Participating Organization(s)	National Institutes of Health (NIH)
Components of Participating Organizations	Division of Program Coordination, Planning and Strategic Initiatives, Office of Research Infrastructure Programs (ORIP)
Funding Opportunity Title	Improvement of Animal Models for Stem Cell-Based Regenerative Medicine (R24)
Activity Code	R24 Resource-Related Research Projects
Announcement Type	New
Related Notices	July 3, 2013 - This PAR has been expired and reissued as PAR-13-252.
Funding Opportunity Announcement (FOA) Number	PAR-13-113
Companion Funding Opportunity	PAR-13-114, R01, Investigator Initiated Research Project Grants PAR-13-115, R21, Exploratory/Development Grants
Number of Applications	See Section III. 3. Additional Information on Eligibility.
Catalog of Federal Domestic Assistance (CFDA) Number(s)	93.351
Funding Opportunity Purpose	This FOA encourages Resource-Related Research Project Grant (R24) applications from institutions and organizations proposing research aimed at characterizing animal stem cells and improving existing and creating new animal models for human disease conditions. The intent of this initiative is to facilitate the use of stem cell-based therapies for regenerative medicine. The initiative focuses on the following areas: 1) comparative analysis of animal and human stem cells to provide information for selection of the most predictive and informative model systems; 2) development of new technologies for stem cell characterization and transplantation; and 3) improvement of animal disease models for stem cell-based therapeutic applications. Preference will be given to investigations that examine general principles involved in developing the most informative animal models for regenerative medicine, rather than focusing on a specific disease. However, investigations involving specific diseases can be used as proof of principle. In all cases, the potential results of investigations should be applicable to the interests of two or more of the NIH Institutes and Centers (ICs). Furthermore, investigations of a disease that predominantly relates to the interests of one NIH IC and peripherally relates to the interests of other NIH ICs are not appropriate for this FOA. The ultimate objective of these efforts should be to provide essential preclinical knowledge that can help inform future clinical investigations.

Posted Date	February 11, 2013
Letter of Intent Due Date(s)	Not Applicable
Application Due Date(s)	Standard dates apply
AIDS Application Due Date(s)	Not Applicable
Scientific Merit Review	Standard dates apply
Advisory Council Review	Standard dates apply
Earliest Start Date	Standard dates apply
Expiration Date	(Now Expired July 3, 2013 per issuance of PAR-13-252), Originally May 8, 2016
Due Dates for E.O. 12372	Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in the PHS 398 Application Guide except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. While some links are provided, applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

Looking ahead: NIH is committed to transitioning all grant programs to electronic submission using the SF424 Research and Related (R&R) format and is currently investigating solutions that will accommodate NIH’s multi-project programs. NIH will announce plans to transition the remaining programs in the NIH Guide to Grants and Contracts and on NIH’s Applying Electronically website.

Part 1. Overview Information
Part 2. Full Text of Announcement
Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

This FOA encourages Resource-Related Research Project Grant (R24) applications from institutions and organizations proposing research aimed at characterizing animal stem cells and improving existing and creating new animal models for human disease conditions. The Division of Comparative Medicine (DCM) in ORIP convened an NIH workshop in 2012 that addressed the current status of animal stem cell biology and made recommendations concerning improvements in technologies and applications of animal stem cells to regenerative medicine. The results of this workshop provide the basis for this FOA. The intent of this initiative is to facilitate the use of stem cell-based therapies for regenerative medicine. The initiative focuses on the following areas: 1) comparative analysis of animal and human stem cells to provide information for selection of the most predictive and informative model systems; 2) development of new technologies for stem cell characterization and transplantation; and 3) improvement of animal disease models for stem cell-based therapeutic applications.

Regenerative Medicine is the process of creating living, functional tissues to repair or replace tissue or organ function lost due to damage or congenital defects. Regenerative medicine has the potential to solve the problem of the shortage of organs available for donation. It also holds the promise of repairing or replacing damaged tissues and organs in the body by stimulating organs previously considered irreparable to heal themselves. The recent discovery of the reprogramming of adult cells to a pluripotent state provides opportunities to address a major problem of regenerative medicine, immune rejection of transplanted tissue. The ability to generate differentiated cells and tissues using cells from specific patients will facilitate individualized medicine and eventually will lead to specialized therapies. The field is moving toward translation to clinical practice and is becoming increasingly dependent on animal models and information regarding the potential therapeutic efficacy of new technologies. Generating the correct type and quantity of the specific cell types required for replacement therapy is a significant challenge, as are the problems associated with introducing these cells into the proper environment in vivo and overcoming immune reactions. Finding solutions to these problems will require extensive testing in experimental animal models.

Major advances have been made in the past several years in deriving pluripotent cells, such as embryonic stem cells (ESCs) and induced pluripotent cells (iPSCs) from both humans and animals. In parallel, other investigations have isolated and characterized multipotent somatic or adult stem cells from various tissues, including Mesenchymal Stem Cells (MSCs) and Germinal Stem Cells (GSCs). The discovery of mouse ESCs in 1981 revolutionized the field of developmental biology and provided new capability for genome manipulation and investigations of gene function. Isolation of human ESCs created new possibilities for the field of regenerative medicine. ES-like cells have been derived from a number of animal species, including rats, fish, cows, pigs and non-human primates. Many characteristics of animal ES-like cells, including surface markers, growth factor requirements, ability to differentiate and others can be quite different from human ESCs.

The field of stem cell research experienced a dramatic new direction with the isolation of iPSCs, derived by reprogramming human or mouse somatic cells to a pluripotent state. Several studies on various animal systems suggest that the basic pluripotency network appears to be conserved among different species, allowing derivation of iPSCs from a variety of animals.

MSCs, a type of somatic stem cell, were originally identified as a subpopulation of bone marrow cells with osteogenic potential. The properties of MSCs have been examined extensively over the past decade. Studies using animal models have shown promising results following MSC therapy for induced injury in the musculoskeletal, cardiovascular, digestive and nervous systems. In addition, many clinical trials have demonstrated the efficacy of MSC infusion for treating various human diseases. Given the wide range of tissue sources, the recognition of subpopulations with specific properties, and the frequent production of genomic alterations upon expansion in cell culture, extensive characterization of MSCs and development of improved techniques are required. Most importantly, there is relatively limited understanding of the normal biological functions of MSCs and the mechanisms by which they participate in tissue repair.

GSCs are another type of somatic stem cells of great interest for regenerative medicine. They are an essential component of reproductive biology. Genetic manipulation of GSCs provides a powerful tool for producing transgenic animals, for elucidating mechanisms underlying germ cell development and differentiation and for understanding the interactions between stem cells and their niche. Further development of the methods for unlimited production of GSCs (for producing either sperm or eggs) will impact the ability to investigate the molecular basis of germ cell differentiation and for treatment of infertility by transplantation. Numerous reports using animal and human GSCs have shown generation of pluripotent cells during in vitro cultivation, which potentially can solve a number of issues. However, it remains difficult to isolate, derive and maintain stable cultures of these cells from humans and model animal species. Furthermore, the mechanisms that determine the reprogramming of GSCs into pluripotent stem cells are not well understood and efficient methods for directed reprogramming of these still have to be developed.

Along with rodents, several other animal species are being developed as models for various studies in the field of regenerative medicine. Understanding the properties and capabilities of stem cells derived from animals such as rabbits, pigs, sheep, goats and monkeys will increase the potential for the use of the most appropriate systems for modeling particular human disease conditions or for other medical applications. Non-rodent species (often referred to as large animal models ) provide important advantages for transplantation studies, including large size, similarity to human physiology and pathology and longer life span, thus facilitating translation to studies in humans. The use of animal stem cells as a model for human cells in procedures related to regenerative medicine requires in-depth understanding of common regulatory pathways as well as species-specific properties and their impact on potential therapeutic applications.

Animal experiments have historically made a significant contribution to understanding human disease. However, animal studies need to be improved in order to better predict the efficacy of treatment strategies in clinical trials. Several possible causes of the disparity between the results of animal studies and clinical trials have been identified, including failure to acknowledge the limitations of animal models, inadequate animal data and conclusions from them, less than optimal disease models and overestimation of treatment efficacy due to the preferred publishing of positive results. These problems should be addressed in the design and execution of preclinical, animal-based studies involving stem-cell based therapies.

Research activities that are being sought to achieve the objectives of the program:

Projects supported by ORIP/DPCPSI under this FOA are intended to improve existing and create new animal models for regenerative medicine. Efficient use of animal models is facilitated by development of specific resources for characterizing, archiving and distributing animals as well as research tools, reagents and stem cell lines of utility to research on a variety of animal species. Development of an animal-based resource often requires preliminary work that is research-based. This resource-related research is often not hypothesis driven and cannot be addressed appropriately by NIH R01 or R21 grant applications. Accordingly, ORIP/DPCPSI supports R24 grants which have the following features:

• The grants support applied studies to characterize and develop new animal based resources or to improve existing resources.
• The grants support research projects that contribute to the knowledge of a model system, making the system more useful and accessible to the research community.
• In all cases, the potential results of investigations must be applicable to the interests of two or more of the NIH Institutes and Centers (ICs). Furthermore, investigations of a disease that predominantly relates to the interests of one NIH IC and peripherally relates to the interests of other NIH ICs are not appropriate for this FOA. Preference will be given to investigations that examine general principles involved in developing the most informative animal models for regenerative medicine, rather than focusing on a specific disease. However, investigations involving specific diseases can be used as proof of principle. An example of an inappropriate request is one exclusively involving an animal model of cancer. The ultimate objective of these efforts should be to provide essential preclinical knowledge that can help inform future clinical investigations.
• The particular emphasis of a specific R24 grant can vary in regard to the balance of research- versus resource-related activities, depending on the state of the art at the time. A R24 grant can be predominantly research based, if the research will plausibly lead to development of a resource, or can be predominantly aimed at final development or enhancement of a resource if most of the necessary research has already been accomplished.
• The R24 grant application must demonstrate a need for the resource (or resource to be developed) by the biomedical research community.
• Cost recovery is not required.

The following are examples of research topics of particular interest to ORIP. Other innovative projects are also encouraged:

• Characterization and enhancement of animal stem cells as model systems for human stem cells. Innovative approaches to understand the biology of stem cells from species widely used in regenerative medicine. Rat stem cells are of particular interest, taking into account current advances in isolation and characterization of stem cells from rats, the progress of the rat genome project and current advances in the ability to manipulate rat genes.
• Development and characterization of stable, well characterized pluripotent stem cell lines from large animal species, such as rabbits, dogs, pigs, sheep and monkeys. Development of stem cell lines from this type of animal model should be justified as having direct relevance to potential uses in the field of regenerative medicine. Creation of biomarkers, standard protocols, species-specific reagents, proteomics, transcriptomics and genetic tools to assist the use of these cells is also of interest.
• Comparative analysis of animal and human stem cells to define criteria that will assist in choosing the most appropriate animal species and stem cell type for a particular application.
• Redirection of existing or creation of new national centralized facilities with robust capacity to purify, characterize and store stem cells from large animal species for regenerative medicine applications, to maintain databases and make biomaterials available to the wide biomedical community as well as to develop and produce isogenic lines.
• Development of new techniques for: Guiding and verification of the accuracy of cell injection, tracking cell migration, evaluating off-target effects, and monitoring long-term integration and the phenotype and function of transplanted stem cells and their derivatives.
• Development of new approaches to: Understand and target the cell fate determining niche to improve extrinsic effects on stem cell function; increase cell survival and proper integration into the host environment; establish correct regulatory connections after cell-grafting experiments.
• Investigations of the therapeutic benefits of human and animal MSCs in animal models and mechanisms of their biological action. Improvement of methods for testing the efficacy and potency of MSCs in animals and for controlling the MSC secretome post-transplantation. Development of definitive markers for the multipotent state of the cells. Investigations of the cause of the high sensitivity of MSCs to the microenvironment. Standardization of culture conditions for scale up of production.
• Investigations of animal GSCs as models for understanding embryogenesis and organogenesis, stem-cell niche interactions and fate decisions. The focus should be on facilitating the application of GSCs for regenerative medicine, for example, exploring potential for generating pluripotent cells and for deriving genetically modified animal models, including the use of haploid cells for this purpose. Preference will be given to applications working with large animal models, such as rabbits, dogs, pigs, sheep and monkeys.
• Investigations to improve existing humanized animal models and create new ones. Preference will be given to studies involving species other than rodents. Of particular interest are advances in the reproducible and cost-effective generation of humanized chimeras, which is currently technically challenging. Development of humanized animals for in vivo generation of complex human tissues and organs using stem cells.
• Development of high throughput genetic and therapeutic screens to study stem cell biology and homeostasis in appropriate animal species, such as Drosophila and zebrafish.
• Improvement and distribution of the reagents, protocols, stem cell lines, vectors, genetically altered animal strains and disease models, suitable for such screening.
• Improvement of animal disease models for regenerative medicine, which will better emulate physiological, cellular and molecular manifestations seen in humans. Development of methods to increase the predictability of stem cell based treatments in regard to effectiveness, major complications, safety and off target effects. Demonstration of the functionality of specific stem cells or their derivatives and the effectiveness of achieving specific results in improved animal disease models.
• Investigations of mammalian stem cell reprograming and somatic cell transdifferentiation. Further development of approaches and protocols for manipulating cell fate using efficient and safe methods, including removable vectors and vector systems with temporal expression of transcription factors, RNA or small molecules. Investigations regarding how these modifications can be used to control the expansion and differentiation of resident progenitor cells for direct reprogramming in vivo.
• Development of animal models for effective and sustained gene therapy using ex-vivo engineered stem cells and their derivatives as well as endogenous stem cell populations to correct gene defects. Preference will be given to applications that provide general approaches for a broad array of uses. Applications should not be focused on therapy for specific diseases. However, a specific disease can be used as a proof of principal, if also applicable to other disease conditions. Improvement and investigations of the safety of newer technologies such as zinc finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs), allowing targeted approaches for the elimination of disease-causing mutations, as tested in animal models.
• Development of solutions to problems of stem cell therapy that have already been identified, such as: Heterogeneity of cell populations, genetic instability, high mutation rate during in vitro manipulations, epigenetic memory of differentiated iPSCs and immune responses induced after stem cell transplantation. Of particular interest is the development of functional assays and high-throughput techniques that will predict the potential immunogenicity of transplants and the tumorigenicity or metastatic potential of stem cell lines.
• Development of new methods or animal models to evaluate the safety of stem cell transplantation in animals, including studies of adsorption, distribution, metabolism, excretion and toxicity of stem cell-based therapeutic products. These models should take into account properties of the specific stem cell populations and should mimic the intended use of the cells in humans.
• Development of public databases that will contain information on: Reproducible experimental conditions; Cell lines and related biomaterials; Results of testing animal and human stem cells in animal models, and; Cross-species and unique phenotypes that will assist future biomedical scientists and medical practitioners in the selection of the most relevant pre-clinical model.

Funding Instrument	Grant: A support mechanism providing money, property, or both to an eligible entity to carry out an approved project or activity.
Application Types Allowed	New Renewal Resubmission Revision The OER Glossary and the PHS 398 Application Guide provide details on these application types.
Funds Available and Anticipated Number of Awards	The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications.
Award Budget	Application budgets are not limited, but need to reflect the actual needs of the proposed project.
Award Project Period	The scope of the proposed project should determine the project period. The maximum project period is 4 years.

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made in response to this FOA.

Higher Education Institutions

• Public/State Controlled Institutions of Higher Education
• Private Institutions of Higher Education

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

• Hispanic-serving Institutions
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions
• Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

• Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

• Small Businesses
• For-Profit Organizations (Other than Small Businesses)

Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)
• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations

Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are noteligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are not allowed.

Applicant organizations must complete the following registrations as described in the PHS 398 Application Guide to be eligible to apply for or receive an award. Applicants must have a valid Dun and Bradstreet Universal Numbering System (DUNS) number in order to begin each of the following registrations.

• System for Award Management (SAM) must maintain an active entity registration (formerly CCR registration), to be renewed at least annually. Use the Sam.gov Manage Entity function to manage your entity registrations. See the Grants Registration User Guide at SAM.gov for additional information.
• eRA Commons

All Program Directors/Principal Investigators (PD(s)/PI(s)) must also work with their institutional officials to register with the eRA Commons or ensure their existing eRA Commons account is affiliated with the eRA Commons account of the applicant organization.

All registrations must be completed by the application due date. Applicant organizations are strongly encouraged to start the registration process at least6 weeks prior to the application due date.

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the PHS 398 Application Guide.

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

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

NIH will not accept any application that is essentially the same as one already reviewed within the past thirty-seven months (as described in the NIH Grants Policy Statement), except for submission:

• To an RFA of an application that was submitted previously as an investigator-initiated application but not paid;
• Of an investigator-initiated application that was originally submitted to an RFA but not paid; or
• Of an application with a changed grant activity code.

Applicants are required to prepare applications according to the current PHS 398 application forms in accordance with the PHS 398 Application Guide.

It is critical that applicants follow the instructions in the PHS 398 Application Guide, except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

Applications must be prepared using the PHS 398 research grant application forms and 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)

At the time of submission, two additional paper copies ofthe application and all copies of the Appendix files must be sent to:

Sheri Hild, Ph.D.
Office of Scientific Review
National Center for Advancing Translational Sciences
6701 Democracy Blvd., Room 1063
Bethesda, MD 20892
Telephone: 301-435-0811
Fax: 301-480-3660
Email: sheri.hild@nih.gov

All page limitations described in the PHS 398 Application Guide and the Table of Page Limits must be followed.

The following section supplements the instructions found in the PHS398 Application Guide, and should be used for preparing an R24 application.

Face Page

All instructions in the PHS 398 Application Guide must be followed.

Description, Project/Performance Sites, Senior/Key Personnel, Other Significant Contributors, Human Embryonic Stem Cells

All instructions in the PHS 398 Application Guide must be followed.

Table of Contents

All instructions in the PHS 398 Application Guide must be followed.

Detailed Budget for Initial Budget Period

All instructions in the PHS 398 Application Guide must be followed.

Budget for Entire Proposed Period of Support

All instructions in the PHS 398 Application Guide must be followed.

Biographical Sketch

All instructions in the PHS 398 Application Guide must be followed.

Resources

All instructions in the PHS 398 Application Guide must be followed, with the following additional instructions:

If cell lines, reagents or other biomaterials are developed, the applicant must specify how duplicate storage facilities will be maintained so that these materials will not be lost in case of natural disaster. If new strains of animals are developed, the applicant must specify how germ plasm will be cryopreserved and stored in duplicate facilities.

Research Plan

All instructions in the PHS 398 Application Guide must be followed, with the following additional instructions:

Letters of Support: Letters of support are not required. However, applicants may include a maximum of 15 letters of support within the application. If letters of support are included they should directly address how the proposed R24 project will help develop or enhance an animal-based resource, as described in the Funding Opportunity Description section of this FOA.

Resource Sharing Plan:Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS)) as provided in the PHS 398 Application Guide, with the following modification:

• All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.

Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix (please note all format requirements) as described in the PHS 398 Application Guide.

Not Applicable.

Part I. Overview Information contains information about Key Dates.

Information on the process of receipt and determining if your application is considered on-time is described in detail in the PHS 398 Application Guide.

Applicants may track the status of the application in the eRA Commons, NIH’s electronic system for grants administration.

This initiative is not subject to intergovernmental review.

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

Pre-award costs are allowable only as described in the NIH Grants Policy Statement.

Applications must be postmarked on or before the due dates in Part I. Overview Information.

Upon receipt, applications will be evaluated for completeness by the Center for Scientific Review, NIH. Applications that are incomplete will not be reviewed.

Applicants requesting $500,000 or more in direct costs in any year (excluding consortium F&A) must contact NIH program staff at least 6 weeks before submitting the application and follow the Policy on the Acceptance for Review of Unsolicited Applications that Request $500,000 or More in Direct Costs as described in the PHS 398 Application Guide.

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-10-115.

Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).

Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

Significance

Does the project address an important problem or a critical barrier to progress in the field? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, or in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

Innovation

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed?

If the project involves clinical research, are the plans for 1) protection of human subjects from research risks, and 2) inclusion of minorities and members of both sexes/genders, as well as the inclusion of children, justified in terms of the scientific goals and research strategy proposed?

Does the application demonstrate a need for the resource by the biomedical community?"

Environment

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.

Protections for Human Subjects

For research that involves human subjects but does not involve one of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Human Subjects Protection and Inclusion Guidelines.

Inclusion of Women, Minorities, and Children

When the proposed project involves clinical research, the committee will evaluate the proposed plans for inclusion of minorities and members of both genders, as well as the inclusion of children. For additional information on review of the Inclusion section, please refer to the Human Subjects Protection and Inclusion Guidelines.

Vertebrate Animals

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following five points: 1) proposed use of the animals, and species, strains, ages, sex, and numbers to be used; 2) justifications for the use of animals and for the appropriateness of the species and numbers proposed; 3) adequacy of veterinary care; 4) procedures for limiting discomfort, distress, pain and injury to that which is unavoidable in the conduct of scientifically sound research including the use of analgesic, anesthetic, and tranquilizing drugs and/or comfortable restraining devices; and 5) methods of euthanasia and reason for selection if not consistent with the AVMA Guidelines on Euthanasia. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

Biohazards

Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.

Resubmissions

For Resubmissions, the committee will evaluate the application as now presented, taking into consideration the responses to comments from the previous scientific review group and changes made to the project.

Renewals

For Renewals, the committee will consider the progress made in the last funding period.

Revisions

For Revisions, the committee will consider the appropriateness of the proposed expansion of the scope of the project. If the Revision application relates to a specific line of investigation presented in the original application that was not recommended for approval by the committee, then the committee will consider whether the responses to comments from the previous scientific review group are adequate and whether substantial changes are clearly evident.

As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.

Applications from Foreign Organizations

Not Applicable.

Select Agent Research

Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Resource Sharing Plans

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: 1) Data Sharing Plan; 2) Sharing Model Organisms; and 3) Genome Wide Association Studies (GWAS).

Budget and Period of Support

Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by the National Center for Advancing Translational Sciences, in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

• May 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 an overall impact score.
• Will receive a written critique..

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center and will compete for available funds with all other recommended applications. Following initial peer review, recommended applications will receive a second level of review by the NIH Council of Councils. The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.

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.

Information regarding the disposition of applications is available in the NIH Grants Policy Statement.

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the grantee’s business official.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. 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.

Any application awarded in response to this FOA will be subject to the DUNS, SAM Registration, and Transparency Act requirements as noted on the Award Conditions and Information for NIH Grants website.

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 and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

Not Applicable

When multiple years are involved, awardees will be required to submit the Non-Competing Continuation Grant Progress Report (PHS 2590 or RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

A final progress report, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone 301-710-0267
TTY 301-451-5936
Email: GrantsInfo@nih.gov

eRA Commons Help Desk (Questions regarding eRA Commons registration, tracking application status, post submission issues)
Phone: 301-402-7469 or 866-504-9552 (Toll Free)
TTY: 301-451-5939
Email: commons@od.nih.gov

Oleg Mirochnitchenko, Ph.D.
Division of Comparative Medicine (DCM)
Office of Research Infrastructure Programs (ORIP)
Division of Program Coordination,
Planning, and Strategic Initiatives, (DPCPSI)
Telephone: 301- 435-0744
Email: oleg.mirochnitchenko@nih.gov

Sheri Hild, Ph.D.
Office of Scientific Review
National Center for Advancing Translational Sciences
National Institutes of Health
Telephone: 301- 435-0811
Email: sheri.hild@nih.gov

Ruthann Rand
Office of Grants Management
National Center for Advancing Translational Sciences
Office of Research Infrastructure Programs
Division of Program Coordination, Planning, and Strategic Initiatives
Telephone: 301- 451-4238
Email: randrudy@mail.nih.gov

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

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 Part 52 and 45 CFR Parts 74 and 92.