Purpose

This Funding Opportunity Announcement (FOA) will continue the Coordinating Center (CC) for a research consortium, the Intestinal Stem Cell Consortium (ISCC). In order to maximize scientific exchange and accelerate this area of research, information, data, biomaterials, models, reagents, resources and methods will be shared within the ISCC and with the research community. The consortium Coordinating Center will facilitate activities of the consortium and facilitate communication of research results, data and methods within the consortium and to the community. The Research Projects are being considered under RFA-DK-18-507 "Limited Competition for the Intestinal Stem Cell Consortium Research Projects (U01 Clinical Trial Not Allowed)."

Background

The absorptive and protective functions of the intestine depend in part on the intestinal epithelium. This epithelium is characterized by continual turnover, with cells lost at the surface (large intestine) or villi (small intestine) and replaced from progenitor cells in the crypts. These stem cells, influenced by other cells, extracellular factors and factors in the lumen, produce the multiple cell types necessary for healthy epithelial function and self-renew to continue to replenish the epithelium. However, in diseased or inflamed conditions, the epithelium may not be renewed at the pace needed to maintain a barrier against the potentially harmful contents of the digestive tract. The resulting exacerbation of inflammation is thought to contribute to the development and/or maintenance of inflammation-related conditions and diseases of the intestine. Thus, the ability of resident stem cells to heal and maintain the epithelial barrier, commensurate with the need resulting from epithelial cell loss, is essential to normal function of the intestine.

Intestinal stem cells (ISCs), residing in specialized compartments called the crypts of Lieberk hn, generate progenitor cells known as transit-amplifying cells, which reside above the ISCs within the crypts. These cells undergo several additional cell divisions as they migrate upward along the crypt axis and their progeny terminally differentiate into a variety of cell lineages including enterocytes, goblet, enteroendocrine, tuft and M cells. ISCs can support repopulation of the entire intestinal epithelium and mediate tissue repair upon injury.

The precise localization and identity of ISCs have been intensely debated. Historically, ISCs have been postulated to be either actively cycling crypt-based columnar cells (CBC) or quiescent label-retaining cells (LRC) residing at approximately the "+4" cell position from the crypt base. Recently, several molecular markers have been reported to identify ISCs, including Lgr5 for CBC cells interspersed between Paneth cells and Bmi1 for ISCs localized to the "+4" cell position in the upper region of small intestine crypts above the Paneth cell zone. Seminal studies defined Lgr5 as a molecular marker of CBC-class ISCs that persist long-term, self-renew, and give rise to all mature intestinal epithelial lineages. Bmi1+ cells appear to be quiescent ISCs residing in approximately the +4 cell position. These cells remain quiescent and act as a reserve population that can give rise to all intestinal cell lineages after tissue damage.

Control of proliferation, self-renewal, and lineage specification of the stem cells in the crypt are believed to be directed by an actively regulated process based on cell-cell and cell-stroma interactions. The ISC niche or microenvironment is composed of epithelial and underlying nonepithelial cells within the lamina propia populated by stromal, immune, endothelial, and neural cells that support paracrine and/or autocrine signaling. The ISC niche also comprises the extracellular matrix (ECM), a highly dynamic structure that continuously undergoes controlled remodeling, mediated by metalloproteinases that are responsible for ECM degradation. The ECM interacts with the different cells in the niche to regulate stem cell fate. Overall, the components of the niche tightly modulate Wnt, Notch, epidermal growth factor , bone morphogenic protein/ transforming growth factor-beta, and Hedgehog signaling pathways to maintain proliferation/differentiation balance. Intestinal epithelial self-renewal, differentiation, and barrier function reflect orchestration of these diverse signals, which support or antagonize each other in different contexts over relatively short distances. Despite the importance of the subepithelial niche, very little is known about its cellular compartments, the specific sources of crucial signals, or how molecular and cellular components are organized for optimal interactions with the epithelium during homeostatic and injured conditions. Any future intestinal stem cell-based therapy, be it humoral, direct ISC injection, or engineered gut segment transplantation, will require a deeper understanding of niche-ISC interactions. Considerable work needs to be done to more fully understand key niche players and their role in maintaining or healing the epithelium. Further work is needed on how this knowledge can best be used to develop therapies that will enhance epithelial repair, and allow for replacement or regeneration of intestinal segments.

Studies in these areas have been aided by a coordinated, collaborative effort established with the first 2 project periods of the ISCC. The ISCC website can be found at http://iscc.coh.org and describes ongoing studies to isolate and characterize intestinal stem cells, compare populations, and determine how their activity is controlled. This initiative began as a result of the NIDDK workshop on Local Influences on Health and Repair of Intestinal Epithelium held March 25-26, 2008. In addition, this research underpins multiple goals in the Research Plan of the National Commission on Digestive Diseases (http://www2.niddk.nih.gov/AboutNIDDK/CommitteesAndWorkingGroups/NCDD/FinalResearchPlanPosting.htm). While this announcement emphasizes stem cells of the small intestine, it is anticipated that the methods and research results from the supported ISCC projects will aid similar studies in other areas of the gastrointestinal tract and other organs.

Coordinating Center (CC) Objectives and Scope

The CC will be responsible for facilitating administration, study development and analysis; obtaining standardized resources; and data and information sharing within the ISCC, as well as data and information sharing with the research community. The continuation of the ISCC will likely provide new opportunities for investigators to collaborate on research and for the CC to develop new data analysis and interface functions. Thus, the CC must include scientific expertise appropriate to the research area of this FOA.

The CC project must include but is not limited to:

• Development and maintenance of means for ongoing, rapid exchange of information and discussion between members of the consortium.
• Development and maintenance of means to store, organize, manage and track access to data and resources generated by ISCC labs.
• Assistance with planning collaborative and shared protocols, including design of uniform data records.
• Assistance with statistical analysis for study design, sample size and data analysis for collaborative projects involving multiple ISCC labs.
• Coordination of the purchase of and distribution of common reagents or other resources for shared protocols and large collaborative projects. As needed above the CC-budgeted amount for such reagents, the CC should implement mechanisms for individual research projects to contribute to costs of common reagents.
• In partnership with the Steering Committee, lead development of policy documents, maintain and make accessible all ISCC documents, maintain records for actions by Committees, Subcommittees and Working Groups as established by policies of the Steering Committee.
• Synthesize a variety of information into a scientifically valid, readily usable, quality-controlled and actively maintained interface for the ISCC and research community.
• Coordination and administration of the activities and meetings (including conference calls) of the Steering Committee, Subcommittees, Working Groups, and External Consultants.
• Generation and maintenance of minutes from meetings of the Steering Committee and Subcommittees as approved by the Chairs and membership of those committees.
• Web-based dissemination of information on availability and means to access validated resources generated by the research projects (to include models, biomaterials, resources and reagents). Note: research projects are responsible for sharing models, biomaterials, resources and reagents with other investigators once they are validated under policies implemented by the Steering Committee. This can be done through the individual laboratories or through depositing the materials in an appropriate resource facility.
• Compilation of validated methods developed through research projects and pilot projects to make them electronically accessible to the ISCC and the research community.
• Coordination, as needed, of an interface with other NIH-supported consortia to benefit both the ISCC and other consortia through sharing of information and expertise.
  

Activities of the CC will be undertaken with input from, and through cooperation with, the Steering Committee and with advice from the External Consultants. It is expected that the CC will make necessary adjustments to accommodate changes to research projects, new collaborations and new research needs as research advances.

Organization of the ISCC

The ISCC will consist of the following components: the NIH, research projects, a Coordinating Center (CC), a Steering Committee and its Subcommittees, External Consultants, Working Groups and other committees as needed.

The NIDDK will be responsible for organizing and providing support for the ISCC and will be involved substantially with the awardees as a "partner" consistent with the Cooperative Agreement mechanism. Designated NIDDK Program Officials will provide programmatic oversight, and will monitor progress and adherence to NIH policies. An NIDDK Project Scientist will also be designated and will have one vote on the Steering Committee. The NIDDK will appoint the Chairperson of the Steering Committee, and the External Consultants.

Steering Committee

A network of synergistic projects will be established through this program to enable multiple, but coordinated, approaches to advance this area of research. The Consortium will be governed by a Steering Committee to coordinate and facilitate research activities for the overall program and to ensure synergy and efficiency. In addition, the Steering Committee will determine policies and implement processes for quality assurance of any data and information disseminated through public resources or activities of the CC. The Steering Committee will also be responsible for establishing a process for recommendation of pilot projects for consideration for funding consistent with expectations set forth in this announcement . The Program Directors/Principal Investigators (PDs/PIs) (or the Contact PD/PI, in the case of Multiple PDs/PIs grants) from all awarded U01 cooperative agreements (research projects and CC) will be members of the Steering Committee. In the case of projects with multiple PDs/PIs, the designation of the member, Contact PD/PI, must be a part of the Multiple PD/PI Leadership Plan.

ISCC members will cooperate within the Consortium to share resources, materials, models, methods, information and data to facilitate progress. All research groups will share responsibility for program development and resource coordination through the ISCC Steering Committee that will be established upon award of the grants. When appropriate, and in accordance with NIH policies (https://grants.nih.gov/grants/policy/data_sharing and https://grants.nih.gov/grants/intell-property_64FR72090.pdf), U01 awardees will be expected to collaborate; share novel reagents, biomaterials, methods, models and resources; and share both positive and negative results that would help guide the research activities of other ISCC members. The NIDDK, in concert with the ISCC Steering Committee, will have the option to redirect research activities within the ISCC grants if it is considered beneficial to the overall program.

During the course of the funding period, knowledge and technologies will likely improve, and the rate of progress and focus of work supported by the cooperative agreement may change. It is expected that the PDs/PIs, in consultation with NIH Program staff and the Steering Committee, will make necessary adjustments to accommodate the changing research environment, to remain focused on appropriate goals, to maintain excellent coordination with the other projects to avoid overlaps and competition within the Consortium, and to incorporate new research advances.

Bi-annual Meetings of the ISCC Steering Committee

Members of the Steering Committee must participate in person in an initial meeting soon after award, as well as meetings to be held at least bi-annually thereafter. Meetings are expected to be 1-2 days long. In addition, Subcommittees and Working Groups of the Steering Committee may be established and require participation by the members through in-person, electronic, or teleconference meetings as appropriate. Steering Committee meetings will be organized and administered by the CC in order to determine the final coordinated research projects to be conducted by the research grantees; determine the administrative and scientific needs to be fulfilled by the CC in coordination with the final research projects; share both positive and negative results; share materials including reagents and techniques; evaluate progress; and identify new research opportunities. At the initial meeting, and thereafter as needed, the Steering Committee members will develop policies for confidentiality, what information and materials will be shared, when they will be shared, and how they will be shared within the ISCC and with the research community. All participants will be obligated to abide by the policies adopted by majority vote of the Steering Committee. The CC is responsible for providing and maintaining a record of minutes of the meetings, which will be approved by the Steering Committee Chair and Committee membership. The CC budget should include costs to arrange the Steering Committee meetings, costs of travel for External Consultants, and costs to generate minutes. Any Subcommittee and conference call meetings will be similarly documented by the CC. The External Consultants will meet approximately yearly with the Steering Committee.

External Consultants

The NIDDK will appoint 3-5 External Consultants to meet with the Steering Committee. This group will be updated on progress and give feedback to the Steering Committee and NIH on adjustments and future directions for the ISCC research projects and CC. The CC will support costs for consultants to meet once yearly with the Steering Committee.

1. Eligible Applicants

Applicant organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• System for Award Management (SAM) (formerly CCR) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
  • NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
• eRA Commons - Applicants must have an active DUNS number and SAM registration in order to complete the eRA Commons registration. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

Program Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

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 SF424 (R&R) Application Guide.

2. Cost Sharing

3. Additional Information on Eligibility

Number of Applications

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101)

1. Requesting an Application Package

Buttons to access the online ASSIST system or to download application forms are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission

For information on Application Submission and Receipt, visit Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications.

Letter of Intent

• Descriptive title of proposed activity
• Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
• Names of other key personnel
• Participating institution(s)
• Number and title of this funding opportunity

The letter of intent should be sent to:

John F. Connaughton, Ph.D.
Chief, Scientific Review Branch
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone: 301-594-7797
e-mail: [email protected]

All instructions in the SF424 (R&R) Application Guide must be followed.

The meetings of the Consortium are the responsibility of the CC and the CC budget should include costs for travel and attendance of the External Consultants at one meeting per year. There will be bi-annual meetings of the Steering Committee, anticipated to take place in Bethesda, MD or sites housing the research projects. There will also be conference calls for meetings of Subcommittees and Working Groups. The CC application should request a budget for costs of the Steering Committee meetings except for costs for research project investigators to travel and attend the meetings.

Budget requests should include costs for the PD/PI and other essential members of the CC to attend the initial meeting and the bi-annual meetings.

Budget requests should include $30,000 per year for purchase of common reagents for collaborative projects and shared protocols.

Research Strategy: Applications should describe ways the Coordinating Center for the Consortium will increase opportunities for the proposed research and maximize its benefits. Projects to be conducted by the consortium will be shaped by the Steering Committee and may incorporate or alter the proposed research to maximize coordination and efficiency of the consortium. Applications for the CC must demonstrate within the research plan the ability to interface with the scientific areas of investigation that are included within this consortium. Because of the central role of the CC to interact with the other PDs/PIs and the scientific community, in order to synthesize and usefully present research results and information, purely administrative responses, without the demonstrated scientific interface, are not appropriate in response to this FOA. The Research Strategy should include a plan for scientific interface with the PDs/PIs and scientific community. The Research Strategy should describe the capacity and flexibility for meeting the needs of the consortium and the research community and for integration of information from the projects. The final plans of the CC will be adjusted to accommodate the final projects undertaken by the consortium.

The following modifications also apply:

• All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan. This plan should address methods for continuing to make public ISCC data available to the NIH and the research community upon completion or termination of the project so that accumulated data remain accessible, for example through databases and public repositories if available.

If you answered Yes to the question Are Human Subjects Involved? on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

3. Unique Entity Identifier and System for Award Management (SAM)

See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov

4. Submission Dates and Times

Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday , the application deadline is automatically extended to the next business day.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.

Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

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.

7. Other Submission Requirements and Information

Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide. Paper applications will not be accepted.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Guidelines for Applicants Experiencing System Issues. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.

The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

1. Criteria

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.

Significance

Does the proposed Coordinating Center address the needs of the research consortium that it will serve? Is the scope of activities proposed for the Center appropriate to meet those needs? Will successful completion of the aims bring unique advantages or capabilities to the research consortium?

Investigator(s)

Are the PD(s)/PI(s) and other personnel well suited to their roles in the Center? Do they have appropriate experience and training, and have they demonstrated experience and an ongoing record of accomplishments in managing basic/translational research projects? Do the investigators demonstrate significant experience with coordinating collaborative basic/translational research? Does the team have the scientific and technical expertise to effectively develop and maintain means for ongoing, rapid exchange of information and discussion between members of the consortium and to set up and maintain a data coordination core? Does the team have demonstrated experience with the coordination of large biomedical data sets, as well as experience at developing frameworks for storing, organizing, managing and tracking access to data and resources?

Innovation

Does the application propose novel organizational concepts or management strategies in coordinating the research consortium the Center will serve? Are the concepts, strategies, or instrumentation novel? Is a refinement, improvement, or new application of organizational concepts or management strategies proposed?

Approach

Are the overall strategy, operational plan, and organizational structure well-reasoned and appropriate to accomplish the goals of the consortium the Center will serve? Will the investigators promote strategies to ensure a robust and unbiased scientific approach across the consortium, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? Are an appropriate plan for work-flow and a well-established timeline proposed? Have the investigators presented adequate plans to ensure consideration of relevant biological variables, such as sex, for studies of vertebrate animals or human subjects?

Specific to this FOA: Does the approach include plans on how to store and facilitate access to data sets, protocols, etc., assist collaborative efforts among ISCC members, ?work with NIH staff and ISCC PIs to define and implement data and protocol validation methods, ?provide assistance with statistical analysis, and develop a roadmap to sustainability, ensuring that the data and tools produced and aggregated by the ISCC program remain available beyond the ISCC program funding period?

Environment

Will the institutional environment in which the Center will operate contribute to the probability of success in facilitating the research consortium it serves? Are the institutional support, equipment and other physical resources available to the investigators adequate for the Center proposed? Will the Center benefit from unique features of the institutional environment, infrastructure, or personnel? Are resources available within the scientific environment to support electronic information handling?

Communication

Are the proposed plans for accessibility of information and data from the research projects adequate to maximize the potential of the ISCC research results to be of benefit to the Consortium members and the scientific community? Does the application demonstrate that the proposed CC has the scientific expertise to communicate with the research projects leads and to synthesize a variety of information into a usable, quality-controlled and actively maintained interface for the user research community?

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 Guidelines for the Review of Human Subjects.

Inclusion of Women, Minorities, and Children

When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of children to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

Vertebrate Animals

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. 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

Renewals

Revisions

Applications from Foreign Organizations

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

Authentication of Key Biological and/or Chemical Resources:

For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

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.

2. Review and Selection Process

• 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.

• 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.
• Evidence that the applicant and investigators are committed to policies as established by the ISCC Steering Committee including confidentiality, sharing of information and resources and cooperative interaction.
• Evidence of past productive, cooperative, collaborative interaction will be considered.

3. Anticipated Announcement and Award Dates

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

1. Award Notices

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 terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this website.

2. Administrative and National Policy Requirements

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person’s race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency. HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research.

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 Federal awarding agency review of risk posed by applicants. This provision will apply to all NIH grants and cooperative agreements except fellowships.

For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see http://www.hhs.gov/ocr/civilrights/resources/laws/revisedlep.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html; and http://www.hhs.gov/ocr/civilrights/understanding/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at http://www.hhs.gov/ocr/office/about/rgn-hqaddresses.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

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 Part 75, 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.

The ISCC consists of Research Project sites and a Coordinating Center, cooperating through a Steering Committee as described above.

The PD(s)/PI(s) will have the primary responsibility for:

• The Awardee will have the primary responsibility for all aspects of the conduct of the study, data collection, quality control, data analysis and interpretation, preparation of publications, and collaboration with NIH staff and other study investigators, unless otherwise provided for in these terms or by action of the Steering Committee, in accordance with processes and goals as delineated in the Funding Opportunity Announcement.
• Awardee(s) agree to the governance of the study through a Steering Committee. Each full member will have one vote. Awardee members of the Steering Committee will be required to accept and implement policies approved by the Steering Committee.
• The PD/PI will assume responsibility and accountability to the applicant organization officials and to the NIH for the performance and proper conduct of the research supported under this Funding Opportunity Announcement in accordance with the terms and conditions of award, as well as all pertinent laws, regulations and policies.
• All staff of the Awardee(s) will be required to participate in a cooperative and interactive manner with NIH staff, one another and with the CC in all aspects of the ISCC.
• All staff of the Awardee(s) will maintain the confidentiality of the information developed by the investigations, including, without limitation, study protocols, data analysis, conclusions, etc. per policies approved by the Steering Committee as well as any confidential information received by third party collaborators.
• ISCC Awardee(s) agree to establish agreements amongst themselves that address the following issues: (1) procedures for data sharing among consortium members and data sharing with outside partners (including both industry and academia); (2) procedures for safeguarding confidential information, including without limitation, any data generated by the consortium as well as information and/or data received from external collaborators; (3) procedures for addressing ownership of intellectual property that result from aggregate multi-party data; (4) procedures for sharing biospecimens under an overarching MTA amongst consortium members that operationalizes material transfer in an efficient and expeditious manner; (5) procedures for reviewing publications, determining authorship, and industry access to publications.
• Awardee(s) agree that any third-party collaboration (including both industry and academia) should be governed by a research collaboration agreement (e.g. CTA, RCA, etc.) with terms that ensure the collaboration is conducted in accordance with the Cooperative Agreement, applicable NIH policies and procedures and any ISCC policies and procedures developed by the ISCC Steering Committee. The NIDDK Program Official may consult with others at NIH including the NIDDK Technology Advancement Office.
• The PDs/PIs or contact PD/PI in the case of multiple PDs/PIs awards, will serve as a voting member of the Steering Committee and will attend all meetings of the Steering Committee.
• The Awardee(s) will be responsible for accepting and implementing the goals, priorities, procedures, protocols, and policies agreed upon by the Steering Committee and Subcommittees
• Awardees must analyze, publish and/or publicly release and disseminate results, data and other products of the study in a timely manner, concordant with the approved plan for making quality-assured data and materials available to the scientific community and the NIDDK, consistent with NIH policies and achieving the goals of the program.
• Upon completion or termination of the ISCC project, the Awardees are responsible for making all study materials and procedures broadly available (e.g., putting into the public domain) or making them accessible to the research community according to the approved plan for making data and materials available to the scientific community and the NIH for the conduct of research.
• 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 current HHS, PHS, and NIH policies.

NIH Project Scientists will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below.

• The NIDDK will designate program staff and a Grants Management Specialist to provide normal program stewardship and administrative oversight of the cooperative agreement. The Program Official and Grants Management Specialist will be named in the Notice of Grant Award.
• The NIDDK will invite External Consultants with relevant scientific expertise. The External Consultants will meet to review the progress of the ISCC projects and to advise NIH staff of scientific developments and opportunities that may enhance the achievement of the ISCC goals.
• The NIDDK Project Scientist will be a member of the Steering Committee and, as determined by that committee, its Subcommittees as needed. The NIDDK Project Scientist will have one vote on the Steering Committee.
• The NIDDK Project Scientist will coordinate and facilitate the ISCC projects, attend and participate in all meetings of the Steering Committee, and act as liaisons between the Steering Committee and the External Consultants.
• The NIDDK Project Scientist will help the Steering Committee develop and draft operating policies
• The NIDDK Project Scientist and Program Official will review the scientific progress of the individual ISCC projects, and review projects for compliance with operating policies developed by the Steering Committee, and may recommend to the NIDDK to withhold support, restrict, suspend, or terminate an award for lack of scientific progress or failure to adhere to policies established by the Steering Committee. Review of progress may include regular communications with the PD/PI and staff, periodic site visits for discussions with awardee research teams, fiscal review, and other relevant matters. The NIH retains the option of periodic external review of progress. The NIDDK reserves the right to terminate or curtail any study or any individual award in the event of (a) substantial shortfall in data collection or submission, quality control, or other major breach of a study protocol or Consortium policy and procedure, (b) substantive changes in a study protocol that are not in keeping with the objectives of the FOA, and/or a human subject ethical issues that may dictate a premature termination.
• The NIDDK Project Scientist will make recommendations for continued funding based on overall progress, cooperation in carrying out the research, and maintenance of high quality research.
• The NIDDK will name additional scientific advisors as necessary from within the NIH whose function will be to assist the Project Scientists and the Steering Committee in carrying out the goals and aims of the approved studies. The NIH will have one vote for all key committees, regardless of the number of NIH personnel involved.
• The NIDDK Project Scientist will have substantial scientific programmatic involvement in quality control, preparation of publications, research coordination and performance monitoring. The NIDDK Project Scientist will have the same access and privileges to any data generated by the ISCC. The dominant role and primary responsibility for these activities resides with the awardees for the project as a whole, although specific tasks and activities in carrying out the studies will be shared among the awardees and the NIDDK Project Scientist.
• The NIDDK Project Scientist serves as a resource with respect to other ongoing NIH activities that may be relevant to the ISCC studies to facilitate compatibility and avoid unnecessary duplication of effort.
• The NIDDK Project Scientist or designee may coordinate activities among awardees by assisting in the design, development, and coordination of common research protocols and statistical evaluations of data and in the publication of results.
• The NIDDK Project Scientist may review procedures for assessing data quality and monitor study performance.
• The NIH Project Scientists or designee may be co-authors on study publications. In general, to warrant co-authorship, the NIH staff must have contributed to one or more of the following areas: (a) design of the concepts or experiments being tested; (b) performance of significant portions of the activity; (c) participation in analysis and interpretation of study results and (d) preparation and authorship of pertinent manuscripts.

Areas of Joint Responsibility include:

• The Steering Committee will be the governing board of the Consortium. All major scientific and policy decisions of the Steering Committee will be determined by majority vote. The Steering Committee will be composed of each of the PDs/PIs, or contact PD/PI in the case of multiple PIs/PDs grants, of the ISCC (including research projects and CC) and the NIH Project Scientists. Only the PDs/PIs or contact PD/PI and the NIDDK Project Scientist or designee will be voting members of the Steering Committee. This committee will operate to develop collaborative protocols, identify impediments to success and strategies to overcome them, develop shared tools for disseminating information about the projects, and identify opportunities for sharing techniques, materials, information and tools developed within each individual project. Steering Committee activities and decisions will factor in the advice of the External Consultants.
• The Steering Committee may, as it deems necessary, invite additional, non-voting scientific consultants to meetings at which research priorities and opportunities are discussed. The NIH reserves the right to augment the expertise of the Steering Committee when necessary.
• There will be an initial meeting and two Steering Committee meetings annually. Approximately once yearly, these meetings will incorporate participation and recommendations of the External Consultants.
• A Chairperson will be chosen by the NIH. In collaboration with the CC and the NIDDK Project Scientist, the Chairperson is responsible for coordinating the Steering Committee activities, for preparing meeting agendas and for chairing meetings.
• The Steering Committee, including the Project Scientists, is responsible for establishing and implementing processes and criteria for recommending Pilot Projects for consideration for discretionary funds by NIH staff in years 2-4.
• Each research project awardee and the CC awardee agree to the governance of the ISCC through the Steering Committee.
• The NIDDK Project Scientist may work with awardees on issues coming before the Steering Committee and, as appropriate, other committees.
• Through the Steering Committee and NIH staff, the ISCC will cooperatively develop and implement processes to submit information and data to the CC, determine criteria and processes for quality control of information and data to be posted for the research community, refine scientific objectives, and implement research advances to facilitate the goals of the study, consistent with NIH policies and achieving the goals of the program as described in the Funding Opportunity Announcement.

Dispute Resolution

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 after first attempting to resolve the issue through the Steering Committee or its subcommittees, as appropriate. An Arbitration Panel composed of three members will be convened. It will have three members: a designee of the Steering Committee chosen without NIH staff 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 dispute resolution procedure in no way affects the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulations 42 CFR Part 50, Subpart D and HHS regulations 45 CFR Part 16.

3. Reporting

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.

In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period. The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 Award Term and Conditions for Recipient Integrity and Performance Matters.

Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)

Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)

Contact Center Telephone: 800-518-4726

Email: [email protected]

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)

Email: [email protected] (preferred method of contact)

Telephone: 301-710-0267

Peter J. Kozel, Ph.D.
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone: 301-594-4721
Email: [email protected]