the time of submission, two additional copies of the application and all copies of the appendix material must be sent to:

Referral Officer
National Cancer Institute
Division of Extramural Activities
6116 Executive Boulevard, Room 8041, MSC 8329
Bethesda, MD 20892-8329 (for U.S. Postal service Express or regular mail)
Rockville, MD 20852 (for non-USPS delivery)
Telephone: (301) 496-3428
FAX: (301) 402-0275
Email: ncirefgrp@mail.nih.gov

3.C. Application Processing

Applications must be received on or before the application receipt date described above (Section IV.3.A.). If an application is received after that date, the application may be delayed in the review process or not reviewed. Upon receipt, applications will be evaluated for completeness by the CSR and for responsiveness by the NCI. Incomplete and/or non-responsive applications will not be reviewed.

The NIH will not accept any application in response to this funding opportunity that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to a funding opportunity, it is to be prepared as a NEW application. That is, the application for the funding opportunity must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes from the previous unfunded version of the application.

Information on the status of an application should be checked by the Principal Investigator in the eRA Commons at: https://commons.era.nih.gov/commons/.

4. Intergovernmental Review

This initiative is not subject to intergovernmental review.

5. Funding Restrictions

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The Grants Policy Statement can be found at NIH Grants Policy Statement.

Pre-award costs are allowable. A grantee may, at its own risk and without NIH prior approval, incur obligations and expenditures to cover costs up to 90 days before the beginning date of the initial budget period of a new or renewal award if such costs: 1) are necessary to conduct the project, and 2) would be allowable under the grant, if awarded, without NIH prior approval. If specific expenditures would otherwise require prior approval, the grantee must obtain NIH approval before incurring the cost. NIH prior approval is required for any costs to be incurred more than 90 days before the beginning date of the initial budget period of a new or renewal award.

The incurrence of pre-award costs in anticipation of a competing or non-competing award imposes no obligation on NIH either to make the award or to increase the amount of the approved budget if an award is made for less than the amount anticipated and is inadequate to cover the pre-award costs incurred. NIH expects the grantee to be fully aware that pre-award costs result in borrowing against future support and that such borrowing must not impair the grantee's ability to accomplish the project objectives in the approved time frame or in any way adversely affect the conduct of the project (see NIH Grants Policy Statement https://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm.)

6. Other Submission Requirements and Information

For U01 applications solicited by this FOA, the PI/PD and another senior key person must attend two, two-day NCI-MMHCC Steering Committee meetings every year, and two more key personnel must attend both NCI-MMHCC Steering Committee meetings or one Steering Committee meeting and one other NCI-MMHCC meeting annually. Applicants should budget for these travel expenses. In addition, the key personnel listed in the NCI-MMHCC Science Leadership U01 applications must attend the two, two-day NCI-MMHCC Steering Committee meetings every year. Applicants should budget for these travel expenses.

Awardees must agree to the "Cooperative Agreement Terms and Conditions of Award" in Section VI.2.A. Award Administration Information.

Appendix Materials

All paper PHS 398 applications submitted must provide appendix material on CDs only. Include five identical CDs in the same package with the application. (See https://grants.nih.gov/grants/guide/notice-files/NOT-OD-08-031.html.)

Do not use the Appendix to circumvent the page limitations of the Research Plan component. An application that does not observe the required page limitations may be delayed in the review process.

Resource Sharing Plan(s)

NIH considers the sharing of unique research resources developed through NIH-sponsored research an important means to enhance the value of, and advance research. When resources have been developed with NIH funds and the associated research findings published or provided to NIH, it is important that they be made readily available for research purposes to qualified individuals within the scientific community. If the final data/resources are not amenable to sharing, this must be explained in Resource Sharing section of the application. See https://grants.nih.gov/grants/policy/data_sharing/data_sharing_faqs.htm.

(a) Data Sharing Plan: Regardless of the amount requested, investigators are expected to include a brief 1-paragraph description of how final research data will be shared, or explain why data-sharing is not possible. Applicants are encouraged to discuss data-sharing plans with their NIH program contact. See Data-Sharing Policy or https://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-032.html.

(b) Sharing Model Organisms: Regardless of the amount requested, all applications where the development of model organisms is anticipated are expected to include a description of a specific plan for sharing and distributing unique model organisms and related resources, or state appropriate reasons why such sharing is restricted or not possible. See Sharing Model Organisms Policy, and NIH Guide NOT-OD-04-042.

(c) Genome-Wide Association Studies (GWAS): Regardless of the amount requested, applicants seeking funding for a genome-wide association study are expected to provide a plan for submission of GWAS data to the NIH-designated GWAS data repository, or provide an appropriate explanation why submission to the repository is not possible. A genome-wide association study is defined as any study of genetic variation across the entire genome that is designed to identify genetic associations with observable traits (such as blood pressure or weight) or the presence or absence of a disease or condition. For further information see Policy for Sharing of Data Obtained in NIH Supported or Conducted Genome-Wide Association Studies, NIH Guide NOT-OD-07-088, and https://grants.nih.gov/grants/gwas/.

Note: Final research data that are described in the Data Sharing Plan should be shared, wherever possible, using the informatics resources of the caBIG™ program (cancer Biomedical Informatics Grid) or caBIG™-compatible informatics.

Section V. Application Review Information

1. Criteria

Only the review criteria described below will be considered in the review process.

2. Review and Selection Process

Applications that are complete and responsive to the FOA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NCI and in accordance with NIH peer review procedures (http://grants1.nih.gov/grants/peer/), using the review criteria stated below.

As part of the scientific peer review, all applications will:

Undergo a selection process in which only those applications deemed to have the highest scientific and technical merit, generally the top half of applications under review, will be discussed and assigned a priority score.
Receive a written critique.
Receive a second level of review by the National Cancer Advisory Board.

This award will include special terms and conditions that differ from the agency's usual terms and conditions. See also Section IV.5, “Funding Restrictions.”

The following will be considered in making funding decisions:

Scientific and technical merit of the proposed project as determined by peer review
Availability of funds
Relevance of the proposed project to program priorities
Compliance with resource sharing policies

The goals of NIH supported research are to advance our understanding of biological systems, to improve the control of disease, and to enhance health. In their written critiques, reviewers will be asked to comment on each of the following criteria in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that an application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a meritorious priority score.

The merits of the two types of applications solicited by this FOA (U01 research project applications and NCI-MMHCC Science Leadership U01 applications) will be assessed independently using the criteria listed below. Submitting (or not submitting) an application for Science Leadership award will not affect in any way the evaluation of the corresponding application for an individual research project.

Review Criteria for U01 Research Project Applications.

Significance: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge or clinical practice be advanced? What will be the effect of these studies on the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

In addition, specific to this FOA: Are the important problems in human cancer research that the application addresses highly likely to benefit from innovation in cancer mouse modeling? If the applicant group achieves the goals of the project, how will the outcomes advance discovery in human cancer research? Is the proposed use of mouse modeling likely to overcome important challenges in translational, clinical, or epidemiological cancer research? Is the research that the applicants propose designed to transform the concepts or approaches that drive the field of cancer modeling and its integration with human cancer research?

Approach: Are the conceptual or clinical framework, design, methods, and analyses adequately developed, well integrated, well reasoned, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? For applications designating multiple PD/PIs, is the leadership approach, including the designated roles and responsibilities, governance, and organizational structure, consistent with and justified by the aims of the project and the expertise of each of the PD/PIs?

In addition, specific to this FOA: Is there evidence that the applicant group is capable of forging new directions in research and of channeling resources to new opportunities?

Innovation: Is the project original and innovative? For example: Does the project challenge existing paradigms, or address an innovative hypothesis or critical barrier to progress in the field? Does the project develop or employ novel concepts, approaches, methodologies, tools, or technologies for this area?

In addition, specific to this FOA: Does the project provide unique perspectives on human cancer research through in-depth characterization or application of mouse cancer models? Is the proposed research an uncommon approach that will provide insights into human cancer that cannot be gleaned from direct study of human subjects?

Investigators: Are the PD/PI(s) and other key personnel appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers? Do the PD/PI(s) and investigative team bring complementary and integrated expertise to the project?

In addition, specific to this FOA: Does the applicant team take full advantage of complementary skills that are required to define a question or questions of critical importance for human cancer research and to apply or develop mouse models that are appropriate for the question(s)? Are there established collaborators or identified consultants who will provide the appropriate depth and breadth of input from the translational, clinical, or epidemiological research communities that are required for the project? Is the applicant team likely to contribute unique expertise or skills to the overall resources of the NCI-MMHCC?

Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed studies benefit from unique features of the scientific environment, or subject populations, or employ useful collaborative arrangements? Is there evidence of institutional support?

Review Criteria for NCI-MMHCC Science Leadership U01 Applications.

Significance: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge or clinical practice be advanced? What will be the effect of these studies on the concepts, methods, technologies, treatments, or preventative interventions that drive this field?

In addition, specific to this FOA: Does the research of the U01 submitted by the Science Leadership team provide a strong conceptual basis for the team to provide science leadership for the NCI-MMHCC in the specified area? Does the Science Leadership plan provide imaginative approaches to integrating mouse models and modeling into human cancer research in the specified research area? Are these approaches, if implemented, highly likely to have a positive impact on human health? Does the science leadership plan include experience with the NCI caBIG™ project and the pre-clinical models informatics developed in collaboration with NCI CBIIT? Are there significant informatics capabilities at the applicant or collaborating institutions that will benefit integrated human/mouse model research?

Approach: Are the conceptual or clinical framework, design, methods, and analyses adequately developed, well integrated, well reasoned, and appropriate to the aims of the project? Do the applicants acknowledge potential problem areas and consider alternative tactics? For applications designating multiple PD/PIs, is the leadership approach, including the designated roles and responsibilities, governance, and organizational structure, consistent with and justified by the aims of the project and the expertise of each of the PD/PIs?

In addition, specific to this FOA: Does the plan outline possible strategies for how the Science Leadership U01 could facilitate communications among the NCI-MMHCC U01 groups that form the research cluster, and between that cluster and the other research clusters in the NCI-MMHCC? Does the plan propose activities to promote and sustain collaborations among the NCI-MMHCC U01s in the specific research cluster? Are there proposals for how to support connections to the greater cancer research community and to other NCI and NIH programs in the specific research area? Does the plan contain some potential ways to promote the development of interdisciplinary research to integrate mouse modeling with human cancer research?

In addition, specific to this FOA: Are there novel concepts for how to incorporate new ideas continually from the translational, clinical, and epidemiological research communities into the activities of the NCI-MMHCC? Are the concepts for pilot and collaborative projects and resources highly original and appropriate for the specific area of science leadership?

In addition, specific to this FOA: Do the blend and unique expertise of the leadership team make them especially suited to provide the necessary vision for the NCI-MMHCC in the chosen area of research? Does the leadership team have experience in building collaborations across disciplines and coordinating large projects? Do the key personnel commit sufficient time and effort to the leadership activities?

Environment: Does the scientific environment(s) in which the work will be done contribute to the probability of success? Do the proposed studies benefit from unique features of the scientific environment, or subject populations, or employ useful collaborative arrangements? Is there evidence of institutional support?

In addition, specific to this FOA: Are there appropriate programs or capabilities at the applicant and collaborating institutions to promote and facilitate implementation of the vision of the Science Leadership U01? Will the capabilities or programs or resources at the applicant and collaborating institutions make unique contributions to the science leadership activities of the NCI-MMHCC?

2.A. Additional Review Criteria:

In addition to the above criteria, the following items will continue to be considered in the determination of scientific merit and the rating:

Protection of Human Subjects from Research Risk: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed (see the Research Plan section on Human Subjects in the PHS 398 instructions).

Inclusion of Women, Minorities and Children in Research: 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 will be assessed. Plans for the recruitment and retention of subjects will also be evaluated (see the Research Plan section on Human Subjects in the PHS 398 instructions).

Care and Use of Vertebrate Animals in Research: If vertebrate animals are to be used in the project, the five points described in the Vertebrate Animals section of the Research Plan will be assessed.

Biohazards: If materials or procedures are proposed that are potentially hazardous to research personnel and/or the environment, determine if the proposed protection is adequate.

2.B. Additional Review Considerations

Budget: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. The priority score should not be affected by the evaluation of the budget.

2.C. Resource Sharing Plan(s)

When relevant, reviewers will be instructed to comment on the reasonableness of the following Resource Sharing Plans, or the rationale for not sharing the following types of resources. However, reviewers will not factor the proposed resource sharing plan(s) into the determination of scientific merit or priority score, unless noted otherwise in the FOA. Program staff within the NCI will be responsible for monitoring the resource sharing.

Data Sharing Plan. [https://grants.nih.gov/grants/policy/data_sharing/data_sharing_guidance.htm]
Sharing Model Organisms. [https://grants.nih.gov/grants/guide/notice-files/NOT-OD-04-042.html]
Genome Wide Association Studies (GWAS). [https://grants.nih.gov/grants/guide/notice-files/NOT-OD-07-088.html]

3. Anticipated Announcement and Award Dates

Not Applicable

Section VI. Award Administration Information

1. Award Notices

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons.

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant. For details, applicants may refer to the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization. The NoA signed by the grants management officer is the authorizing document. Once all administrative and programmatic issues have been resolved, the NoA will be generated via email notification from the awarding component to the grantee business official (designated in item 12 on the Application Face Page). If a grantee is not email enabled, a hard copy of the Notice of Award will be mailed to the business official.

Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs. See Also Section IV.5. Funding Restrictions.

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General (https://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm) and Part II Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities (https://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm).http://db2dev.od.nih.gov/oer/programs/coop/index.htm)

The following Terms and Conditions will be incorporated into the award statement and will be provided to the Principal Investigator as well as to the appropriate institutional official, at the time of award.

2.A. Cooperative Agreement Terms and Conditions of Award

The following 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 (Part 92 is applicable when State and local Governments are eligible to apply), and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in, and otherwise working jointly with, the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

Throughout these Terms and Conditions of Award, the NCI Mouse Models of Human Cancers Consortium (NCI-MMHCC) refers to all individual NCI-MMHCC U01 Research Projects and Science Leadership U01 awardees. All the awardee institution(s), principal investigators (PI/PDs) and other key personnel must agree to collaborate on the goals of the NCI-MMHCC.

2. A.1. Awardees and Principal Investigator Rights and Responsibilities

The PD/PI(s) has (have) 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. The PD/PI(s) assume(s) responsibility and accountability to the applicant organization officials and to the NCI for the performance and proper conduct of the NCI-MMHCC research supported by the U01 in accordance with these terms and conditions of the award.

Specific rights and responsibilities will include the following:

Each U01 research project awardee must designate two representatives to serve as voting members on the NCI-MMHCC Steering Committee. Both are required to attend the semi-annual Steering Committee meetings. Both representatives could be PD/PIs (if the multiple PD/PIs option is used) or the PD/PI and another designated senior investigator. These representatives will collectively have two votes.
Each NCI-MMHCC Science Leadership U01 awardee must designate one representative to serve as a voting member of the NCI-MMHCC Steering Committee. The representative is required to attend the semi-annual Steering Committee meetings. The representative could be one of the PD/PIs (if the multiple PD/PIs option is used) or another designated senior investigator, but may not be the same person as either of the representatives for the related U01 research project award. This representative will have one vote.
All awardees must agree to abide by the decisions of the Steering Committee. The PD/PI(s) of the NCI-MMHCC U01 awards will be responsible for accepting and implementing the goals, priorities, procedures, and policies agreed upon by the Steering Committee.
The PD/PI(s) of the U01awards will be responsible for close coordination and cooperation with the other U01awardees of the research cluster(s) of the NCI-MMHCC with which they are affiliated, with the Science Leadership U01 awardee(s) of their research cluster(s), and with NCI staff.
The PD/PI(s) will be responsible for ensuring that any bioinformatics activities funded on the NCI-MMHCC research U01 awards and the NCI-MMHCC Science Leadership U01 awards are coordinated with the activities of the NCI CBIIT (http://ncicb.nci.nih.gov).
The PD/PI(s) will be responsible for providing an annual progress report as described below in 3. Reporting.
Awardees will retain custody of, and have primary rights to, the data and software 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 FOA.
Awardees may be required (upon request from the NCI) to transfer 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 stocks and data about them and/or to continue the research. Awardees must ensure that third parties supported under these awards are informed of this responsibility. The applicant institution must append to the “Research Plan” a statement to that effect.

In addition to these general responsibilities, PD/PIs on the NCI-MMHCC Science Leadership U01 Awards will be responsible for the following:

Stimulating collaborations among the U01 awards in their respective research clusters;
With the U01 awardees in their research cluster, developing a strategic plan for approaches to incorporate, from the wider cancer research community, new perspectives on human cancer research, additional expertise, and emerging technologies and methods that will enhance the research in their respective clusters;
Promoting and coordinating interactions with the other research clusters of the NCI-MMHCC;
Cooperating with the NCI to coordinate communications among the U01 awards within their research cluster;
Cooperating with the NCI to coordinate interactions with other NCI- and NIH-funded networks and consortia;
Ensuring that new bioinformatics solutions developed on the U01awards in their respective research clusters are compatible, and properly coordinated, with the NCI’s bioinformatics support of the NCI-MMHCC through the NCI CBIIT and caBIG™ project;
Promoting and coordinating the development of concepts for NCI-MMHCC pilot and collaborative projects and common resources in their respective research clusters;
Promoting and coordinating with the other research clusters the development of concepts for pilot and collaborative project and common resources for the NCI-MMHCC;
Proposing to the Steering Committee the concepts for NCI-MMHCC pilot and collaborative project and common resources developed in collaboration with the U01 awardees in their respective research clusters.
Providing an annual report on the Science Leadership activities in their NCI-MMHCC research cluster, as described below in Section VI. 3. Reporting.

2. A.2. NIH Responsibilities

A designated NCI Program Director acting as a Project Scientist will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below. Additional NCI staff members from the NCI Extramural Divisions and the NCI Center for Biomedical Informatics and Information Technology (NCI CBIIT) will have substantial involvement as Project Coordinators. The NCI Project Scientist and the NCI Project Coordinators will not attend peer review meetings of renewal (competing continuation) and/or supplemental applications. If such participation is essential, these individuals will seek NCI waiver according to the NCI procedures for management of conflict of interest.

Additionally, an NCI Program Director acting as the Program Official will be responsible for the normal scientific and programmatic stewardship of the awards and will be named in the award notice. Some Program Officials may have substantial programmatic involvement (as Project Scientists/Coordinators). In that case, the individual involved will not attend peer review meetings of renewal (competing continuation) and/or supplemental applications, or will seek NCI waiver.

The main NCI responsibilities pertinent to NCI-MMHCC awards include the following activities.

The NCI Project Scientist will be a voting member of the NCI-MMHCC Steering Committee. The NCI Project Coordinators representing each of the NCI Extramural Divisions and the NCI CBIIT will be non-voting members of the Steering Committee;
The NCI Project Scientist and the NCI Project Coordinators will serve as liaison between the Steering Committee, the NCI-MMHCC, the NCI CBIIT, and the NCI;
The NCI Project Scientist and the NCI Project Coordinators will provide technical assistance and advice to the NCI-MMHCC awardees and will facilitate and coordinate their interactions with other NCI staff members and other NCI and NIH programs as needed;
The NCI Project Scientist will assist the Steering Committee in developing and drafting operating policies;
The NCI Project Scientist will ensure that the recommendations of the Steering Committee regarding the concepts for NCI-MMHCC pilot and collaborative projects and resources are transmitted to the NCI leadership for consideration for funding from the set-aside funds in the NCI-MMHCC Science Leadership awards;
The NCI Project Scientist will notify the Steering Committee of the NCI decisions regarding the funding of NCI-MMHCC pilot and collaborative projects and resources;
The NCI Project Scientist and the NCI Project Coordinators will review the scientific progress of individual NCI-MMHCC U01 awards and the compliance of the awardees with the operating policies developed by the Steering Committee;
The NCI Project Scientist 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;
The NCI will ensure that there are appropriate core services available to the NCI-MMHCC U01 awardees to coordinate the activities of the research clusters and sub-committees and to integrate data emerging from the NCI-MMHCC projects with data from other NCI programs of human cancer research. The NCI Project Scientist and the NCI Project Coordinator from the NCI CBIIT will facilitate the latter process by coordinating the NCI-MMHCC efforts with the NCI CBIIT and the caBIG™ project.

2.A.3. Collaborative Responsibilities

The NCI Project Scientist and the PD/PIs of the NCI-MMHCC U01 awards will be responsible for forming a Steering Committee, the main governing board of the NCI-MMHCC, as defined below.

The Steering Committee will be composed of the following voting members: The two designated representatives of each NCI-MMHCC U01 research project awardee (who could include two PD/PIs, if the multiple PD/PI option is used, or the PD/PI and another senior scientist); the single designated representative of each NCI-MMHCC Science Leadership U01 awardee (who must be a different person from either of the representatives of the related U01 research project awardee); and, the NCI Project Scientist.
The Project Coordinators from each NCI Extramural Division and the NCI CBIIT will be non-voting members of the Steering Committee. One or more NCI-MMHCC patient advocates will also be included as non-voting members of the Steering Committee;
The Steering Committee chairperson(s) may not be an NCI representative. The Steering Committee may establish sub-committees, as it deems appropriate. The NCI Project Scientist will serve on sub-committees, as s/he deems appropriate. The NCI Project Coordinators from the NCI Extramural Divisions and the NCI CBIIT will serve on committees as they deem appropriate;
The Steering Committee may, when it deems it to be necessary, invite additional, non-voting science advisors to the meetings. The NCI reserves the right to propose such additional candidates to augment the research or patient advocate expertise of the NCI-MMHCC when necessary;
The Steering Committee will meet twice every year, at locations selected by the NCI in consultation with the Steering Committee;
The Steering Committee will consider the merit of the concepts for NCI-MMHCC pilot and collaborative projects and common resources developed within and among the research clusters, and recommend them to the NCI for funding from the set-aside funds in the Science Leadership U01s.

2.A.4. Arbitration Process

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to arbitration. An Arbitration Panel composed of three members will be convened: A designee of the Steering Committee chosen without NIH staff members voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special arbitration procedure in no way affects the awardee's right to appeal an adverse action that otherwise can be appealed in accordance with PHS regulations 42 CFR Part 50, Subpart D and HHS regulations 45 CFR Part 16.

3. Reporting

Awardees will be required to submit the Non-Competing Continuation Grant Progress Report (PHS 2590) annually and financial statements as required in the NIH Grants Policy Statement.

Reporting by U01 research awardees

In addition to the standard information about research accomplishments (as required by the PHS 2590 instructions, https://grants.nih.gov/grants/funding/2590/phs2590.doc#_Toc186430767, Section 2.2.6 “Progress Report Summary”), U01 research project awardees will be required to include in their PHS 2590 Reports information on:

Their collaborative activities within their research cluster(s) and with other NCI-MMHCC awardees;
Their participation in the NCI-MMHCC Steering Committee and other meetings; and
Their cooperative activities with the NCI.

The final Non-Competing Continuation Grant Progress Report for the project period must contain a list of all publications that result from the funding of the U01 research award.

Reporting by NCI-MMHCC Science Leadership U01 awardees

In Section “Progress Report Summary” of their PHS 2590 reports, NCI-MMHCC Science Leadership U01 awardees will be required to report on their efforts to:

Stimulate collaborations within their respective research clusters and promote and coordinate interactions with the other research clusters;
Cooperate with the NCI to coordinate communications within their research cluster,
Promote interactions with other NCI- and NIH-funded networks and consortia, and bioinformatics efforts;
Develop concepts for NCI-MMHCC pilot and collaborative projects and common resources in their respective research clusters and with the other research clusters; and,
Ensure that their clusters’ concepts are presented to the Steering Committee.

A final progress report, invention statement, and Financial Status Report are required when an award is relinquished, when a recipient changes institutions, or when an award is terminated.

Section VII. Agency Contacts

We encourage your inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues:

1. Scientific/Research Contacts:

Cheryl L. Marks, Ph.D.
Division of Cancer Biology
National Cancer Institute
6130 Executive Boulevard, Suite 5000
Bethesda, MD 20892-7387 (for U.S. Postal Service Express or regular mail)
Rockville, MD 20852 (for non-USPS delivery)
Telephone: (301) 594-8778
Fax: (301) 496-8656
Email: marksc@mail.nih.gov

2. Peer Review Contacts:

Referral Officer
National Cancer Institute
Division of Extramural Activities
6116 Executive Boulevard, Room 8041, MSC 8329
Bethesda, MD 20892-8329 (for U.S. Postal Service Express or regular mail)
Rockville, MD 20852 (for non-USPS delivery)
Telephone: (301) 496-3428
FAX: (301) 402-0275
Email: ncirefgrp@mail.nih.gov

3. Financial or Grants Management Contacts:

Crystal Wolfrey
Office of Grants Administration
National Cancer Institute
6120 Executive Boulevard, Room 2433, MSC 7150
Bethesda, MD 20892-7150 (For U.S. Postal Service Express or regular mail)
Rockville, MD 20852 (for non-USPS delivery)
Telephone: (301) 496-8634
FAX: (301)496-8601
Email: wolfrey@@mail.nih.gov

Section VIII. Other Information

Required Federal Citations

Use of Animals in Research:
Recipients of PHS support for activities involving live, vertebrate animals must comply with PHS Policy on Humane Care and Use of Laboratory Animals (https://grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf) as mandated by the Health Research Extension Act of 1985 (https://grants.nih.gov/grants/olaw/references/hrea1985.htm), and the USDA Animal Welfare Regulations (http://www.nal.usda.gov/awic/legislat/usdaleg1.htm) as applicable.

Human Subjects Protection:
Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained (http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm).

Data and Safety Monitoring Plan:
Data and safety monitoring is required for all types of clinical trials, including physiologic toxicity and dose-finding studies (phase I); efficacy studies (Phase II); efficacy, effectiveness and comparative trials (Phase III). Monitoring should be commensurate with risk. The establishment of data and safety monitoring boards (DSMBs) is required for multi-site clinical trials involving interventions that entail potential risks to the participants (NIH Policy for Data and Safety Monitoring, NIH Guide for Grants and Contracts, https://grants.nih.gov/grants/guide/notice-files/not98-084.html).

Sharing Research Data:
Investigators submitting an NIH application seeking $500,000 or more in direct costs in any single year are expected to include a plan for data sharing or state why this is not possible (https://grants.nih.gov/grants/policy/data_sharing).

Investigators should seek guidance from their institutions, on issues related to institutional policies and local IRB rules, as well as local, State and Federal laws and regulations, including the Privacy Rule. Reviewers will consider the data sharing plan but will not factor the plan into the determination of the scientific merit or the priority score.

Policy for Genome-Wide Association Studies (GWAS):
NIH is interested in advancing genome-wide association studies (GWAS) to identify common genetic factors that influence health and disease through a centralized GWAS data repository. For the purposes of this policy, a genome-wide association study is defined as any study of genetic variation across the entire human genome that is designed to identify genetic associations with observable traits (such as blood pressure or weight), or the presence or absence of a disease or condition. All applications, regardless of the amount requested, proposing a genome-wide association study are expected to provide a plan for submission of GWAS data to the NIH-designated GWAS data repository, or provide an appropriate explanation why submission to the repository is not possible. Data repository management (submission and access) is governed by the Policy for Sharing of Data Obtained in NIH Supported or Conducted Genome-Wide Association Studies, NIH Guide NOT-OD-07-088. For additional information, see https://grants.nih.gov/grants/gwas/

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 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 funding opportunity 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.

Sharing of Model Organisms:
NIH is committed to support efforts that encourage sharing of important research resources including the sharing of model organisms for biomedical research (see https://grants.nih.gov/grants/policy/model_organism/index.htm). At the same time the NIH recognizes the rights of grantees and contractors to elect and retain title to subject inventions developed with Federal funding pursuant to the Bayh Dole Act (see the NIH Grants Policy Statement https://grants.nih.gov/archive/archive/grants/policy/nihgps_2003/index.htm). All investigators submitting an NIH application or contract proposal, beginning with the October 1, 2004 receipt date, are expected to include in the application/proposal a description of a specific plan for sharing and distributing unique model organism research resources generated using NIH funding or state why such sharing is restricted or not possible. This will permit other researchers to benefit from the resources developed with public funding. The inclusion of a model organism sharing plan is not subject to a cost threshold in any year and is expected to be included in all applications where the development of model organisms is anticipated.

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 "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines is 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 Clinical Research:
The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all clinical research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them.

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 (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 applications for research involving human subjects and individuals designated as key personnel. The policy is available at https://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

Human Embryonic Stem Cells (hESC):
Criteria for federal funding of research on hESCs can be found at http://stemcells.nih.gov/index.asp 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 (http://escr.nih.gov). It is the responsibility of the applicant to provide in the project description and elsewhere in the application as appropriate, 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.

NIH Public Access Policy Requirement:
In accordance with the NIH Public Access Policy (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-08-033.html) investigators must submit or have submitted for them their final, peer-reviewed manuscripts that arise from NIH funds and are accepted for publication as of April 7, 2008 to PubMed Central (http://www.pubmedcentral.nih.gov/), to be made publicly available no later than 12 months after publication. As of May 27, 2008, investigators must include the PubMed Central reference number when citing an article in NIH applications, proposals, and progress reports that fall under the policy, and was authored or co-authored by the investigator or arose from the investigator’s NIH award. For more information, see the Public Access webpage at http://publicaccess.nih.gov/.

Standards for Privacy of Individually Identifiable Health Information:
The Department of Health and Human Services (DHHS) issued final modification to the "Standards for Privacy of Individually Identifiable Health Information", the "Privacy Rule", on August 14, 2002. The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights (OCR).

Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website (http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on "Am I a covered entity?" Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at https://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.

URLs in NIH Grant Applications or Appendices:
All applications and proposals for NIH funding must be self-contained within specified page limitations. For publications listed in the appendix and/or Progress report, internet addresses (URLs) must be used for publicly accessible on-line journal articles. Unless otherwise specified in this solicitation, Internet addresses (URLs) should not be used to provide any other information necessary for 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 FOA 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 at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372. Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at https://grants.nih.gov/grants/policy/policy.htm.

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.

Loan Repayment Programs:
NIH encourages applications for educational loan repayment from qualified health professionals who have made a commitment to pursue a research career involving clinical, pediatric, contraception, infertility, and health disparities related areas. The LRP is an important component of NIH's efforts to recruit and retain the next generation of researchers by providing the means for developing a research career unfettered by the burden of student loan debt. Note that an NIH grant is not required for eligibility and concurrent career award and LRP applications are encouraged. The periods of career award and LRP award may overlap providing the LRP recipient with the required commitment of time and effort, as LRP awardees must commit at least 50% of their time (at least 20 hours per week based on a 40 hour week) for two years to the research. For further information, please see: http://www.lrp.nih.gov.

	Office of Extramural Research (OER)			National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892			Department of Health and Human Services (HHS)
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