Department of Health and Human Services


Part 1. Overview Information
Participating Organization(s)

National Institutes of Health (NIH)

Components of Participating Organizations

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Funding Opportunity Title

Continuation of ChiLDReN, the Childhood Liver Disease Research Network (U01)

Activity Code

U01 Research Project – Cooperative Agreements

Announcement Type

Reissue of RFA-DK-08-005

Related Notices

  • August 21, 2013: Removed reference to ASSIST in section IV.3, since ASSIST is currently only available for multi-project applications.

Funding Opportunity Announcement (FOA) Number

RFA-DK-13-011

Companion Funding Opportunity

None

Number of Applications

See Section III. 3. Additional Information on Eligibility.

Catalog of Federal Domestic Assistance (CFDA) Number(s)

93.847 

Funding Opportunity Purpose

The purpose of this funding opportunity announcement (FOA) is to continue the support of a Data Coordination Center and Clinical Centers of the Childhood Liver Disease Research and Education Network as the Childhood Liver Disease Research Network (ChiLDReN).  ChiLDReN will continue clinical and translational research on rare pediatric liver diseases that include: Biliary Atresia; Alagille syndrome; alpha-1-antitrypsin deficiency; Progressive Familial Intrahepatic Cholestasis syndromes; Bile acid synthesis defects; Mitochondrial hepatopathies; Idiopathic Neonatal Hepatitis; and Cystic Fibrosis Liver Disease. 

Key Dates
Posted Date

July 18, 2013

Open Date (Earliest Submission Date)

October 20, 2013    

Letter of Intent Due Date(s)

October 20, 2013 

Application Due Date(s)

November 20, 2013, 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.

AIDS Application Due Date(s)

Not Applicable

Scientific Merit Review

March-April 2014  

Advisory Council Review

May 2014

Earliest Start Date

July 2014

Expiration Date

November 21, 2013

Due Dates for E.O. 12372

Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. 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.

Table of Contents

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

Part 2. Full Text of Announcement


Section I. 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 to continue the Childhood Liver Disease Research and Education Network as 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) at the commencement of the prior funding cycle.  The overarching research mission of ChiLDReN has been to improve our understanding of 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; and Cystic Fibrosis Liver Disease.  To this end, the prior accomplishments of this Network 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; and the assessment of the effectiveness of fat-soluble vitamin supplementation in biliary atresia; among many other accomplishments.   Additionally, the ChiLDReN Network developed a robust biospecimen repository with over 1100 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.  As such, the ChiLDReN Network is poised to exploit the resources of the biosample repository to further our understanding of the pathogenesis of these pediatric liver diseases.  The evolution of the omics technologies and sciences presents itself as an opportune pathway to explore.  The ChiLDReN Network should also focus on capitalizing upon the findings from the recently completed START trial in terms of evaluating disease pathogenesis concepts and prioritizing new research challenges.  In addition to biliary atresia, the ChiLDReN Network had previously studied patients with the other above mentioned liver diseases.  The collection of clinical data and biosamples from these populations also serve as an opportunity to explore issues such as the variable disease phenotype expression and the mechanisms and factors that may modify disease expression. 

In order to meet the future research challenges and opportunities in pediatric liver diseases, the ChiLDReN Network will need to prioritize those diseases currently being studied that are optimally positioned to exploit the scientific opportunities that will translate into feasible and achievable advancement of the understanding of the pathogenesis or advancement in the clinical management of the disease.  Some of the Network challenges may require the further identification and enrollment of patients into one of the prioritized diseases; in others, the currently available collected data, biosamples, or identified patients may be sufficient to embark upon a scientific endeavor or clinical study or trial.

Organization of the ChiLDReN Network

The ChiLDReN Network will be a cooperative network of up to 15 Clinical Centers (CC) and one Data Coordinating Center (DCC).  Clinical Centers will be responsible for proposing 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 clinical center PDs/PIs will be strongly encouraged to fully commit their center resources and efforts to the Network protocols.  The DCC 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 Data and Biospecimen Respository as per NIDDK policy (https://www.niddkrepository.org/niddk/home.do).  Applicants for the DCC should also propose a subcontract selection process that may be utilized to develop additional services in support of the scientific activities of the ChiLDReN Network that may include but are not limited to a Bioinformatics Core; a DNA extraction service; analytic genomics services.  Ultimately, the specific activities of any core or services in the conduct of the scientific activities of ChilLDReN will be dependent upon the scientific priorities of the Steering Committee.

Two types of applications will be accepted for this funding opportunity: Clinical Centers and Data Coordination Center.

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 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, and treatment options for children with rare liver diseases and those who undergo liver transplantation. The specific objectives of the newly formed ChiLDReN could include but are not limited to:

1. Survey on-going genome-wide association studies and exome sequencing projects currently underway within the Network in order to develop a unified, ChiLDReN Network list of prioritizations for whole exome or whole genome sequencing of disease cohorts for discovery based research in order to improve the understanding of the etiologies, gene interactions, and modifiers of disease phenotype.  This endeavor should strongly consider partnering with expertise that is likely to reside outside of the newly formed ChilLDReN that will provide time efficient and cost effective approaches to achieve these scientific objectives.

2. Utilize the findings of the START Trial to pursue mechanistic based studies with the biospecimens and data collected to explore the pathogenesis of biliary atresia.

3. Prioritization of the various prospective longitudinal studies of ChiLDReN and of the data elements to be collected that will provide data and biospecimens that will 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.

4. Continuation of the prospective longitudinal study of cystic fibrosis liver disease (CFLD) aimed at identifying predictors of development of liver disease in children with CF as well as predictors of outcome in children with CFLD.

5. 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. Phase I/II studies of new agents to treat cholestatic liver disease or liver fibrosis in children.

7. Study of modifier genes in the various pediatric liver diseases studied by ChiLDReN.

This is a one-time 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.   

Background Information

Although a rare condition in children, the pediatric cholestatic liver diseases are a devastating condition and are research priorities in the Trans-NIH Action Plan for Liver Disease Research (http://www2.niddk.nih.gov/AboutNIDDK/ResearchAndPlanning/Liver_Disease/Action_Plan_For_Liver_Disease_Intro.htm).  Children with biliary atresia or any of the other cholestatic liver diseases studied by ChiLDReN account for the majority of the liver transplantations performed in the United States in children.  In addition, liver disease is the second or third leading cause of death in children with cystic fibrosis.   

Composition of the ChiLDReNThe ChiLDReN will consist of the following: the NIH, up to fifteen CCs, a DCC, an Executive Committee, a Steering Committee and its subcommittees, Data and Safety Monitoring Boards (DSMB), and other committees as needed.  Cores in support of the research activities of ChiLDReN are headed by a Program Director/Principal Investigator or a director and are funded as a cooperative agreement or as subcontracts through either the DCC or one or more of the CCs. The responsibilities of each entity of the Network are described in the Terms and Conditions of Award.

The NIDDK 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 adherence to NIDDK policies. The NIDDK will appoint the 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.

Ongoing Clinical studies:  It is anticipated that current studies and those being developed will continue as written or as planned with no disruption once ChiLDReN is continued. 

Clinical Centers for ChiLDReN. The Clinical Centers (CCs) will continue to recruit subjects into the newly prioritized and approved as well as the currently ongoing ChiLDReN studies and will conduct the clinical trials and longitudinal follow-up as described in the study protocols. An overview of currently active protocols may be found at the ChiLDReN website: http://www.childrennetwork.org.  No deviations will be allowed.  All individual CCs will be required to participate in a cooperative and interactive manner with one another, with the DCC, and with the NIDDK in all aspects of the ChiLDReN (see Terms and Conditions of Award).  Only investigators who wish to continue to carry out the protocols of the ChiLDReN, be open to the concept of a centralized Intuitional Review Board at their institution, and agree to be governed by the policies and procedures of the ChiLDReN and its steering committee should apply under this FOA.  It should be noted however, that not all CCs will necessarily participate in all of the approved ChiLDReN protocols. 

Data Coordinating Center for ChiLDReN. The DCC will take on the administrative and data collection/analysis functions and will be responsible for the conduct of all of the ongoing and future studies of ChiLDReN.  Thus, they should include methodology and plans for transferring and capturing all data currently being collected by ChiLDReN.  An overview of currently active protocols may be found at the ChiLDReN website: http://www.childrennetwork.org.  In addition, the DCC will be responsible for supporting any protocol development or modifications; providing sample size calculations, statistical advice, questionnaires, and data analysis; supporting development, implementation, and maintenance of a data base of clinical information and blood samples; developing or modifying any data safety and monitoring plans; supporting manuscript preparation; exploring the integration of web based data entry, digital data storage, automated electronic medical record downloads of data to a centralized database; and providing overall study coordination and quality assurance, including coordination of the activities and meetings (including conference calls or face to face meetings) of the Data and Safety Monitoring Boards (DSMB), the Steering Committee, and other needed committees. The DCC will prepare or modify protocols for submission to the DSMB and the Steering Committee for their approval prior to the implementation of any study protocols or protocol change. The DCC will be responsible for preparation of documents to the Food and Drug Administration (FDA) in support of Investigational New Drug Applications (INDs) held by the NIDDK on behalf of ChiLDReN.  The DCC will also prepare all reports including data reports for review by the DSMBs at their meetings. The DCC will also be responsible for the logistics and planning of the meetings of the Steering Committee and the various operational committees of ChiLDReN. The Data Coordinating Center will be responsible for acquiring and administering subcontracts as needed. (See Terms and Conditions of Award). The NIDDK has established Central Biosample, Genetic, and Data Repositories for the ongoing and archival storage of data and biospecimens collected in large, multi-site studies funded by NIDDK. The DCC will work with the NIDDK Biosample, Genetic and Data Repositories and the CCs to coordinate procedures for coding, shipping, processing, receipt, and storage of study samples that are to be maintained in the Repositories and dispensed to steering committee approved ancillary study sites.  In addition, the DCC will coordinate with the NIDDK Data and Biospecimen Repository to prepare the collected data and biosamples for eventual archiving and distribution.  All samples and data transferred to the Repositories will be under the custodianship of the NIDDK, although the ChiLDReN Steering Committee will have proprietary control of and exclusive access to the samples and data for an agreed-upon period of time.  Only investigators who wish to continue to carry out the protocols of the ChiLDReN, be open to the concept of a centralized Intuitional Review Board at their institution, and agree to be governed by the policies of the ChiLDReN and its steering committee should apply under this FOA.

Steering Committee. The Steering Committee will be the main governing body of the ChiLDReN (see Terms and Conditions of Award). An Executive Committee comprised of the Study Chair and Co-Chair, if appropriate, will be appointed by the NIDDK; the Program Director/Principal Investigator of the DCC; 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, as needed for efficient progress of the trial. Other subcommittees of the Steering Committee will be prioritized and operationalized 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 as appropriate.

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 DCC. All protocols or changes to protocols will be approved by Institutional Review Boards, 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 Project Scientist. 

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. Applicants must explicitly indicate their willingness to:

1. Participate in Steering Committee meetings (expected to occur in person 3-4 times a year in the Washington DC/Baltimore metropolitan area or other suitable meeting venue as appropriate, and as monthly teleconferences, or as needed), site visits required by the NIDDK, and regular 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;

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. 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 (Clinical Centers only);

8. Transmit study data to the Data and Coordinating Center in a timely and accurate manner (Clinical Centers only);

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 chair subcommittees and protocol committees as assigned by the steering committee or the NIDDK;

12. Accept the “Cooperative Agreement Terms and Conditions of Award” in Section VI.2.A “Award Administration Information”.

Section II. Award Information
Funding Instrument

Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, NIH scientific or program staff will assist, guide, coordinate, or participate in project activities.

Application Types Allowed

New
Renewal

The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.

Funds Available and Anticipated Number of Awards

NIDDK intends to commit a total of $6.5 million for up to 16 awards for fiscal year 2014. Future year amounts will depend on annual appropriations.

Although the financial plans of the IC(s) provide support for this program, awards pursuant to this funding opportunity are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications.

Award Budget

Awards to each Clinical Center will be approximately $166,666 in direct costs ($266,000 in total costs) and to the Data Coordination Center will be approximately $1.6 million in direct costs ($2.5 million in total costs).  Application budgets are not limited, but need to reflect the actual needs for the proposed project.  Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. 

Award Project Period

The project period may not exceed five years. 

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

Section III. Eligibility Information


1. Eligible Applicants


Eligible Organizations

Higher Education Institutions

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

Nonprofits Other Than Institutions of Higher Education

For-Profit Organizations

Governments

Other

 For practical ChiLDReN Network operational coordination, logistics, and management, non-domestic (non-U.S.) Entities (Foreign Institutions) will be limited to those based in North America.

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.

Required Registrations

Applicant Organizations

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

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

All PD(s)/PI(s) must have an eRA Commons account and should work with their organizational officials to either create a new account or to affiliate an existing account with the applicant organization’s eRA Commons account. 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.

Eligible Individuals (Program Director/Principal Investigator)

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

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.

2. Cost Sharing

This FOA 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.

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

Section IV. Application and Submission Information


1. Requesting an Application Package

Applicants must download the SF424 (R&R) application package associated with this funding opportunity using the “Apply for Grant Electronically” button in this FOA or following the directions provided at Grants.gov.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

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

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:

The letter of intent, preferably electronically, should be sent to:

Francisco O. Calvo, Ph.D.
Chief, Review Branch
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
National Institutes of Health
6707 Democracy Boulevard, Room 752, MSC 5452
Bethesda, MD 20892-5452
(Courier use 20817)
Telephone: 301-594-8897
Email: calvof@mail.nih.gov

Page Limitations

All page limitations described in the SF424 Application Guide and must be followed, with the following exceptions or additional requirements:

Required and Optional Components

The forms package associated with this FOA includes all applicable components, required and optional. Please note that some components marked optional in the application package are required for submission of applications for this FOA. Follow all instructions in the SF424 (R&R) Application Guide to ensure you complete all appropriate “optional” components.

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.

SF424(R&R) Senior/Key Person Profile

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

R&R or Detailed Budget

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions: Budget requests from CC's should reflect anticipated clinical activity in the currently ongoing clinical studies in ChiLDReN.  The current studies are: PROBE: A prospective study of infants and children with cholestasis; BASIC: A prospective database study of older children with biliary atresia; LOGIC: A longitudinal study of genetic causes of intrahepatic cholestasis; and MITOHEP: A longitudinal study of mitochondrial hepatopathies.  The current studies may be found at:  http://www.childrennetwork.org/research.html.  A CC budget request for a currently ongoing scientific core for the next ChiLDReN funding cycle should be fully justified. The final decision on the acceptance of the core for future ChiLDReN scientific activities will be at the discretion of the NIDDK based upon the availability of support.  A budget for the scientific research plan requested of each CC applicant should be included in the application.  In addition, the budget request for the scientific research plan should also be delineated in a separate PHS 2590 budget page that is appended to the appendix of the application.              

PHS 398 Cover Letter

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:

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.

Applications for the CCs will be assessed upon two main components, 1) the future availability of patients and the clinical capacity to recruit, enroll, and retain subjects into the currently active study protocols (currently active protocols may be found at the ChiLDReN website: http://www.childrennetwork.org); and 2) upon a scientific research plan to assess PD/PI identification of essential research challenges in pediatric liver diseases studied by the ChiLDReN Network that may be addressed by the collected data and biospecimens.  The scientific research plan may eventually become a future ChiLDReN Network wide study or an individual ancillary study.  CC applications must provide detailed plans for future subject recruitment and retention related to the ongoing research studies of the ChiLDReN and a description of the type of disease and the number of children seen at their CC within the past two years who may be candidates to be enrolled in ChiLDReN and more importantly, future projections with biliary atresia, idiopathic neonatal hepatitis, Alagille syndrome, Alpha-1-antitrypsin deficiency, progressive familial intrahepatic cholestasis, bile acid synthesis defects, mitochondrial hepatopathies and cystic fibrosis liver disease.  Each CC submitting an application in response to this FOA must provide evidence of their ability to carry out the protocols already approved by the ChiLDReN Steering Committee.

Applications for the CCs must also include a scientific research plan for the purposes of assessment of PD/PI knowledge and identification of current research challenges in the pediatric liver diseases studied by ChiLDReN.  The scientific research plan should utilize the currently available ChiLDReN data, biospecimen repository, or enrolled patients.  The scientific research plan may encompass a range of analyses analogous to an ancillary study proposal in scope that will exploit the vast data, biosample repositories and patient enrollees of the ChiLDReN Network.   With over 100,000 serum/plasma/urine/tissue specimens collected by the ChiLDReN Network for these rare pediatric liver conditions, this repository of data and biosamples represents an abundant opportunity to utilize these resources for advancing our understanding of these diseases.  In addition to the 1100 biliary atresia DNA samples, the Network also has within its inventory approximately 1700 DNA specimens from corresponding parents; 2200 frozen liver specimens across the liver diseases studied within the Network; and 340 biliary atresia bile duct specimens.  Scientific research plans should advance our understanding or fill a knowledge gap of the disease at either the clinical or translational level.  Scientific research plans may span from clinical to translational sciences.  Examples of topics may include but are not limited to: 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 micro RNA species associated with disease state or progression; defining the role of autotaxin in cholestatic liver disease; determining proteomic signatures for disease diagnosis or progression; determining the role of altered developmental signaling in disease pathogenesis.

Each CC must delineate how they will be able to submit data to the DCC and biospecimens to the NIDDK Repositories (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 DCC 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, Publications, etc.) and the establishment of uniform procedures and policies.

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 approved protocols. Plans for data collection beyond the transplant period should also be included in the application. 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.

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 all approved studies of ChiLDReN and any future approved studies 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 the availability of support.  

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 translational 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 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.  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 DCC to transmit and edit data and should discuss their capability to participate in a distributed data entry system.

Supplemental Instructions for Data Coordinating Center (DCC):

The application for the DCC must demonstrate experience in the area of coordination of multi-center clinical trials and epidemiological studies in all phases from start-up (e.g., protocol development, manual of operation) through analysis and publication preparation and submission.  The applicant for a DCC must demonstrate experience in the area of coordinating multi-center clinical trials and epidemiological studies in all phases: protocol and manual of operations development, staff training in study procedures, research instrument development, data collection and management, quality assurance, data analysis, distributed data entry, electronic communications, administrative management and coordination. Specific experience in coordinating or monitoring studies of liver disease is not required, but the applicant may wish to consider a hepatologist in the application as a collaborator or advisor.

DCC applications should discuss the applicant's familiarity and experience with various aspects of study design in rare pediatric diseases that would be important in developing clinical protocols, for example: eligibility criteria; baseline and outcome measures; methods of randomization; important considerations for making sample size and power calculations; methods and frequency of data collection and entry; monitoring accuracy of data collection; quality control procedures including training and certification for multiple protocols, some of which may occur simultaneously; managing labeling and handling of serum and tissue samples (see below); and plans for statistical analysis. The DCC application should also describe their familiarity with model plans for managing the Data and Safety Monitoring Board.

The applicant for the DCC should delineate how laboratory specimens will be handled.  NIDDK anticipates that some clinical outcome measures may be centrally assessed.  Laboratories responsible to the DCC will manage specimens and laboratory studies as required by the Steering Committee.  The costs of performing specific laboratory tests will be budgeted as a part of the per patient costs of each CC. The costs of specimen shipment as well as laboratory data acquisition and management will be a part of the budget of the DCC. Estimated shipping and handling costs for specimens should be included in the budget of DCC.

In the event that additional scientific cores in support of the ChiLDReN Network are deemed scientifically necessary by the Steering Committee and the NIDDK, the DCC application should provide a detailed process by which applications are solicited, reviewed, and recommended for consideration by the NIDDK.  Applications for a core facility in support the ChiLDReN scientific activities should be entertained from both within and outside of the Network sites.

It is expected that the PD/PI of the DCC will carry out a significant leadership role in the network. A description of past and future participation in a leadership role must be included. 

The DCC applicant must also address the following regarding responsibilities and requirement for the DCC:

1. Participation in the design of all research studies and the development or updating of the manual of operation, data collection forms, and questionnaires;

2. Development and implementation of systems for communication among Steering Committee members and among study sites;

3. Data collection, editing, processing, analysis and reporting utilizing the latest technology to assure timely reporting to the NIDDK, the investigators and the DSMB;

4. Monitoring of adherence to the research plan and of data quality;

5. Establishment of procedures that insure the safety and confidentiality of all records.

6. Procedures for coordinating submission of biospecimens from the CCs to the NIDDK Repositories, central laboratories, and biological cores and to ancillary study participants.

7. Ability to fill out necessary regulatory documents in support of the Food and Drug Administration Investigational New Drug Application (IND).

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS)) as provided in the SF424 (R&R) Application Guide.

Appendix: Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.  Clinical Center applications will append the scientific research plan budget on a PHS 2590 budget page in to the appendix.

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. Submission Dates and Times

Part I. Overview Information contains information about Key Dates. 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.

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.  If a Changed/Corrected application is submitted after the deadline, the application will be considered late.

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.

4. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

5. Funding Restrictions

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

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

6. Other Submission Requirements and Information

Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide.

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

For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically.

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

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

See more tips for avoiding common errors.

In order to expedite review, applicants are requested to notify the NIDDK Referral Office by email at calvof@mail.nih.gov  when the application has been submitted. Please include the FOA number and title, PD/PI name, and title of the application.

Post-Submission Materials

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

Section V. Application Review Information


1. Criteria

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

Overall Impact

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).

Scored Review Criteria

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

Significance

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

Investigator(s)    

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

Innovation

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

Approach

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

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

Environment

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

Additional Review Criteria

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.

For Clinical Center Applications:

Future patient enrollment potential: Are the CC patient recruitment, enrollment, and retention plans sufficient to contribute to the long term follow up of patients?  Is the projected number of future patients representative of that centers prior experience in pediatric cholestatic liver disease patients?

Scientific research plan: Did the scientific research plan suggest a study that would utilize the ChiLDReN data or biospecimen repository or of the patients enrolled in ChiLDReN?  Does the scientific research plan address a clinical or translational scientific knowledge gap in the understanding of pediatric liver disease?  Does the scientific research plan address a current research challenge for a rare pediatric liver disease?  Is the scientific research plan practical in achieving the scientific goals within a five year or less time frame?

Cores: Does the core bring additional scientific value to the ChiLDReN Network activities?  Do the personnel have the appropriate expertise, experience, and capabilities to provide the scientific services?

For Data Coordination Center Applications:

Does the core selection plan provide for rigorous and impartial solicitation and review process of applications?  Are reviewer conflicts of interest addressed in the plan and is the conflict remediation plan adequate?  Is there a process for reviewer selection and is it appropriate?   Is there a timeline for the initiation and completion of the core selection process?

Protections for Human Subjects

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

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

Inclusion of Women, Minorities, and Children 

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

Vertebrate Animals

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

Biohazards

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

Resubmissions

Not Applicable

Renewals

For Renewals, the committee will consider the progress, participation and leadership roles made in the last funding period.

Revisions

Not Applicable

Additional Review Considerations

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

Applications from Foreign Organizations

Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.

Select Agent Research

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

Resource Sharing Plans

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

Budget and Period of Support

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

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:

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

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 FOA. Following initial peer review, recommended applications will receive a second level of review by the National Diabetes and Digestive and Kidney Diseases Advisory Council (NDDKAC). The following will be considered in making funding decisions:

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

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

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 grantee’s business official.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.      

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

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, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

Cooperative Agreement Terms and Conditions of Award

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 45 CFR Parts 74 and 92 (Part 92 is applicable when State and local Governments are eligible to apply), and other HHS, PHS, and NIH grant administration policies.

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

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). Awardee(s) will name investigators to serve as members on a Steering Committee and other subcommittees, as appropriate, meeting periodically. Awardees will be required to accept and implement the common protocol(s) and procedures approved by the Steering Committee.

3. Designating Protocol Chairs. The PDs/PIs (for studies involving multiple protocols) shall designate a single Protocol Chairperson (if the PD(s)/PI(s) 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 awardee/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 and completeness. Awardees 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, to the NIDDK Program Director including as a minimum, summary data on protocol performance. For coordinated multiple awards or a multi-site single award, the NIDDK Program Director may require additional information from individual awardees/sites. Such reports are in addition to the required annual noncompeting continuation progress report.

7. Establishing procedures, where applicable, for all participating institutions in coordinated awards to comply with FDA regulations for studies involving investigational agents or devices and to comply with the requirements of 45 CFR Part 46 for the protection of human subjects, and the NIH policy requirements for the inclusion of women, minorities and children.

8. Reporting of the study findings.  Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.  The awardee 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 awardees consistent with NIH and study policies.

9. Support or other involvement of industry or any other third party in the study -- e.g., participation by the third party; involvement of study resources or citing the name of the study or NIDDK support; or special access to study results, primary data/summary information, or resources -- may be advantageous and appropriate. However, except for licensing of patents or copyrights, support or involvement of any third party is permitted only after concurrence by NIDDK.

10.  Study investigators are encouraged to publish and to release publicly and disseminate results and other products of the study, in accordance with study protocols and steering committee policies on publications.

11.  Maintaining confidentiality of information:  The awardee(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 a company collaborating with the study.

12. The NIDDK has established Central Biosample, Genetic, and Data Repositories for the

archiving and storage of data and biosamples collected in large, multi-site studies funded by NIDDK. The PD/PI or his/her designee will coordinate with the NIDDK Data Repository to prepare the collected data for eventual archiving and distribution. In addition, if applicable, the PD/PI or his/her designee will work with the NIDDK Biosample Repository to coordinate procedures for coding, shipping, processing, receipt, and storage of study samples that are to be maintained in the Repository. All samples and data transferred to the Repositories will be under the custodianship of the NIDDK, although the study’s Steering Committee will have proprietary control of and exclusive access to the samples and data for an agreed-upon period of time. Subsequently samples and data will be available to the wider scientific community in accordance with the NIH policy on Data Sharing   (http://grants.nih.gov/grants/policy/data_sharing/ and, http://grants.nih.gov/grants/policy/data_sharing/data_sharing_guidance.htm#goals, and http://grants.nih.gov/grants/policy/data_sharing/data_sharing_faqs.htm).

13.  The Food and Drug Administration Amendments Act of 2007 (FDAAA or US Public Law 110-85) was passed on September 27, 2007. The law requires mandatory registration and results reporting for certain clinical trials of drugs, biologics, and devices. If trials conducted under this grant are applicable clinical trials subject to FDAAA, the sponsor or his/her designee will perform the mandatory study registration and reporting of study results to ClinicalTrials.gov. For more information about this law and requirements for sponsors and/or investigators, visit the PRS and U.S. Public Law 110-85 Information Page at http://prsinfo.clinicaltrials.gov/fdaaa.html. In addition, grantees should be aware that clinical trials not covered by FDAAA may still require registration in an approved registry in order to be published, according to the guidelines issued by the International Committee of Medical Journal Editors (http://www.icmje.org/publishing_10register.html).

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 awardee (s). As required for the coordination of activities and to expedite progress, NIDDK may designate additional NIDDK staff to provide advice to the awardee on specific scientific and/or analytic issues. Such staff may include another Project Scientist or Analyst, who will provide direct technical assistance to the awardees 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 designee 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 awardees 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 NDDK Project Scientist or designee may coordinate activities among awardees 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 designee 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 principal investigator(s) on a regular basis to monitor study progress. Monitoring may include: regular communications with the 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 a Data and Safety Monitoring Board (DSMB) as appropriate; the NIDDK Program Official or their designee will serve as the Executive Secretary and/or NIDDK program representative on the DSMB.

Areas of Joint Responsibilities include:

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

1. 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 awardees, 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 PDs/PIs, (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.

A Chairperson of the Steering Committee, other than the NIDDK Project Scientist, will be selected by the NIDDK. The Chairperson provides leadership to the Committee by conducting the Steering Committee meetings, representing the study group to the External Oversight Committee established by the NIDDK and by interacting closely with the awardees during protocol development and implementation.

2. External Study Oversight.

An independent Data and Safety Monitoring Board will be established by the NIDDK for Phase III clinical trials or other high risk studies as appropriate. An Observational Study Monitoring Board (OSMB) will be established for observational/epidemiologic studies. These Boards will review study progress, safety data and interim results, as appropriate, and provide guidance to the NIDDK.

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 awardee (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 awardee'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 CR Part 16.

3. Reporting

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

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

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

Section VII. Agency Contacts

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

Application Submission Contacts

eRA Commons Help Desk (Questions regarding eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

Web ticketing system: https://public.era.nih.gov/commonshelp
TTY: 301-451-5939
Email: commons@od.nih.gov

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact Center Telephone: 800-518-4726

Web ticketing system: https://grants-portal.psc.gov/ContactUs.aspx
Email: support@grants.gov

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone: 301-435-0714
TTY: 301-451-5936
Email: GrantsInfo@nih.gov

Scientific/Research Contact(s)

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: ed56o@nih.gov

Averell Sherker, M.D., FRCP (C)
Scientific Advisor for Viral Hepatitis and Liver Diseases
Liver Diseases Research Branch
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone: 301-451-6207
Email: averell.sherker@nih.gov 

Peer Review Contact(s)

Francisco O. Calvo, Ph.D.
Chief, Review Branch
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone: 301-594-8897
Email: calvof@mail.nih.gov

Financial/Grants Management Contact(s)

Mr. Kieran Kelley, MAS
Senior Grants Management Specialist
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone: 301-594-2193
Email: kelleykieran@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.

Authority and Regulations

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Parts 74 and 92.


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