Part 1. Overview Information

Key Dates

All applications are due by 5:00 PM local time of applicant organization. 

Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide, except where instructed to do otherwise (in this NOFO or in a Notice from NIH Guide for Grants and Contracts).

Conformance to all requirements (both in the Application Guide and the NOFO) is required and strictly enforced. 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.

Part 2. Full Text of Announcement

Section I. Notice of Funding Opportunity Description

Nonalcoholic Steatohepatitis (NASH) is the most serious form of Nonalcoholic Fatty Liver Disease (NAFLD) and is a significant cause of chronic liver disease and cirrhosis in the United States.  NASH has the potential to result in end-stage liver disease and primary liver cancer, both devastating complications with costly burdens on the health care system. With the advent of effective treatments for chronic hepatitis C, NASH has surpassed that disease to become the dominant cause of chronic liver disease. NASH and alcohol associated liver disease are currently the leading indications for liver transplantation in the United States.  It is estimated that 24% of U.S. adults have NAFLD and up to 6% have NASH.  Not only are these individuals at risk for the consequences of chronic liver disease, but there is growing evidence that they also have an increased risk of mortality due to cardiovascular disease and nonhepatic malignancies.  NASH is classically considered to be a disease of obese, middle-aged adults -- often in association with other manifestations of the metabolic syndrome.  A major shift in this thought has occurred, as NASH is now frequently recognized in young adults and children, and can occur in the absence of obesity.

Accurate diagnosis and staging of NASH require liver biopsy.  However, this procedure is not readily accepted by patients and their caregivers, which hinders referral, accurate diagnosis, and assessment of response to interventions.  From a public health perspective, the need for a liver biopsy for rigorous diagnosis hinders determination of the prevalence of NASH. Efforts to replace liver biopsy as a means of diagnosis and staging have yielded studies fraught with inaccuracies and with limited clinical translatability.  Biomarkers and imaging techniques have recently been developed and refined to assist in determining the risk of the presence and severity of NASH. These noninvasive approaches require full validation before they can be accepted as clinical diagnostic tools and as endpoints for therapeutic trials in this disease.

There are no licensed therapies for NASH.  The current standard of care for NASH is weight loss through diet and exercise which is a clinically challenging goal to achieve. The NASH CRN has completed the PIVENS and TONIC studies of vitamin E, pioglitazone and metformin, as well as the FLINT study of obeticholic acid, and the CyNCH study of cysteamine bitartrate. These studies have demonstrated the feasibility of conducting rigorous, entry and exit liver biopsy measures in adult and child interventional trials in this disease. Despite these accomplishments, other therapies require rigorous evaluation to determine their effectiveness.In recent years, the pharmaceutical industry has been actively studying a large number of novel therapeutic strategies for NASH. In the prior funding cycle, the NASH CRN performed the phase 2 STOP-NAFLD study of losartan in children and adolescents with fatty liver disease. Unfortunately, this study was terminated for futility.

The discovery of the association of variants in the PNPLA-3 gene with fatty liver disease in 2008 was a major advance that validated observational studies of a hereditary factor.  Genetic factors appear to be just one component in the propensity to develop fatty liver disease and NASH.  A number of other factors such as body fat mass and its distribution, constituents of the diet, the host microbiome, host inflammatory status, lipotoxicity of lipids and free fatty acids, the host autophagy pathways via endoplasmic reticulum-associated protein degradation, and a plethora of other invoked injury signaling pathways have been implicated in the pathogenesis of NASH.  It remains unresolved which of these various factors are most relevant in the development of clinical disease.

In addition to the liver condition in and of itself, the presence of NASH has been independently associated with the risk of developing cardiovascular complications.  In an important network study, A total of 1773 adults with NAFLD were followed for a median of 4 years. Fibrosis stages F3 and F4 were associated with increased risks of liver-related complications and all-cause mortality. The main causes of death were liver and cardiovascular complications, cancer, and sepsis. Thus, NASH may serve as a surrogate marker for other extrahepatic complications.  Several important unresolved issues related to the nonhepatic consequences in the setting of fatty liver disease remain with respect to metabolic, cardiovascular, and neoplastic diseases.

The NASH Clinical Research Network (NASH CRN) has been sponsored by NIDDK since 2002. The network is currently composed of 17 clinical sites across the United States (funded through eight Clinical Center grants) and a Scientific Data Coordinating Center.  The NASH CRN is a nationally and internationally recognized leader as a network that is focused on clinical studies of fatty liver disease and NASH.  Over its existence, the NASH CRN has enrolled over 4800 adults and children in the Network’s databases, including over 1200 adults and over 200 children with biopsy proven NASH in the current Database 3. The Network has amassed a vast repository of over 700,000 biosamples, including serum, plasma, liver tissue and DNA from well-phenotyped cases of nonalcoholic fatty liver disease. A large number of imaging studies have been performed, including over 6000 vibration-controlled transient elastography scans, measuring liver stiffness. Because of the unique prominence of the NASH CRN, the NIDDK has engaged several industry partners through CRADAs, CTAs, and other contractual agreements.  These public-private partnerships have matured into the development of several clinical trials which have been published in prominent journals.  Studies of genomics, metabolomics, lipidomics, proteomics, and environmental exposures are ongoing. Additionally, a longitudinal study of liver stiffness is being performed and spleen stiffness measurement, a correlate of portal hypertension, has been initiated. Through a collaboration with the NIEHS-supported HHEAR network, NASH CRN investigators are studying pediatric environmental exposures in the disease. Network investigators are collaborating with the FNIH NIMBLE biomarkers consortium, using NASH CRN biosamples to qualify biomarkers for fatty liver disease.

The network is currently enrolling the Vitamin E Dosing Study (VEDS) in adults to determine the minimum effective dose of vitamin E in fatty liver disease. It is anticipated that the results of this study will inform a larger, pivotal controlled trial using disease endpoints.

The NASH CRN has initiated more than 130 ancillary or pilot studies some of which are still ongoing. Furthermore, the Network has a number of publications on secondary analyses of the clinical trials and cohort study in various stages of preparation.  Thus, this clinical research network is positioned to yield important new translatable clinical information with the potential to improve clinical management for patients with NASH.

The overriding objective of this research program is to pursue clinical research on adult and pediatric NASH, with a secondary objective to encourage reverse-translational research focusing upon elucidating the pathogenesis, that will provide the basis for understanding the natural history and developing means of diagnosis, treatment, and clinical management. The NIDDK proposes to continue the NASH CRN.  The specific objectives of the planned renewal of the NASH CRN are:

1. Completing enrollment, execution, analysis and publication of the VEDS clinical trial in adults.
2. Completing enrollment, execution, analysis and publication of the network’s prospective database.

The remaining specific objectives could include, but are not limited to:

1. Utilization of the available biospecimens, histological, and clinical data of the NASH CRN to develop and validate non-invasive biomarkers for the diagnosis and staging of NASH.  These may include both imaging and non-imaging modalities.
2. Utilization of the resources of the NASH CRN, including genomic and transcriptomic data to further advance the understanding of the genetic predictors of NASH with respect to pathogenesis, diagnosis, prognosis and treatment, as well as extrahepatic outcomes.  The NASH CRN investigators are strongly encouraged to seek out scientific expertise outside of the NASH CRN Clinical sites to augment and synergize the scientific opportunities.
3. Utilization of the resources of the NASH CRN, including proteomic, metabolomic, and lipidomic data to further advance the understanding of the pathogenesis and progression of NASH and inform the diagnosis, treatment, and clinical management of the disease.
4. Utilization of the prospective accrual of liver and spleen stiffness measurement in assessment of their utility in reflecting disease progression and their association with other surrogate markers for fibrosis and portal hypertension.

This is a one-time notice of funding opportunity to continue the NASH CRN for a maximum of three years, contingent on satisfactory study recruitment, patient retention, progress of translational studies, and availability of funds.

ORGANIZATION OF THE NASH CRN:

The NASH CRN will consist of the following components: the NIH, up to eight Clinical Centers (CC), a Scientific Data Coordinating Center (SDCC), a Steering Committee and its subcommittees, a Data and Safety Monitoring Board (DSMB), and other committees as needed.  The responsibilities of each component of the Network are described in the Terms and Conditions of Award.

The NIDDK will be responsible for organizing and providing support for the NASH CRN and will be involved substantially with the awardees as a scientific and administrative "partner", consistent with the Cooperative Agreement mechanism.  A designated NIDDK Project Scientist, who will provide programmatic oversight, will monitor subject recruitment and study progress, ensure disclosure of conflicts of interest and adherence to NIDDK policies.  The NIDDK will appoint Chairperson(s) of the Steering Committee and all members of the DSMB.  An additional NIDDK Program Official will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.

Through subcontracts and/or involvement of appropriate clinical departments within an applicant institution, CC applicants are encouraged to involve both Adult and Pediatric investigators.  CCs will be responsible for proposing protocols, participating in their overall development, conducting the research, and disseminating research findings.  For each investigational or therapeutic protocol, one CC will take the lead responsibility in conjunction with a protocol development subcommittee for drafting the protocol, although the Steering Committee will provide input and will be responsible for assuring development of a common protocol to be implemented by all of the CCs.  All CC principal investigators will be strongly encouraged to fully commit their center resources and efforts to the Network protocols and will disclose to the Steering Committee any applicant institutional specific clinical studies that may overlap with the clinical activities of the NASH CRN.  The CCs will  conduct the clinical trials and longitudinal follow-up as described in the study protocols. No deviations will be allowed.  All individual CCs will be required to participate in a cooperative and interactive manner with one another, with the SDCC, and with the NIDDK in all aspects of the NASH CRN (see Terms and Conditions of Award).  Only investigators who wish to continue to carry out the protocols of the NASH CRN, are willing and able to participate in a centralized Institutional Review Board at their institution, and agree to be governed by the policies and procedures of the NASH CRN and its steering committee should apply under this NOFO.

STUDY GOVERNANCE

STEERING COMMITTEE. The Steering Committee will be the main governing body of the NASH CRN (see Terms and Conditions of Award). The Steering Committee will be composed of the principal investigators of each CC in the Network, the principal investigator of the SDCC, the NIDDK Project Scientist and the NIDDK Program Official. Pediatric and Adult co-Chairs will be appointed by NIDDK.  Each CC, the SDCC, and the NIDDK Project Scientist will have one vote.  The Steering Committee will have primary responsibility for the general organization of the NASH Clinical Research Network, and approval of publications and ancillary studies.  The Steering Committee will be responsible for the conduct and monitoring of studies and reporting study results.  Topics for investigational and treatment protocols will be proposed and prioritized by the Steering Committee. An Executive Committee comprised of Pediatric and Adult Study Co-Chairs (appointed by NIDDK), the Principal Investigator of the SDCC, the NIDDK Project Scientist, and NIDDK Program Official will be convened to effect management decisions required between Steering Committee meetings, as required for the function of the network.  Other NIDDK personnel, as deemed necessary by the Project Scientist and Program Official, may also be included.  Other subcommittees of the Steering Committee will be established and will operate as necessary, such as publications, ancillary, protocol, pathology and radiology.  All face to face Steering Committee, DSMB, and other necessary face to face meetings requiring the presence of NIDDK personnel will be held in the Washington, DC/Baltimore metropolitan area or other suitable venue.

DATA SAFETY AND MONITORING BOARD. An independent Data and Safety Monitoring Board (DSMB) will be established by the NIDDK to review protocols and monitor patient safety and performance of each study.  As a part of its responsibilities, the DSMB will submit recommendations to the NIDDK regarding the continuation of each study. The DSMB will be responsible for final approval of the Data and Safety Monitoring Plan developed by the SDCC. All protocols or changes to protocols will be approved by the centralized Institutional Review Boards, the Steering Committee, the NASH CRN DSMB, and the NIDDK before initiation.

OTHER SPECIAL PERFORMANCE REQUIREMENTS

The NASH CRN will continue to be a collaborative effort that will require frequent interactions of awardees between themselves and with the NIDDK. Applicants must explicitly indicate their willingness to:

1. Participate in Steering Committee meetings (expected to occur in person 2-3 times a year in the Washington DC/Baltimore metropolitan area or other suitable venue), and as monthly (or as needed) videoconference, site visits as required by the NIDDK, and regular subcommittee telephone conference calls;
2. Cooperate with other awardees in the development and design or modification of research protocols, and cooperate with other awardees in carrying out approved research protocols and state willingness to disclose to the Steering Committee any applicant institutional specific clinical studies that may overlap with the clinical activities of the NASH CRN;
3. Abide by common definitions; common methods for patient selection and enrollment; and common protocols, procedures, tests, and reporting forms as chosen by majority vote of the Steering Committee;
4. Actively seek to implement each consortium-wide protocol approved by the DSMB and the NIDDK that the site is selected for participation;
5. Comply with all study policies and quality assurance measures approved by the Steering Committee;
6. Agree to oversight of the study by a Data and Safety Monitoring Board (DSMB),
7. Transmit study data to the Data and Coordinating Center in a timely and accurate manner (Clinical Centers and subsites only);
8. Report all adverse events in accordance with procedures established by the Steering Committee, and NIDDK and FDA policies;
9. Cooperate with other awardees in the publication of study results and the eventual release to the scientific community of study procedures and other resources;
10. Serve on and chair subcommittees and protocol committees as assigned by the steering committee or the NIDDK;
11. Engage a broader set of investigators external to the immediate study group to provide opportunities to analyze the data and participate in the parent study by means of ancillary studies;
12. Develop opportunities for local analysis of data by study investigators and other qualified researchers at their institutions, and investigators outside the study group ("disseminated data analysis");
13. Accept the “Cooperative Agreement Terms and Conditions of Award” in Section VI.2.A “Award Administration Information”.

See Section VIII. Other Information for award authorities and regulations.

Investigators proposing NIH-defined clinical trials may refer to the Research Methods Resources website for information about developing statistical methods and study designs.

Section II. Award Information

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

Section III. Eligibility Information

1. Eligible Applicants

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)

Local 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)

Federal Governments

• 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)  

Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.

Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement, are not allowed. 

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 Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

• System for Award Management (SAM) – 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.
  • Unique Entity Identifier (UEI) - A UEI is issued as part of the SAM.gov registration process. The same UEI must be used for all registrations, as well as on the grant application.
• eRA Commons - Once the unique organization identifier is established, organizations can register with eRA Commons in tandem with completing their Grants.gov registrations; all registrations must be in place by time of submission. 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 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.

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 their organization to develop an application for support. Individuals from diverse backgrounds, including underrepresented racial and ethnic groups, individuals with disabilities, and women are always encouraged to apply for NIH support. See, Reminder: Notice of NIH's Encouragement of Applications Supporting Individuals from Underrepresented Ethnic and Racial Groups as well as Individuals with Disabilities, NOT-OD-22-019.

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.

Add additional eligibility requirements for individuals.

1.For a Diversity NOFO that restricts eligibility by targeting diverse individuals, insert standard language from the Diversity Guidance posted on the templates page. Note that NOFOs can target institutions or individuals but typically not both, contact OER/DBRW for more details.

2.For an R15 NOFO, insert the specialized text from the document “R15 Additional text” on the templates page.

Only the currently participating NASH CRN Program Director(s)/Principal Investigator(s) are eligible to apply to this NOFO. 

Only the currently participating NASH CRN Program Director(s)/Principal Investigator(s) are eligible to apply to this NOFO. 

2. Cost Sharing

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

3. Additional Information on Eligibility

Number of Applications

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

The NIH will not accept duplicate or highly overlapping applications under review at the same time, per NIH Grants Policy Statement Section 2.3.7.4 Submission of Resubmission Application. This means that the NIH will not accept:

• 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 NIH Grants Policy Statement 2.3.9.4 Similar, Essentially Identical, or Identical Applications).

Section IV. Application and Submission Information

1. Requesting an Application Package

The application forms package specific to this opportunity must be accessed through ASSIST, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace are available in Part 1 of this NOFO. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide except where instructed in this notice of funding opportunity 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.

Letter of Intent

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.
 
By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:

• 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
Email: [email protected]

Page Limitations

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed.

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this NOFO.

SF424(R&R) Cover

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

SF424(R&R) Project/Performance Site Locations

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

SF424(R&R) Other Project Information

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

Applications will be assessed upon their past enrollment and participation in the NASH CRN and their capability to complete enrollment, execution, analysis, and publication of network studies. Each CC will present a patient retention plan for clinical trials and a patient retention plan should be presented for patients enrolled in Database 3.  Each CC submitting an application in response to this NOFO must provide evidence of their ability to carry out the protocols already approved by the NASH CRN Steering Committee. 

If a CC application includes a new subsite, then the subsite must demonstrate how they will contribute to the network's mission. CCs must show how they will work in collaboration with the SDCC to implement procedures for uniform data collection, handling and transmittal of data, as well as data audits and other data quality control procedures, as established by the study protocol. CCs must also provide information regarding future plans for involvement with operational committees of the NASH CRN (e.g. Recruitment, Publications, etc.) and the establishment of uniform procedures and policies.  There should be evidence of strong institutional support for the CC, including adequate space in which to conduct clinical and research activities and office space for staff. Institutional resources for patient care and follow-up including personnel, space, and special laboratory facilities must be described in the CC application.

An organizational structure for the CC should be set forth in the application, delineating specific personnel (e.g., pathologists, radiologists, etc.) available to carry out the approved protocols.  Each CC application may consider the addition of other scientific personnel who must be fully justified.  The additional scientific personnel must demonstrate the capability to provide substantial scientific expertise that is consistent with and aligns with the objectives of the NASH CRN.  The final decision on the acceptance of the additional scientific personnel will be at the discretion of the NIDDK based upon network objectives and the availability of support.  The PD/PI should state his/her general support of collaborative research and interaction with the NIDDK, the other CCs, and the DCC through the Network concept.

The NIDDK Technology Advancement Office must be consulted early in the process when an NIDDK-funded study enters into a collaboration agreement and the NIDDK Regulatory Specialist consulted early in the process when a protocol may be required to operate under an IND/IDE.

NASH CRN clinical study protocols must be overseen by a centralized IRB.  Investigators are encouraged to express their willingness to consider this model or comment on barriers to implementation of centralized IRB review and ongoing oversight at their individual institutions.

In order to maximize the impact and efficiency of the NASH CRN, investigators are requested to state their willingness to present site-specific fatty liver disease studies that may potentially conflict with the activities of the Network to the NASH CRN Steering Committee for comment and consideration as network-wide studies.

SF424(R&R) Senior/Key Person Profile

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

R&R or Modular Budget

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

R&R Subaward Budget

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

PHS 398 Cover Page Supplement

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

PHS 398 Research Plan

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

The purpose of this limited competition notice of funding opportunity (NOFO) is to continue the support of the Clinical Centers of the NASH Clinical Research Network (NASH CRN) as they complete and report their active clinical treatment trial, and close out, analyze, and report the network’s prospective database (DB3).

Applicants should describe their capabilities, resources, and willingness to achieve these goals.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide.

Other Plan(s): Note: Effective for due dates on or after January 25, 2023, the Data Management and Sharing Plan will be attached in the Other Plan(s) attachment in FORMS-H application forms packages.

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

• All applicants planning research (funded or conducted in whole or in part by NIH) that results in the generation of scientific data are required to comply with the instructions for the Data Management and Sharing Plan. All applications, regardless of the amount of direct costs requested for any one year, must address a Data Management and Sharing Plan.

Appendix: Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

• No publications or other material, with the exception of blank questionnaires or blank surveys, may be included in the Appendix.

PHS Human Subjects and Clinical Trials Information

When involving human subjects research, clinical research, and/or NIH-defined clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

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.

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start). All instructions in the SF424 (R&R) Application Guide must be followed.

PHS Assignment Request Form

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 Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications.

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 How to Apply – Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. 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 form. 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 NOFO for information on registration requirements.

The applicant organization must ensure that the unique entity identifier provided on the application is the same identifier 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.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by NIDDK, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

Use of Common Data Elements in NIH-funded Research

Many NIH ICs encourage the use of common data elements (CDEs) in basic, clinical, and applied research, patient registries, and other human subject research to facilitate broader and more effective use of data and advance research across studies.  CDEs are data elements that have been identified and defined for use in multiple data sets across different studies.  Use of CDEs can facilitate data sharing and standardization to improve data quality and enable data integration from multiple studies and sources, including electronic health records.  NIH ICs have identified CDEs for many clinical domains (e.g., neurological disease), types of studies (e.g. genome-wide association studies (GWAS)), types of outcomes (e.g., patient-reported outcomes), and patient registries (e.g., the Global Rare Diseases Patient Registry and Data Repository).  NIH has established a “Common Data Element (CDE) Resource Portal" (http://cde.nih.gov/) to assist investigators in identifying NIH-supported CDEs when developing protocols, case report forms, and other instruments for data collection.  The Portal provides guidance about and access to NIH-supported CDE initiatives and other tools and resources for the appropriate use of CDEs and data standards in NIH-funded research.  Investigators are encouraged to consult the Portal and describe in their applications any use they will make of NIH-supported CDEs in their projects.?

Post Submission Materials

Applicants are required to follow the instructions for post-submission materials, as described in the policy

Section V. Application Review Information

1. Criteria

Only the review criteria described below will be considered in the review process.  Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.

A proposed Clinical Trial application may include study design, methods, and intervention that are not by themselves innovative but address important questions or unmet needs. Additionally, the results of the clinical trial may indicate that further clinical development of the intervention is unwarranted or lead to new avenues of scientific investigation.

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.

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.

Specific to this NOFO:

• How likely will the CC patient follow up and retention plans contribute to the long term follow up of patients in Database 3?
• How appropriate and feasible are the strategies to optimize enrollment, retention and follow-up of the ongoing VEDS clinical trial?

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.

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by the NIDDK, 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 will receive a written critique.

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.

Appeals of initial peer review will not be accepted for applications submitted in response to this NOFO.

Applications will be assigned to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this NOFO. Following initial peer review, recommended applications will receive a second level of review by the National Diabetes and Digestive and Kidney Diseases Advisory Council. 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.

3. Anticipated Announcement and Award Dates

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. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

Information regarding the disposition of applications is available in the NIH Grants Policy Statement Section 2.4.4 Disposition of Applications.

Section VI. Award Administration Information

1. Award Notices

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 recipient's business official.

Recipients must comply with any funding restrictions described in Section IV.6. 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 NOFO 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.

Individual awards are based on the application submitted to, and as approved by, the NIH and are subject to the IC-specific terms and conditions identified in the NoA.

ClinicalTrials.gov: If an award provides for one or more clinical trials. By law (Title VIII, Section 801 of Public Law 110-85), the "responsible party" must register and submit results information for certain “applicable clinical trials” on the ClinicalTrials.gov Protocol Registration and Results System Information Website (https://register.clinicaltrials.gov). NIH expects registration and results reporting of all trials whether required under the law or not. For more information, see https://grants.nih.gov/policy/clinical-trials/reporting/index.htm

Institutional Review Board or Independent Ethics Committee Approval: Recipient institutions must ensure that all protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the recipient must provide NIH copies of documents related to all major changes in the status of ongoing protocols.

Data and Safety Monitoring Requirements: The NIH policy for data and safety monitoring requires oversight and monitoring of all NIH-conducted or -supported human biomedical and behavioral intervention studies (clinical trials) to ensure the safety of participants and the validity and integrity of the data. Further information concerning these requirements is found at http://grants.nih.gov/grants/policy/hs/data_safety.htm and in the application instructions (SF424 (R&R) and PHS 398).

Investigational New Drug or Investigational Device Exemption Requirements: Consistent with federal regulations, clinical research projects involving the use of investigational therapeutics, vaccines, or other medical interventions (including licensed products and devices for a purpose other than that for which they were licensed) in humans under a research protocol must be performed under a Food and Drug Administration (FDA) investigational new drug (IND) or investigational device exemption (IDE).

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Recipients, and Activities, including of note, but not limited to:

• Federal-wide Standard Terms and Conditions for Research Grants
• Prohibition on Certain Telecommunications and Video Surveillance Services or Equipment
• Acknowledgment of Federal Funding

If a recipient is successful and receives a Notice of Award, in accepting the award, the recipient agrees that any activities under the award are subject to all provisions currently in effect or implemented during the period of the award, other Department regulations and policies in effect at the time of the award, and applicable statutory provisions.

Should the applicant organization successfully compete for an award, recipients of federal financial assistance (FFA) from HHS will be required to complete an HHS Assurance of Compliance form (HHS 690) in which the recipient agrees, as a term and condition of receiving the grant, to administer their programs in compliance with federal civil rights laws that prohibit discrimination on the basis of race, color, national origin, age, sex and disability, and agreeing to comply with federal conscience laws, where applicable. This includes ensuring that entities take meaningful steps to provide meaningful access to persons with limited English proficiency; and ensuring effective communication with persons with disabilities. Where applicable, Title XI and Section 1557 prohibit discrimination on the basis of sexual orientation, and gender identity. The HHS Office for Civil Rights provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-providers/provider-obligations/index.html and https://www.hhs.gov/civil-rights/for-individuals/nondiscrimination/index.html.

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. 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 NOFO.

• For guidance on meeting the legal obligation to take reasonable steps to ensure meaningful access to programs or activities by limited English proficient individuals see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/fact-sheet-guidance/index.html and https://www.lep.gov.

• For information on an institution’s specific legal obligations for serving qualified individuals with disabilities, including providing program access, reasonable modifications, and to provide effective communication, see https://www.hhs.gov/civil-rights/for-individuals/disability/index.html.

• HHS funded health and education programs must be administered in an environment free of sexual harassment, see https://www.hhs.gov/civil-rights/for-individuals/sex-discrimination/index.html. For information about NIH's commitment to supporting a safe and respectful work environment, who to contact with questions or concerns, and what NIH's expectations are for institutions and the individuals supported on NIH-funded awards, please see https://grants.nih.gov/grants/policy/harassment.htm.

• For guidance on administering programs in compliance with applicable federal religious nondiscrimination laws and applicable federal conscience protection and associated anti-discrimination laws see https://www.hhs.gov/conscience/conscience-protections/index.html and https://www.hhs.gov/conscience/religious-freedom/index.html.

Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.html or call 1-800-368-1019 or TDD 1-800-537-7697.

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 and 2 CFR Part 200.206 “Federal awarding agency review of risk posed by applicants.” This provision will apply to all NIH grants and cooperative agreements except fellowships.”

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (HHS) grant administration regulations at  2 CFR Part 200, 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 recipients 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 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 recipients for the project as a whole, although specific tasks and activities may be shared among the recipients and NIH as defined below.

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

1. Developing the research design and study protocol, including definition of objectives and approaches, sample size and power calculations, and establishing procedures for participant recruitment and follow-up, data collection, quality control, interim data and safety monitoring, final data analysis and interpretation, and publication of results.

2. Establishing a Steering Committee to implement, coordinate and manage the project(s). Recipient(s) will name investigators to serve as members on a Steering Committee and other subcommittees, as appropriate, meeting periodically. Recipients will be required to accept and implement the common protocol(s) and procedures approved by the Steering Committee.

3. Designating Protocol Chairs. The Program Directors/Principal Investigators (for studies involving multiple protocols) shall designate a single Protocol Chairperson (if the Program Director/Principal Investigator does not assume this role) for each protocol to be carried out by the study group. The Protocol Chairperson shall function as the scientific coordinator for the protocol and shall assume responsibility for obtaining approval to implement the protocol from the Steering Committee and for developing and monitoring the protocol. Significant modifications to approved protocols must be approved by the Steering Committee.

4. Implementing collection of data specified by the study protocol.  For a multi-center study, each recipient/site is required to ensure that data will be submitted expeditiously to the Data Coordinating Center. Additionally, individual investigators/sites must demonstrate the ability to implement the strategy specifically designed for their individual study population.

5. Establishing procedures for data quality, completeness, and security. Recipients are responsible for ensuring accurate and timely assessment of the progress of each study, including development of procedures to ensure that data collection and management are: (1) adequate for quality control and analysis; (2) for clinical trials, as simple as appropriate in order to facilitate cooperation/referral of study participants by physicians to avoid unnecessary expense; and (3) sufficiently staffed across the participating institutions. For research involving multiple sites, a plan for analysis of pooled data will be developed by the Steering Committee.

6. Submitting interim progress reports, when requested or agreed upon by both parties, to the NIDDK Program Official including as a minimum, summary data on protocol performance. For coordinated multiple awards or a multi-site single award, the NIDDK Program Official may require additional information from individual clinical sites. Such reports are in addition to the required annual noncompeting continuation progress report.

7. Reporting of the study findings.  Recipients 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 DHHS, PHS, and NIH policies.  The recipient must also be adherent to Study Publication and Presentation Policy.  The NIDDK will have access to and may periodically review all data generated under an award. NIDDK staff may co-author publications of findings with recipients consistent with NIH policies and network/consortium policies.

8. Any third-party collaboration (including but not limited to interactions with organizations from industry, academia, and nonprofit institutions) should be governed by a research collaboration agreement (e.g., Clinical Trial Agreement, Research Collaborative Agreement, etc.) or any third-party contract mechanism(s) with terms that ensure the collaboration is conducted in accordance with the Cooperative Agreement, applicable NIH/NIDDK policies and procedures, and with written approval from NIDDK Program staff. Any relevant proposed third-party agreements related to the network/consortium studies between grantee and third-party will be provided to the NIDDK Program staff and NIDDK Technology Advancement Office for review, comment, and approval to assure compliance with NIH/NIDDK policies and network/consortium policies. Further, at the request of the NIDDK Program staff, any other network/consortium-relevant third-party agreements must be shared with NIDDK. Failure to comply with this term may prompt action in accordance with NIH Grants Policy Statement, Section 8.5 titled: “Special Award Conditions and Remedies for Noncompliance (Special Award Conditions and Enforcement Actions)”, and Section 8.5.2, titled: “Remedies for Noncompliance or Enforcement Actions: Suspension, Termination, and Withholding Support”, noncompliance with the terms and conditions of award will be considered by the funding IC for future funding and support decisions and may result in termination of the award.”

9. Any involvement of a third-party (including but not limited to industry, academia, and nonprofit institutions) in the study and network/consortium activities that includes access to any network/consortium generated resources (i.e., data and bio-samples), or study results that are not publicly available, or using the name of the network/consortium or study or the name of the NIH or NIDDK, is permitted only after written permission by the NIDDK Program staff who will consult with others at NIH and NIDDK Technology Advancement Office.

10.  Maintaining confidentiality of information:  The recipient(s) will maintain the confidentiality of the information developed by the investigators (i.e., protocols, data analysis, conclusions, etc.) as well as proprietary information of an individual company or other entity collaborating with the study or network/consortium. Any exception requires written approval from NIDDK Program staff.

11. Data Management and Sharing Plan: In accordance with the NIH Policy for Data Management and Sharing (NIH NOT-OD-21-013), the NIDDK approved plan will become a term and condition of award, be routinely monitored during the award period, and compliance may factor into future funding decisions. By the end of the funding or proprietary period, a recipient or study group may not continue to use or share study generated resources until those resources are available to the public via a NIDDK approved repository per the NIDDK approved plan. The NIDDK has established a Central Repository to support the receipt, storage, and distribution of data, bio-samples, and other resources generated in clinical studies funded by the NIH/NIDDK. When the NIDDK Central Repository is to be utilized, prior to enrolling participants, the PI or his/her designee will coordinate with the NIDDK Program and Central Repository staff to prepare for eventual archiving and distribution of the study generated resources that are to be maintained in the Central Repository. These resources will be available to the wider scientific community in accordance with the NIH Data Management and Sharing policy  (http://grants.nih.gov/grants/policy/data_sharing/ and, https://grants.nih.gov/policy/sharing.htm, and http://grants.nih.gov/grants/policy/data_sharing/data_sharing_faqs.htm), per the NIDDK approved data management and sharing plan. 

12.  Study investigators are required to publish and to release publicly and disseminate results and other products of the study, in accordance with study protocols, Steering Committee policies on publications, and the NIDDK approved Data Management and Sharing Plan (DMSP).

13.  Study investigators are required to comply with NIH Policy on the Dissemination of NIH Funded Clinical Trial Information as stated at https://grants.nih.gov/policy/clinical-trials/reporting/understanding/nih-policy.htm. Per policy, the recipient is responsible for meeting the expectations of this policy. Refer to additional information at https://grants.nih.gov/policy/clinical-trials/reporting/index.htm.

NIH staff have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:

An NIDDK Project Scientist with substantial involvement will:   

1. Serve as the contact point for all facets of the scientific interaction with the recipient (s). As required for the coordination of activities and to expedite progress, NIDDK may designate additional NIDDK staff to provide advice to the recipient on specific scientific and/or analytic issues. Such staff may include another Project Scientist or Project Coordinator, who will provide direct technical assistance to the recipients to optimize the conduct and/or analysis of the study; or who may assist in the coordination of activities across multiple sites.

2. For multi-center studies, participate in the Steering Committee that oversees study conduct. The NIDDK Project Scientist or Project Coordinator will be a full participant and voting member of the Steering Committee and, if applicable, Subcommittees.

3. Serve as a resource to study investigators with respect to other ongoing NIDDK activities that may be relevant to the study to facilitate compatibility with the NIDDK missions and avoid unnecessary duplication of effort.

4. Have substantial involvement assisting in the design and coordination of research activities for recipients as elaborated below:

a. Assisting by providing advice in the management and technical performance of the investigations, coordinating required regulatory clearances for investigational agents used in the study, which are held by NIDDK. The NIDDK may reserve the right to cross file or independently file an Investigational New Drug Application or an Investigational Device Exemption form with the FDA.

b. The NIDDK Project Scientist or Project Coordinator may coordinate activities among recipients by assisting in the design, development, and coordination of a common research or clinical protocol and statistical evaluations of data; in the preparation of questionnaires and other data recording forms; and in the publication of results.

c. Reviewing procedures for assessing data quality and study performance monitoring.

d. The NIDDK Project Scientist or Project Coordinator may be co-authors on study publications. In general, to warrant co-authorship, NIDDK staff must have contributed to 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.

The NIDDK Program Official identified in the Notice of Award will:

1. Interact with the Program Director(s)/Principal Investigator(s) on a regular basis to monitor study progress. Monitoring may include: regular communications with the Program Director/Principal Investigator and staff, periodic site visits, observation of field data collection and management techniques, quality control, fiscal review, and other relevant matters; as well as attendance at Steering Committee, data safety and monitoring board, and related meetings. The NIDDK retains, as an option, periodic review of progress by researchers not involved with the study.
2. Review and approve protocols prior to implementation to insure they are within the scope of peer review, for safety considerations, as required by Federal regulations.
3. The NIDDK Program Official will monitor protocol progress, and may request that a protocol study be closed to accrual for reasons including: (a) accrual rate insufficient to complete study in a timely fashion; (b) accrual goals met early; (c) poor protocol performance; (d) patient safety and regulatory concerns; (e) study results that are already conclusive; (f) low likelihood of showing a benefit of the intervention (futility); and (g) emergence of new information that diminishes the scientific importance of the study question. The NIDDK will not permit further expenditures of NIDDK funds for a study after requesting closure except as specifically approved by the NIDDK.
4. Make recommendations for continued funding based on: a) overall study progress, including sufficient patient and/or data accrual; b) cooperation in carrying out the research (e.g., attendance at Steering Committee meetings, implementation of group decisions, compliance with the terms of award and reporting requirements); and/or c) maintenance of a high quality of research, which will allow pooling of data and comparisons across multiple cooperative agreement awards for common data elements.
5. Appoint an independent Data and Safety Monitoring Board (DSMB) as appropriate for Phase III clinical trials or other high-risk studies, or an Observational Study Monitoring Board (OSMB) for observational/epidemiologic studies; these Boards will review study progress, safety data, and interim results, as appropriate, and provide guidance to the NIDDK. The NIDDK Program Official or their Project Coordinator will serve as the Executive Secretary and/or NIDDK program representative on the DSMB/OSMB.

Areas of Joint Responsibility include:

In addition to the interactions defined above, NIDDK Project Scientist and Recipients shall share responsibility for the following activities:

Steering Committee

A Steering Committee organized by the study investigator(s) will be the main governing body of the study.

The Steering Committee has primary responsibility to design research activities, establish priorities, develop common protocols and manuals, questionnaires and other data recording forms, establish and maintain quality control among recipients, review progress, monitor patient accrual, coordinate and standardize data management, and cooperate on the publication of results. Major scientific decisions regarding the core data will be determined by the Steering Committee. The Steering Committee will document progress in written reports to the NIDDK Program Official and will provide periodic supplementary reports upon request.

The Steering Committee will be composed of all Program Director(s)/Principal Investigator(s), (including those of data coordinating /statistical centers, if any) and co-investigators as deemed necessary, and the NIDDK Project Scientist. The final structure of the Steering Committee and voting procedures will be established at the first meeting. The NIDDK Project Scientist will have voting membership on the Steering Committee, and as appropriate, its subcommittees. The frequency of Steering Committee meetings will be dictated by a vote of the members of the Steering Committee.  The NIDDK Program Official may serve as a non-voting member on the Steering Committee.

A Chairperson of the Steering Committee will be selected and voted on by the Steering Committee members.  The Chairperson provides leadership to the Committee by conducting the Steering Committee meetings and by interacting closely with the recipients during protocol development and implementation.  The NIDDK Project Scientist may not serve as Chairperson. The NIDDK Program Official should be consulted regarding the selection of the Chairperson to provide any feedback regarding concerns regarding potential for bias or conflict of interest or lack of required expertise.

External Consultants

An independent panel of External Consultants may be established by the Steering Committee.  The External Experts will review periodically interim progress of the U01s and report to the Steering Committee members. Members of the panel of External Experts may be asked, on an ad hoc basis, to participate in the peer review of applications for new research initiatives that utilize special “opportunity pool” funds.

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between recipients and NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened: 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 recipient. This special dispute resolution procedure does not alter the recipient's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and HHS regulation 45 CFR Part 16.

3. Data Management and Sharing

Note: The NIH Policy for Data Management and Sharing is effective for due dates on or after January 25, 2023.

Consistent with the NIH Policy for Data Management and Sharing, when data management and sharing is applicable to the award, recipients will be required to adhere to the Data Management and Sharing requirements as outlined in the NIH Grants Policy Statement. Upon the approval of a Data Management and Sharing Plan, it is required for recipients to implement the plan as described.

4. Reporting

When multiple years are involved, recipients will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

A final RPPR, 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. NIH NOFOs outline intended research goals and objectives. Post award, NIH will review and measure performance based on the details and outcomes that are shared within the RPPR, as described at 45 CFR Part 75.301 and 2 CFR Part 200.301.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for recipients of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later.  All recipients 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 the threshold.  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 2 CFR Part 200.113 and Appendix XII to 45 CFR Part 75 and 2 CFR Part 200, 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 and 2 CFR Part 200 – Award Term and Condition for Recipient Integrity and Performance Matters.

Section VII. Agency Contacts

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

eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten submission by the due date, and post-submission issues)

Finding Help Online: https://www.era.nih.gov/need-help (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: [email protected] (preferred method of contact)
Telephone: 301-480-7075

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: [email protected]

Averell H. Sherker, M.D., FRCPC
Scientific Advisor for Viral Hepatitis and Liver Diseases
Division of Digestive Diseases and Nutrition
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone: 301-451-6207
Email: [email protected]

Edward Doo, M.D.
Director, Liver Diseases Research Program
Division of Digestive Diseases and Nutrition 
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) 
Telephone: 301-451-4524 
Email: [email protected]

Paul Rushing, Ph.D. 
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone: 301-594-8895
Email: [email protected]

Sunshine Wilson
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone: 301-827-4670
Email: [email protected]

Section VIII. Other Information

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 Part 75 and 2 CFR Part 200.