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

Purpose:

The National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health of the U.S. Department of Health and Human Services is seeking applications for the Clinical Centers (CC) of the Childhood Liver Disease Research Network (ChiLDReN).  The ChiLDReN Network was established with the merging of the Biliary Atresia Research Consortium (BARC) and the Cholestatic Liver Consortium (CLiC) under RFA-DK-08-005.  The overarching research mission of ChiLDReN has been to improve our understanding of cholestatic and rare pediatric liver diseases that have included: Biliary Atresia; Alagille syndrome; alpha-1-antitrypsin deficiency; Progressive Familial Intrahepatic Cholestasis syndromes; Bile acid synthesis defects; Mitochondrial hepatopathies; Idiopathic Neonatal Hepatitis; Cystic Fibrosis Liver Disease; and pediatric primary sclerosing cholangitis.

To this end, the historical focus and prior accomplishments of this Network had been clinical in nature and have included the completion of the safety and efficacy of steroid use following hepatoportoenterostomy (HPE) in children newly diagnosed with biliary atresia (START); the cataloging of major birth anomalies associated with biliary atresia; the assessment of the effectiveness of fat-soluble vitamin supplementation in biliary atresia; the safety and feasibility of intravenous immunoglobulin for biliary atresia (PRIME); and a clinical trial under a CRADA to test the efficacy and safety of Intestinal Bile Acid Transport Inhibitor LUM001 in the treatment of Pruritus in Alagille Syndrome patients (ITCH); among many other accomplishments.   Additionally, the ChiLDReN Network developed a robust biospecimen repository with over 1800 biliary atresia patient DNA specimens; frozen liver specimens from the range of liver diseases under study; and bile duct specimens from children undergoing hepatic portoenterostomy for biliary atresia.  With these unique and well characterized biospecimens, the ChiLDReN Network was more recently charged by the NIDDK to exploit the resources of the biosample repository through Network-wide translational science studies to further our understanding of the pathogenesis of these pediatric liver diseases.  Previously, the NIDDK sponsored a one-day research workshop in June 2017 on the topic of biliary atresia with a focus upon the various mechanisms postulated to be pathophysiologic towards disease initiation and progression.  The meeting summary manuscript (Hepatology. 2018 Sep;68(3):1163-1173. doi: 10.1002/hep.29905.) concluded with a summary of clinical and scientific research challenges and priorities that would further the understanding of biliary atresia.  The workshop research challenges formed the impetus for a ChiLDReN genomic analysis effort of biliary atresia and led to the paradigm shifting discovery of the association of PKD1L1.  Likewise, other genetic modifiers of disease severity across the other cholestatic liver diseases under study have been identified.  

The ChiLDReN Network is positioned to address future research challenges in pediatric cholestatic liver diseases through the pursuit of clinical and translational science opportunities  available within the Network or through collaborations with expertise outside the Network with mutual scientific interests that will translate into feasible and achievable advancement in the understanding of the pathogenesis or the clinical management of the various diseases.  In certain cases, some Network cholestatic liver diseases may require the further identification and enrollment of patients into one of the ongoing Network studies (https://childrennetwork.org/Clinical-Studies/); in others, the currently available collected data, biosamples, or previously identified patients may be sufficient to embark upon a scientific endeavor or clinical study or trial. For this NOFO, the following ongoing ChiLDReN Network studies will continue into the next funding cycle: Genetic Collection; Prospective Database of Infants with Cholestasis (PROBE); Biliary Atresia Study in Infants and Children (BASIC); Longitudinal Study of Genetic Causes of Intrahepatic Cholestasis (LOGIC); Longitudinal Study of Mitochondrial Hepatopathies (MitoHep); and Prospective Observational Study of Primary Sclerosing Cholangitis (PSC).

Organization of the ChiLDReN Network:

The ChiLDReN Network has been and will continue to be a cooperative research network composed of Clinical Center (CC) grantees, a single Scientific and Data Coordinating Center (SDCC) grantee, and the NIDDK/NIH through the Cooperative Agreement terms and conditions.  Steering Committee: The Steering Committee will be the main governing body of the ChiLDReN (see Terms and Conditions of Award).  Voting members of the Steering Committee will be the Principal Investigator (PI) or designee for each U01 Clinical Center grant, the Scientific and Data Coordination Center PI, and the NIDDK. Executive Committee: An Executive Committee comprised of at a minimum the Network Chair and Co-Chair who will be determined by the Steering Committee with concurrence by the NIDDK at the initiation of the new funding cycle; the Program Director/Principal Investigator of the SDCC; and the NIDDK Project Scientist and Program Official and other NIDDK personnel as deemed necessary by the Project Scientist and Program Official will be convened to effect management decisions required between Steering Committee meetings, that is needed for efficient progress of the Network scientific activities.  Other subcommittees, working groups, and task forces of the Steering Committee will be prioritized and operationalized or de-operationalized as necessary, such as publications, ancillary, protocol, pathology and radiology.  Data Safety and Monitoring Board: An independent Data and Safety Monitoring Board (DSMB) has been established by the NIDDK to review Network protocols and monitor patient safety and the performance of each study.  As a part of its responsibilities, the DSMB will submit recommendations as per the DSMB Charter 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 Network protocols or changes to the Network protocols will be approved by the central or single Institutional Review Board, the Steering Committee, the ChiLDReN Data and Safety Monitoring Board, and the NIDDK before initiation. Any specific collaboration involving the resources of ChiLDReN will require approval by the Steering Committee and the NIDDK Program Official. 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 as appropriate for the operational efficiency of Network scientific activities and for the Programmatic oversight of cost-efficient Network resource management.

ChiLDReN Network Components and Responsibilities:

Composition of the ChiLDReN: The components of ChiLDReN will consist of the following: the NIDDK/NIH as the sponsor of the Network, up to fourteen CC grantees, and a single SDCC grantee, that will be operationalized by an Executive Committee, a Steering Committee and its subcommittees, Data and Safety Monitoring Boards (DSMB), and other committees as needed as noted above in: Organization of the ChiLDReN Network.

The Clinical Centers (CCs) will continue to recruit subjects into the current ongoing ChiLDReN studies (https://childrennetwork.org/Clinical-Studies/) as well as into any future newly prioritized, and Steering Committee approved studies and will conduct the clinical trials and longitudinal follow-up studies as described in the current and any future study protocols.  The overarching expectation is that all CCs will operationalize all Steering Committee approved Network protocols. No deviations will be allowed.  All individual CCs will be required to participate in a cooperative and interactive manner with all other CCs, with the SDCC, and with the NIDDK in all aspects of the ChiLDReN Network that has been highly successful in synergizing the scientific opportunities in a network structure environment (see Terms and Conditions of Award).  Only investigators who wish to continue to carry out the protocols of the ChiLDReN, and agree to be governed by the policies and procedures of the ChiLDReN and its Steering Committee should apply under this NOFO.  It should be noted however, that in certain circumstances, not all CCs will necessarily participate in all the Steering Committee approved ChiLDReN protocols due in part to the feasibility challenges in studying rare diseases or availability of resources.

Clinical Centers will be responsible for proposing Network-wide protocols, participating in their overall development, conducting the research, and disseminating research findings.  For each new investigational or therapeutic protocol, one Clinical Center 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 participating CCs.  The Clinical Center PD/PI leading the development of the protocol will also provide protocol oversight and management if implemented as a ChiLDReN study.  All CC PDs/PIs will be strongly encouraged to fully commit their center resources and efforts to the Network protocols.  The SDCC will support protocol development, provide sample size calculations, statistical advice, questionnaires, and data analysis; coordinate implementation, training, and logistical support for the conduct of the studies; support manuscript preparation; organize committee meetings; and provide overall study coordination and quality assurance, including coordination of the logistical activities of the Data and Safety Monitoring Board(s), the Steering Committee and other standing committees; coordination of the biospecimens, tracking, distribution, and eventual depositing of both data and biospecimens into the NIDDK Central Repository or other NIDDK approved repository(ies) as appropriate as per NIDDK policy (https://www.niddkrepository.org/niddk/home.do) and NIH policy (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-21-013.html). 

Cores in support of the research activities of ChiLDReN such as a diagnostic or the administrative core are headed by a Program Director/Principal Investigator or a director and are funded as a cooperative agreement or as subcontracts through either the SDCC or one or more of the CCs. The responsibilities of each entity of the Network are described in the Terms and Conditions of Award.

Translational Science Coordination Centers in support of the research activities of ChiLDReN should support cross-cutting translational research activities either for a single disease or across the various liver diseases; or support the development of a research resource for the public investigator community.   Examples of Network translational sciences that may benefit from a Translational Science Coordination Center are: bioinformatics; genomics; transcriptomics; imaging; induced pluriopentent stem cell resource. A Translational Science Coordination Center is headed by a CC Program Director/Principal Investigator or a director and are funded as a cooperative agreement to a CC or as subcontracts through either the SDCC or one or more of the CCs. The responsibilities of each entity of the Network are described in the Terms and Conditions of Award.

Scientific and Data Coordination Center: A Scientific and Data Coordination Center will be integral to the operations of the ChiLDReN Network.  The applicant for the Scientific and Data Coordination Center for the ChiLDReN is referred to RFA-DK-23-018 regarding Network related responsibilities and obligations in support of the scientific research activities of the ChiLDReN Network.

NIDDK: The NIDDK/NIH will be responsible for organizing and providing support for the ChiLDReN and will be involved substantially with the awardees as a "partner," consistent with the Cooperative Agreement mechanism.  A designated NIDDK Project Scientist, who will provide scientific oversight, will monitor subject recruitment and study progress, ensure disclosure of conflicts of interest and Network adherence to NIDDK policies. The Chairperson and Vice-Chairperson of ChiLDReN will be determined by the Steering Committee with NIDDK concurrence.  The NIDDK will appoint 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.

Objective of this Research Program:

To promote clinical and translational research on pediatric liver diseases focusing upon elucidating the pathogenesis and natural history and developing means of treatment and clinical management, the NIDDK proposes to continue the ChiLDReN Network.  The Network would accelerate clinical and translational research and progress in understanding the pathogenesis of rare pediatric liver diseases and treatment strategies with currently available or investigational therapeutic agents. ChiLDReN would thus facilitate the ability of the Network to discover new diagnostics, etiologic, pathogenic mechanisms, and treatment options for children with rare liver diseases and those who undergo liver transplantation as a result of these diseases. The rare pediatric cholestatic liver diseases that will be addressed in this NOFO are: Biliary Atresia; Alagille syndrome; alpha-1-antitrypsin deficiency; Progressive Familial Intrahepatic Cholestasis syndromes; Bile acid synthesis defects; Mitochondrial hepatopathies; Idiopathic Neonatal Hepatitis; and pediatric primary sclerosing cholangitis.  The specific objectives of the newly formed ChiLDReN could include but are not limited to:

1. Establishment of Translational Science Coordination Centers in support of various large single disease or cross disease scientific endeavors. Presently, the ChiLDReN Network has several genomic and proteomic projects, both to-be developed and ongoing, that may synergize and have more efficient and rigorous research output through the support of centralized coordination of omic analytic activities or centralized coordination of bioinformatic support as examples.
2. Completion of genomic screens, which are currently underway or planned by the Genomics Working Group.  Furthermore, to undertake when feasible initial validation studies of genomic screen candidates in order to improve the understanding of the etiologies, gene interactions, and modifiers of disease phenotype.  In certain situations, this endeavor should strongly consider partnering with expertise that is likely to reside outside the newly formed ChilLDReN that will provide time efficient and cost-effective approaches to achieve these scientific objectives.
3. Complete the Fibroscan in Pediatric Cholestatic Liver Disease (FORCE) study biomarker assays that are underway or currently planned by the FORCE Working Group.
4. Prioritization of the various prospective longitudinal studies of ChiLDReN and explore potential opportunities for convergence of the longitudinal studies and of the data elements to be collected that will provide more uniformed and more efficient data and biospecimen collections to better inform disease modeling, end-point verification, natural history, and for ancillary studies aimed at discovering new diagnostics, etiologic and treatment options for children, both pre and post liver transplantation.
5. Discovery, identification and validation of non-invasive markers of liver disease activity, stage, or portal hypertension in pediatric patients including but not limited to new imaging modalities and serum biomarkers.
6. Conceive, develop, and initiate Phase I/II studies of new or currently available agents to treat cholestatic liver disease or liver fibrosis or other aspects of significant morbidity associated with the various liver diseases undertaken by this Network.  The NIDDK will negotiate on behalf of the ChiLDReN Network with any potential industry partners for which mutual scientific interests have been established in order to move forward with formalizing a private public partnership.
7. Ongoing Clinical studies: It is anticipated that current studies (Genetic Collection; PROBE; BASIC; LOGIC; MitoHep; and PSC) and those under development or under consideration for development will continue as planned with no disruption once ChiLDReN is re-established.
8. Conceive, develop, and initiate pilot and feasibility translational studies based upon the diseases under study by the Network. The NIDDK will reserve up to $50,000 per year from the allocated set aside for this NOFO on an annual basis to support meritorious pilot and feasibility translational studies that will be administered through the administrative core of the Network  
9. Develop approaches utilizing telemedicine methodologies for the collection of data

This is a funding opportunity to continue the ChiLDReN for a maximum of five years, contingent on satisfactory study recruitment, patient retention, progress of translational studies, and availability of funds.  

Other Special Performance Requirements:

ChiLDReN will continue to be a collaborative effort that will require frequent interactions of awardees among themselves and with the NIDDK in order to operate efficiently and effectively. 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 meeting venue as appropriate, and on monthly webinars, or as needed), site visits or webinars required by the NIDDK, and regular webinar conference calls;
2. Cooperate with other awardees in proposing, development and design or modification of research protocols, and cooperate with other awardees in carrying out approved research protocols;
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 Network-wide protocol approved by the sIRB, DSMB and the NIDDK;
5. Comply with all Network and study policies, procedures, and quality assurance measures approved by the Steering Committee;
6. Agree to oversight of the studies by a Data and Safety Monitoring Board (DSMB) and by a central or single Institutional Review Board
7. Accept awards for the support of research based on per-patient (capitated) rates and the actual numbers of subjects enrolled, followed, and completing the study;
8. Transmit study data to the Scientific and Data and Coordinating Center in a timely and accurate manner;
9. Report all adverse events in accordance with procedures established by the Steering Committee and NIDDK and FDA policies;
10. Cooperate with other awardees in the publication of study results and the eventual release to the scientific community of study procedures and other resources;
11. Serve on and/or chair subcommittees and protocol committees as assigned by the Executive or Steering committee or the NIDDK;
12. Engage a broader set of investigators external to the immediate study group to provide opportunities to analyze the biospecimens or data by means of ancillary studies;
13. Accept the “Cooperative Agreement Terms and Conditions of Award” in Section VI.2 “Award Administration Information”;
14. Agree to abide by the Network Duality of Interests Disclosure Policy.

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 eligible to apply.

Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement, are 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.

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.

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.

The additional instruction must be followed:

In the Introduction to Application, the PI/PD should state their willingness to comply with the Other Special Performance Requirements as noted in Section I.

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.

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:

Applications for the CCs will be assessed upon three main components that will further the traditional clinical research focus of the ChiLDReN Network and simultaneously, expand upon the potential translational scientific opportunities and build upon the prior accomplishments of the Network.  As such, all applicants will be required to provide 1) the future availability of patients and the clinical capacity to recruit, enroll, and retain subjects into each of the disease categories; 2) a scientific research plan that is either translational science or clinical data analysis in nature to assess PD/PI understanding of essential research challenges with the pediatric liver diseases studied by the ChiLDReN Network; and 3) propose a Phase II clinical intervention trial for pediatric primary sclerosing cholangitis.

Once the ChiLDReN Network is re-established, the scientific research plan put forth will be prioritized by the ChiLDReN Steering Committee and may become operationalized as a CC site specific project or as a future ChiLDReN Network wide study.  The determination of operationalization of scientific research plans will be based upon the availability of Network resources, Steering Committee assessment of the scientific merits, and feasibility at the Network level, and with NIDDK/NIH approval.

Research Strategy: Applications for the CCs must include a scientific research strategy that encompasses all three of the above mentioned required elements for the purposes of assessment of PD/PI knowledge and identification of current research challenges in the pediatric liver diseases studied by ChiLDReN.  A Translational Science Coordination Center project is not a requirement and is entirely optional. The Scientific research strategy must address the first three items below:

1. Future availability of patients with the rare pediatric liver diseases from their center.  A description of the total number of patients seen with each of the ChiLDReN liver diseases at the CC as well as the average number of new annual referrals must be provided.  Applications also need to describe a strategy for recruiting the patients into the ChiLDReN.
2. A translational mechanistic or discovery science or clinical data analysis project.  The project must focus upon a ChiLDReN disease or diseases and should address any of a number of significant research priorities and challenges that would advance the understanding of the disease pathophysiology or clinical features associated with disease trajectory. Due to the practical constraints in conducting rare disease research, the scientific strategy may utilize a variety of approaches such as: hypothesis testing or generating; discovery based; biomarker discovery or validation; database analysis; or research resource development; as examples. The project should advance our understanding or fill a knowledge gap of the disease at either the clinical or mechanistic translational level. Examples of topics may include but are not limited to: determinants of quality of life; defining risk factors for disease progression or regression; defining clinical risks for developing extra-hepatic complications; refining the natural history of cholestatic liver disease; biomarkers for liver fibrosis, liver function, and portal hypertension; defining omic signatures associated with disease state or progression; determining proteomic signatures for disease diagnosis or progression; determining the role of altered developmental signaling in disease pathogenesis; defining mechamisms of disease initiation or injury pathogenesis. The project is strongly encouraged to utilize the vast collection of ChiLDReN data and biospecimens which may be found at https://repository.niddk.nih.gov/home/.  The proposal may utilize animal models if scientifically appropriate, and the scientific plan of the proposal should not exceed 5 years in duration.
3. Pediatric primary sclerosing cholangitis Phase II intervention trial.  A Phase II magnitude clinical intervention trial must be proposed.  The interventional trial should be assumed to be operationalized within all the ChiLDReN Network CCs. Applicants are asked to refer to the PHS Human Subjects and Clinical Trials Information form for details as they develop their trial.  The clinical trial project must address and provide justifications for the following protocol parameters:
   1. Inclusion and exclusion criteria
   2. Type of intervention to be used and dosing
   3. Study design
   4. Frequency of follow-up visits
   5. Duration of intervention
   6. Definition of clinical events and primary and secondary endpoints to be assessed
   7. Definition of safety signals to be monitored
   8. Statistical analysis strategy
   9. Patient recruitment plan
   10. Approaches to incorporate telemedicine methodologies for the collection of data
   11. The Pediatric primary sclerosing cholangitis Phase II intervention trial project  is to be presumed to be operationalized by the entire ChiLDReN Network.  However, for the purposes of your individual CC  budget request, it should be reflective of and be proportional to your anticipated needs for the operationalization of your clinical trial project at your CC site.
4. (Optional) Translational Science Coordination Center. A Translational Science Coordination Center proposal is entirely optional.  The ChiLDReN Network has developed a vast repository of clinical and translational data across the various liver diseases as well as a robust biospecimen collection. For instance, over the past years, various smaller scaled omics projects have yielded large volumes of data. In the next funding cycle, the Network should be positioned to more efficiently and effectively coordinate the various datasets presently generated at various CCs that may synergistically accelerate analysis through improved integration and harmonization of data sets under appropriate expertise to support scientific rigor in the analytic procedures and protocols.  Likewise, the Network is positioned to pursue further biospecimen analytics across omic platforms and for developing research resources for the investigator community. Thus, a Translational Science Coordination Center project may focus upon providing coordinated support for Network activities in bioinformatics; genomics; transcriptomics; or induced pluripotent stem cell libraries as examples.  For all Translational Science Coordination Center project, at a minimum, the following must be addressed:
   1. State the type of translational science coordination to be undertaken for the benefit of the Network or the greater investigator community.
   2. Approaches to engage the expertise of CCs in the re-established ChiLDReN in a cooperative fashion.
   3. Approaches to cooperatively coordinate data transfers between the Translation Science Coordination Center and the SDCC.
   4. Investigative team along with individual experience and expertise must be delineated.
   5. Investigative team members must state his/her general support of collaborative, cooperative research and interaction with the NIDDK, the other CCs, and the SDCC through the Network concept.
   6. Access to or availability of necessary laboratory equipment and space to efficiently operationalize the Translational Science Coordination Center’s activities.    

Each CC must delineate how they will be able to submit data to the SDCC and biospecimens to the NIDDK Central Repository (supported by an independent contract from NIDDK) and to central laboratories and biological cores as approved by the Steering Committee. 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 ChiLDReN (e.g., Recruitment committee, Publications committee, etc.) and the establishment of uniform procedures and policies.

Clinical Centers that include a core as part of the application must describe the functions, capabilities and willingness of the core facility to carry out supportive roles in the conduct of ChiLDReN studies or administrative support as appropriate. The final decision on the acceptance of the core for ChiLDReN scientific activities will be at the discretion of the NIDDK based upon Network scientific priorities and the availability of support. 

An organizational structure for the CC should be set forth in the application, delineating specific personnel (e.g., coordinators, hepatologists, pathologists, radiologists, etc.) available to carry out the Network 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 scientific objectives of the ChiLDReN Network.  The final decision on the acceptance of the additional scientific personnel will be at the discretion of the NIDDK based upon the scientific value that the individual adds to the scientific objectives of the Network and upon 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 SDCC through the Network concept.  Applicants should discuss their willingness, and that of the institutions involved, in pursuing a per patient basis (capitation) of operational costs.

CCs must be able to interact with the SDCC to transmit and edit data and should discuss their capability to participate in a distributed data entry system. 

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.

Section 2 - Study Population Characteristics

2.5 Recruitment and Retention Plan

For the required pediatric primary sclerosing cholangitis clinical trial, please include a discussion of the availability of potential participants for the proposed study and anticipated yield from recruitment and screening efforts. The plan should also include a discussion of past experience in recruiting and retaining similar populations, expected challenges to recruitment and retention, and possible contingency plans.

For the currently ongoing ChiLDReN Network-wide clinical studies and trials that will continue into the next funding cycle, CC applications must describe detailed plans for future subject recruitment and retention related to each of the ongoing research studies that the Clinical Center is actively participating in and a description of the type of diseases and the number of children seen at their CC within the past two years who may be candidates to be enrolled in those ChiLDReN Network-wide studies.  More importantly, each CC should describe future projections to recruit patients into the active Network-wide protocols at their site.  Each CC application must describe their plans for retaining study subjects, so that a longitudinal assessment of pediatric liver disease can be accomplished according to the ongoing Network-wide protocols.

2.9 Inclusion Enrollment Report

For the required pediatric primary sclerosing cholangitis clinical trial, if there is more than one site, please provide a table showing the expected number and demographics of the population to be recruited at each site.

Section 4 – Protocol Synopsis

4.2 Outcome Measures

For the required pediatric primary sclerosing cholangitis clinical trial, applications should indicate all time-points when an outcome measure will be collected.

4.3 Statistical Design and Power

For the required pediatric primary sclerosing cholangitis clinical trial, the sample size and statistical power calculations should contain enough detail, including a description of any assumptions made, so that a reviewer can readily duplicate the sample size. The power analysis should include a discussion of the anticipated level of adherence to the intervention and rates of follow-up (i.e., drop out/lost to follow up) during key outcome collection contacts. There should be a discussion of how missing data will be handled. Any planned interim analyses should also be described.

Section 5 - Other Clinical Trial-related Attachments

5.1 Other Clinical Trial-related Attachments

For the required pediatric primary sclerosing cholangitis clinical trial : Milestone Plan. The filename "Milestone Plan.pdf" must be used for this attachment.  You should append milestone plan for each study record. For example, for study record 1, its filename should be “Milestone Plan1.pdf”, for study record 2 its filename should be “Milestone Plan2.pdf”, etc.

The Milestone Plan attachment is separate and distinct from the Study Timeline attachment. For the required pediatric primary sclerosing cholangitis clinical trial, applicants are required to provide detailed interim performance measures and timelines for completing key objectives and administrative functions for the proposed clinical trial(s), as applicable. Milestones should be easily measurable and realistic. Milestones may include, as applicable, but are not limited to:

• Finalization of the clinical trial protocol(s) and informed consent/assent forms (with program director agreement, if applicable) and establishment of a single IRB and provision of IRB approval
• Registration of the clinical trial(s) in ClinicalTrials.gov
• Completion of all required regulatory approvals (e.g., Investigational New Drug Application or Investigational Device Exemption from the Food and Drug Administration)
• Contracts/third party agreements, including intervention product supply
• Training of study staff
• Anticipated date of enrollment of the first participant
• Randomization of 25%, 50%, 75% and 100% of the target sample size
• Follow-up visit completion, if applicable, of 25%, 50%, 75% and 100% of the enrolled or randomized study population, including women, minorities and children
• Expected drop-out or lost-to-follow-up rate overall, or by treatment arm
• Anticipated rate of adherence to the intervention(s)
• Completion of data collection
• Completion of primary endpoint and secondary endpoint data analyses
• Completion of final study report and manuscript submission
• Closeout plans/communication of results to participants
• Reporting of results in ClinicalTrials.gov.

These milestones will be negotiated at the time of the award, as appropriate. If milestones are not achieved fully, NIDDK may request development of a remedial plan and more frequent monitoring of progress or take other remedial actions.

Applications that propose a clinical trial that lack the Milestone Plan are considered incomplete and will not be peer reviewed.

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.

Foreign Institutions

Foreign (non-U.S.) institutions must follow policies described in the NIH Grants Policy Statement, and procedures for foreign institutions described throughout the SF424 (R&R) Application Guide.

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.

Applicants to this NOFO have been required to provide the following:

1. A Pediatric primary sclerosing cholangitis Phase II intervention clinical trial focused on scientific issues with Pediatric primary sclerosing cholangitis Phase II clinical trial development in a network environment and is a disease currently being studied by the ChiLDReN Network.  The standard review criteria noted in this NOFO should be applied to the research strategy of the Pediatric primary sclerosing cholangitis Phase II intervention clinical trial.
2. A description of the CC’s patient population that may contribute to the conduct of the currently ongoing clinical studies or trials in the ChiLDReN Network and potentially into the future.  The description of the patient population at each CC should be assessed independently of the patient population being studied in the proposed Pediatric primary sclerosing cholangitis Phase II intervention clinical trial.
3. A translational science project or a clinical data analysis project that addresses a significant disease pathophysiologic mechanism or a significant clinical knowledge deficit that if achieved would improve the understanding of disease pathophysiology or yield clinical details that may inform future disease trajectory or be used for intervention endpoints.  The standard review criteria noted in this NOFO should be applied.

An optional Translational Science Coordination Center research strategy may be included in the application.  The Translational Science Coordination Center research strategy should focus upon methods and approaches to support increased cross cutting research synergy, efficiencies, and scientific rigor in pursuit of gaining a better understanding of the pathogenic mechanisms or development of research resources that lead to increased efficiency of liver disease research with one or more of the rare pediatric liver diseases being studied by the ChiLDReN Network.  Standard review criteria noted in this NOFO should be applied if an optional Translational Science Coordination Center research strategy is included in the application. 

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.

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 convened by 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 NIDDK 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 (DHHS) 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 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 recipients for the project as a whole, although specific tasks and activities may be shared among the recipients and the NIH as defined below. 

The Program Director(s)/Principal Investigator(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 include 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..

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 U01 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 disagreement that may arise on scientific/programmatic matters (within the scope of the award), between award recipients and the NIDDK may be brought to dispute resolution. A dispute resolution panel will be composed of three members --one selected by the recipient (or the Steering Committee, with the NIDDK member not voting), a second member selected by NIDDK, and the third member elected by the two prior selected members. These special dispute resolution procedures in no way affect the recipient's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulations at 42 CFR Part 50, Subpart D, and HHS regulations at 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: GrantsInfo@nih.gov (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: support@grants.gov

Edward Doo, M.D.
Division of Digestive Diseases and Nutrition 
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) 
Telephone: 301-451-4524 
Email: ed56o@nih.gov

Katrina Loh, M.D.
Division of Digestive Diseases and Nutrition
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone: 301-827-1079
Email: katrina.loh@nih.gov

Cheryl Nordstrom, Ph.D.
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone: 301-402-6711
Email: jian.yang@nih.gov

Ms. Elizabeth Gutierrez
National Institute of Diabetes and Digestive and Kidney Diseases(NIDDK)
Telephone: 301-594-8844
Email: gutierrezel@niddk.nih.gov 

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.