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

Limited Competition for the Continuation of the Drug Induced Liver Injury Network   Data Coordinating Center (U24)

Activity Code

U24 Resource-Related Research Projects – Cooperative Agreements

Announcement Type

Reissue of RFA-DK-13-502

Related Notices

None

Funding Opportunity Announcement (FOA) Number

RFA-DK-17-510

Companion Funding Opportunity

RFA-DK-17-509, U01 Research Project – Cooperative Agreements

Number of Applications

Only one application per institution is allowed as defined in 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 is for a limited competition for the continuation of the Data Coordinating Center of the Drug-induced Liver Injury Network (DILIN).

The Data Coordinating Center will provide managerial, logistic, and analytic functions for the DILIN and built a collaboration with the National Center for Natural Products Research (NCNPR), University of Mississippi to attempt the identification of specific hepatotoxic ingredients in HDS implicated in liver toxicity. This RFA and  companion RFA-DK-17-509 will seek the continuation of the Data Coordinating Center and six Clinical Centers

The Drug-induced liver injury (DILI) is one of the more challenging forms of liver disease; both in diagnosis and management. Several hundred drugs, nutritional supplements and herbal medications have been implicated in causing liver injury.  Their clinical presentation can be highly variable and mimic almost any form of liver disease. Over the last 14 years, the DILIN Network throughout its publications (http://www.dilin.org/publications/) have become the major source of information and progress in understanding and possibly decreasing the burden of drug-induced liver injury for clinicians, hepatologists, researchers, and the public at large in the US and Worldwide.

The Network has made major advances in the understanding of the clinical presentation and outcomes of DILI as well as exploratory inroads on the pathogenesis of DILI and remains the only structured, systematic and prospective effort in the United States and world-wide to characterize DILI.

The Network future approaches may continue in three main areas:

1) Clinical, biochemical, histologic and biologic characterization of DILI: Acute and chronic disease; HDS-induced, ethnic and racial differences, genetic studies, cytokines and immunological profiling.

2) Pilot/feasibility studies that would lay the groundwork for future studies on treatment of severe DILI: Acute and symptomatic chronic cases.

3) Pharmacovigilance of HDS and newly approved prescription medications (collaboration with FDA) and public resource for accurate information on DILI (DILIN centers and Livertox).

Key Dates
Posted Date

August 14, 2017

Open Date (Earliest Submission Date)

November 5, 2017

Letter of Intent Due Date(s)

November 5, 2017

Application Due Date(s)

December 5, 2017), by 5:00 PM local time of applicant organization. All types of non-AIDS applications allowed for this funding opportunity announcement are due on this date.

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

February 2018

Advisory Council Review

May 2018

Earliest Start Date

July 2018

Expiration Date

December 6, 2017

Due Dates for E.O. 12372

Not Applicable

Required Application Instructions

It is critical that applicants follow the Research (R) 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.


There are several options available to submit your application through Grants.gov to NIH and Department of Health and Human Services partners. You must use one of these submission options to access the application forms for this opportunity.

  1. Use the NIH ASSIST system to prepare, submit and track your application online.
  2. Use an institutional system-to-system (S2S) solution to prepare and submit your application to Grants.gov and eRA Commons to track your application. Check with your institutional officials regarding availability.

  3. Go to Grants.gov to download an application package to complete the application forms offline or create a Workspace to complete the forms online; submit your application to Grants.gov; and track your application in eRA Commons.
Learn more about the various submission options.

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

The National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health through a limited competition is seeking applications to continue the Data Coordinating Center for the Drug-Induced Liver Injury Network (DILIN) established by NIDDK in 2003. The DILIN has made major advances in the study of the epidemiology and clinical spectrum of hepatotoxicity due to drugs and to herbal and dietary supplements (HDS). This RFA and a companion RFA-DK-17-509 will seek the continuation of the Data Coordinating Center and six Clinical Centers to enhance the enrollment of cases and controls (when justified) from a diverse demographic background and a wide geographic distribution. A major aim of the network study is to pursue genetic analyses to find predictive biomarkers as well as genetic “fingerprints” useful for elucidating the pathogenesis of Drug-Induced Liver Injury (DILI) and ultimately for developing specific means of prevention and or treatment. 

The Network will be composed of 6 Clinical Centers with expertise in diagnosis and management of DILI and a Data Coordinating Center with expertise in the management of multicenter studies and clinical and translational datasets.  This RFA requests applications for a single Data Coordinating Center as a part of this limited competition. The Clinical Centers will be solicited through a separated RFA (RFA-DK-17-509).

The DILIN Data Coordinating Center is expected to build on the collaboration with the National Center for Natural Products Research (NCNPR), University of Mississippi to establish an analytical core at the NCNPR. The collaboration with the NCNPR will attempt the identification of specific hepatotoxic ingredients in HDS implicated in liver toxicity, using different approaches and targets, both agnostic and specific hepatotoxins through several phases.

Background Information and Research Objectives

Drug-induced liver injury (DILI) is the leading cause of acute liver failure in the US and the most common reason for US FDA regulatory actions regarding approved medications. Implicated drugs include not only prescription medications but also herbal products and over-the-counter dietary supplements and medications. Persons who develop hepatocellular DILI with jaundice have at least a 10% chance of dying from the injury and DILI patients that progress to acute liver failure have only a 25% chance of spontaneous recovery. While DILI caused by an agent can be serious, it is relatively uncommon, with an estimated frequency that ranges from 1 per 10?000 to 1 per 1?000?000 patient-years of exposure. Therefore, the low incidence of DILI coupled with the limited knowledge of the biochemical mechanism(s) or pathways responsible for this ‘idiosyncratic’ adverse event make it difficult to identify high-risk patients. Furthermore, pre-clinical testing does not always provide a reliable assessment of the hepatotoxic risk of new medications, and because DILI is a rare event, pre-marketing clinical studies conducted in highly selected populations over a relatively short period of time also may not detect a potential for liver injury. Therefore, the hepatotoxicity of a specific medication often becomes apparent only after regulatory approval and when the drug is used by large numbers of unselected patients in the general population. Finally, the biochemical, clinical and histological features of DILI from initial onset to clinical presentation can not only mimic most other known forms of acute and chronic liver disease but can also vary substantially with a single agent. Thus, at present, there is no objective ‘gold standard’ for diagnosing DILI and its identification largely relies on excluding other more common causes of liver disease and having a ‘compatible’ time of onset and evolution. Drug-induced liver disease is challenging because of the ever-increasing number of drugs used in the management of diseases and the growing number of individuals who take medications. 

Furthermore, the literature on drug-induced liver disease, often as short reports or letters to the editor whose validity is difficult to assess, is large and dispersed in many disciplines – including hepatology, gastroenterology, pharmacology, internal medicine, pediatrics, and surgery.  For this reason, it is a challenge to keep abreast of the literature on drug-induced liver disease, and literature searches to specific medications are often incomplete.

For many of these reasons, the Liver Disease Research Branch of the National Institute of Diabetes and Digestive Diseases in collaboration with the National Library of Medicine and the Drug-Induced Liver Injury Network developed a web site dedicated to providing up-to-date, comprehensive clinical information on drug-induced liver disease for both the general physician and the subspecialist (http://livertox.nih.gov/).

It is noteworthy that since inception of the DILIN in 2003, the number of enrolled cases of Herbal and Dietary supplements (HDS) induced liver injury have steadily increased. HDS products now account for more than 20% of cases of DILI reported in DILIN.  Furthermore, the liver injury from these products can be severe and lead to need for emergency liver transplant (in 13% of cases).

This FOA seeks to continue the DILIN Data Coordinating Center to provide the resources (analytical and managerial) to pursue the Drug Induced Liver Injury Network objectives in three main areas:

1) Clinical, biochemical, histologic and biologic characterization of DILI: Acute and chronic disease; HDS-induced, ethnic and racial differences, genetic studies, cytokines and immunological profiling.

These areas can be enhanced by seeking enrollment of cases (and controls when justified) from a wide demographic and geographic distribution. The network should make efforts to capture cases of DILI both from pediatric and adult's populations, and particularly from underrepresented minorities population from their sites and abroad by engaging minority investigators and pediatricians from academic and community clinical medical centers in the US willing to identify and capture cases of DILI, using an online case report system developed by the DILIN investigators, NIDDK.

Developing means of identifying and enrolling patients into DILIN at an early stage during drug-induced liver injury on whom accurate and complete clinical information combined with serially collected specimens of serum, plasma, urine, and liver tissue can be obtained, are essential to support mechanistic studies of the pathogenesis of the drug- or HDS-induced liver injury, in addition to genetic studies.

The continuation of the HDS repository of products associated with liver injury repository is an important tool to characterize the epidemiology, clinical presentation and outcomes of DILI and HDS-ILI. A better characterization of the chemical components of herbal mixtures and dietary supplements implicated in cases of liver injury may provide insights into the nature of the injury, suggest innovative approaches to mechanistic studies and ultimately provide means of prevention or treatment. The DILIN Data Coordinating Center will build on the collaboration with the National Center for Natural Products Research (NCNPR), University of Mississippi to establish an analytical core at the NCNPR. The collaboration with the NCNPR will attempt the identification of specific hepatotoxic ingredients in HDS implicated in liver toxicity, using different approaches and targets, both agnostic and specific hepatotoxins through several phases.  The DILIN DCC will provide approaches for the use of Big Data Analytics to study, along with DILIN and NCNPR Investigators, the association between individual ingredients in HDS and patterns of liver injury.  “Big data” is a term applied to data sets whose size is beyond the ability of commonly used software tools to capture, manage, and process the data within a tolerable elapsed time. HDS compounds typically have multiple ingredients and ascertaining liver injury to one particular product has been a challenge. Moreover, patients consuming HDS products typically consume multiple products and further add to the complexity of causality assessment. Using Big Data analytics, a data driven approach will be pursued to pick up any signals related to a particular ingredient and its association with liver injury.

2)  Pilot/feasibility studies that would lay the groundwork for future studies on treatment of severe DILI: Acute and symptomatic chronic cases. During the last grant cycle, the DILIN investigators have established the feasibility of enrolling acute DILI cases and obtaining serial biospecimens from them.  These facts along with the significant morbidity attributed to DILI, with up to 20 % of subjects having continued liver injury 6 months after presentation, established the feasibility and need to explore studies that would lay the groundwork for future randomized controlled trials, possibly in life threatening acute and symptomatic chronic DILI cases.

3) Pharmacovigilance of HDS and newly approved prescription medications (collaboration with FDA) and public resource for accurate information on DILI (DILIN centers and Livertox).

Develop a computer-based, reliable instrument for the diagnosis of drug-induced liver injury that can be used broadly by the medical community.  The instrument should be simple enough to be readily used, but detailed enough to provide an accurate assessment of the likelihood that the liver injury is due to the suspected medication, herbal or dietary supplement.  The DILIN database of well characterized cases of drug-induced liver injury can be used to develop this diagnostic instrument and demonstrate its reliability (sensitivity, specificity) across a wide range of medications and types of injury.

As a public resource for accurate information on DILI, the DILIN centers will continue to expand and maintain Livertox (http://livertox.nih.gov/) as an authoritative, complete and updated internet web site for drug-induced liver injury. To explore the use of livertox case report for the identification, characterization and submission of cases of DILI detected at the clinical practices through the US.

Organization of the Drug Induced Liver Injury Network

The Drug Induced Liver Injury Network (http://dilin.org/) will continue in its current format. The organization will be a cooperative network of the following entities: the NIDDK, six Clinical Centers (CCs), a Data Coordinating Center (DCC), an Executive Committee, a Steering Committee and its subcommittees, a Data and Safety Monitoring Board (DSMB), and other committees as needed.  The responsibilities of each entity of the Network are described in the Terms and Conditions of Award.

The applicant for the DCC should be willing to work collaboratively with other members of the Consortium, the Clinical Centers (CC), the Data Safety Monitoring Board and the NIDDK Central repository. The functions of the DCC can be divided into three categories: managerial, logistic, and analytic.  The DCC will run the Steering Committee (SC), which is responsible for all of the operational decisions of the DILIN (including approval of all DILIN projects, and collaborations with external investigators), along with all of the subcommittees (e.g., recruitment and phenotyping, internal and external collaborations, analysis, publication) which report to the SC.  The DCC is responsible for maintaining the schedule and developing the agendas of conference calls and meetings, and recording and archiving the minutes of these committees. The DILIN Data Coordinating Center will built on the collaboration with the National Center for Natural Products Research (NCNPR), University of Mississippi to establish an analytical core at the NCNPR.

The DCC will take on the administrative and data collection/analysis functions and will be responsible for the conduct of all the ongoing and future studies of the Consortium. 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; maintaining web-based data entry, digital data storage, and 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 Executive and Steering Committees, 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 the Consortium.  The DCC will prepare all reports including data reports for review by the DSMBs at their meetings. The DCC will provide DSMB meeting logistics and provide planning logistics in conjunction with the NIDDK. The DCC will also be responsible for the logistics and planning of the meetings of the Steering Committee and the various operational committees of the DILIN. The DCC will be responsible for acquiring and administering subcontracts as needed (see Terms and Conditions of Award). The DCC is also responsible for movement of biological samples, and deposition of data and samples in the NIDDK Repository. The DCC will work with the NIDDK Repository 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 as per NIDDK policy (www.niddkrepository.org).  All samples and data transferred to the Repositories will be under the custodianship of the NIDDK, although the Steering Committee will have proprietary control of and exclusive access to the samples and data for an agreed-upon period of time.

The NIDDK Biosample Repository (www.niddkrepository.org) will be used as the specimen repository for the Network.  This repository is not part of the FOA and is funded independently.

Governance

Steering Committee. The Steering Committee will be the main governing body of the DCC (see the Terms and Conditions of Award). The Steering Committee will be composed of the Program Directors/Principal Investigators (PDs/PIs) of each CC in the Consortium, the PD/PI of the DCC, the NIDDK Project Scientists and the NIDDK Program Official. Study Co-Chairs will be appointed by NIDDK.  The Steering Committee will have primary responsibility for the general organization of the DILIN, and approval of publications and ancillary studies.  The Steering Committee will be responsible for the conduct and monitoring of studies and reporting study results.  Topics for investigational and treatment protocols will be proposed and prioritized by the Steering Committee. Other subcommittees of the Steering Committee will be established and will operate as necessary, such as publications, ancillary, protocol, pathology and radiology.  All face to face Steering Committee, DSMB, and other necessary face to face meetings requiring the presence of NIDDK personnel will be held in the Washington, DC/Baltimore metropolitan area or other suitable venue.

Executive Committee. An Executive Committee will be comprised of Study Co-Chairs (appointed by NIDDK), the PD/PI of the DCC, the NIDDK, and NIDDK Program Official.  The Chair of the Executive Committee will be appointed by the NIDDK.  The Executive Committee will be convened to effect management decisions required between Steering Committee meetings, as required for the function of the Consortium.  Other NIDDK and DCC personnel, as deemed necessary by the Project Scientists and Program Official, may also be included. 

Data and Safety Monitoring Board. An independent Data and Safety Monitoring Board (DSMB) will be established by the NIDDK and ad hoc members from other NIH institutes, as necessary, 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 Data and Safety Monitoring Board, and the NIDDK before initiation.

Other Special Performance Requirements

The DILIN will continue to be a collaborative effort that will require frequent interactions of awardees among themselves and with the NIDDK. Applicants are expected to:

  • 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 venue), and as monthly (or as needed) teleconference, site visits as required by the NIDDK and regular subcommittee telephone conference calls;
  • Cooperate with other awardees in the development and design or modification of research protocols, and cooperate with other awardees in carrying out approved research protocols and disclose to the Steering Committee any applicant institutional specific clinical studies that may overlap with the clinical activities of the DILIN;
  • 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;
  • Actively seek to implement each consortium-wide protocol approved by the DSMB and the NIDDK that the site is selected for participation;
  • Comply with all study policies and quality assurance measures approved by the Steering Committee;
  • Agree to oversight of the study by a Data and Safety Monitoring Board (DSMB);
  • Transmit study data to the Coordinating and Data Management Center in a timely and accurate manner (Clinical Centers and subsites only);
  • Report all adverse events in accordance with procedures established by the Steering Committee, and NIDDK and FDA policies;
  • Cooperate with other awardees in the publication of study results and the eventual release to the scientific community of study procedures and other resources;
  • Serve on and chair subcommittees and protocol committees as assigned by the steering committee or the NIDDK; and
  • Accept the “Cooperative Agreement Terms and Conditions of Award” in Section VI.2.A “Award Administration Information".

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

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. See Section VI.2 for additional information about the substantial involvement for this FOA.

Application Types Allowed

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 $1,500,000 in FY 2018 to fund one award.  

Award Budget

The awards to the Data Coordinating Center will be up to $900,000 in direct costs inclusive of consortium F&A for fiscal year 2018.  Patient Care Cost in support of the Clinical Centers should not be included in the application. Post award, NIDDK will stablish a Patient Care Cost fund to be administered by the DCC.  

Award Project Period

The maximum project period is 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

 Only the current awardee(s) of the Drug Induced Liver Injury Network (DILIN) Clinical Centers are eligible to apply to this Funding Opportunity Announcement.

Foreign Institutions

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

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.

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

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

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

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

The NIH will not accept duplicate or highly overlapping applications under review at the same time.  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 NOT-OD-11-101).
Section IV. Application and Submission Information
1. Requesting an Application Package

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

2. Content and Form of Application Submission

It is critical that applicants follow the Research (R) Instructions in the SF424 (R&R) Application Guide, including Supplemental Grant Application Instructions 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:

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

The letter of intent should be sent to:

John F. Connaughton, Ph.D.
Chief, Scientific Review Branch
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone: 301-594-7797
Email: NIDDKLetterofIntent@mail.nih.gov

Page Limitations

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed. With the following exceptions or additional requirements:

For this specific FOA, the Research Strategy section is limited to 30 pages

Instructions for Application Submission

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

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 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: 

Research Strategy:

The Research Strategy section should include descriptions of how new activities will be implemented throughout the period of award. In particular, describe how the applicant will:

  • Support the efforts of the Clinical Network to increase clinical recruiting productivity and efficiency, through activities such as, but not exclusively: New pilot studies of recruiting approaches, social media systems upgrade and supporting a central Institutional Review Board, and other activities.
  • Support the design and conduct of new studies and trials (as selected by the DILIN Steering Committee) to replace ongoing trials, or new trials in newly described at-risk populations. Document the applicant's experience ability to fulfill the IND and/or IDE regulatory requirements of the FDA to support clinical trials of the network.
  • Support the design and conduct of mechanistic studies using DILIN subject populations.  

The DCC must describe how it will support the DILIN general functions by addressing their abilities pertaining to the following items:

  • Document the ability to execute all DILIN study protocols according to schedules and procedures contained in the study Manuals of Operations in collaboration with NIDDK staff and with the Clinical Centers and Affiliate Sites at which participants are screened, enrolled, treated, and followed.
  • Document the ability to receive, manage, and analyze data obtained from the Clinical Centers and Affiliate Sites. Data analysis will include the preparation of reports of the results of these assessments for presentations and publications; and the transmission of data to the NIDDK repository in a standardized format. The applicant must document their ability to protect patient confidentiality at all phases of the submission and analysis of data and ensuring the technical integrity and security of the data management systems.  This includes developing and updating standardized study forms; performing quality control on data supplied by the Clinical Centers and Affiliate Sites; editing and entering data into the master database; storing, retrieving, maintaining, protecting, reviewing, processing and analyzing the data; preparing reports of the results of these assessments for presentations and publications; and transmitting data to the NIDDK repository in a standardized format. 
  • Document the ability to assure adherence to all research plans by conducting site visits to monitor the quality of record keeping, source documentation, and accuracy of data entry as well as overseeing data quality control, including but not limited to regular data queries and data monitoring cleaning to ensure data completeness and quality.
  • Document their ability to provide statistical support, expertise, and oversight throughout DILIN studies; by conducting interim and final analyses per protocols; collaborating with the clinical investigators in preparation of presentations and primary and secondary publications; and providing additional analyses at the request of the Data Safety Monitoring Board (DSMB), External Scientific Committee (ESC), or the NIDDK.
  • Document the ability to implement study-wide communications, dissemination of study materials such as protocol Manuals of Operations, forms or other study documents, and development and maintenance of the DILIN internal and public websites.
  • Describe their key role in the operational oversight of the DILIN Centers and subcontractors. The DCC provides training and technical assistance to the Clinical Centers in the course of their implementation of protocols, including screening, enrollment, treatment and follow-up assessments. The DCC oversees all aspects of Clinical Center performance, including timeliness and quality of data and sample submission.
  • Describe the ability to procure and administer subcontracts for an analytical core at the National Center for Natural Products Research (NCNPR). The collaboration with the NCNPR will attempt the identification of specific hepatotoxic ingredients in HDS implicated in liver toxicity, using different approaches and targets, both agnostic and specific hepatotoxins through several phases.  The DILIN DCC will provide approaches for the use of Big Data Analytics to study, along with DILIN and NCNPR Investigators, the association between individual ingredients in HDS and patterns of liver injury.  “Big data” is a term applied to data sets whose size is beyond the ability of commonly used software tools to capture, manage, and process the data within a tolerable elapsed time. HDS compounds typically have multiple ingredients and ascertaining liver injury to one particular product has been a challenge.
  • As needed, the DCC will be required to provide temporary infrastructure support to Clinical Centers or Affiliate Sites though subcontracts. The DCC will provide capitated reimbursements to the Clinical and Affiliate Sites for study visits and procedures performed in the course of study conduct. Include descriptions of any plans for interacting with potential private sector collaborators.
  • Document the ability to provide administrative and logistical support services for the DILIN, including preparation of publications, organization of periodic meetings, workshops, and conference calls. The DCC will also be responsible for preparing reports for and organizing meetings of the DILIN DSMB. It will work collaboratively with the NIDDK and study investigators in preparation of papers for publication in the scientific literature.
  • Document the ability to ensure the transfer of all biosamples and data to the NIDDK central repositories according to a timeline developed with the NIDDK, as appropriate and consistent with achieving the goals of the program. The applicant must document their ability to support and promote data sharing by preparing a limited personal health information or de-identified data set in a format appropriate for data sharing for submission to a secure NIDDK data repository according to agreed-upon schedules for data sharing, as appropriate and consistent with achieving the goals of the program
  • The Program Director/Principal Investigator for the DCC application must state his/her long term commitment to the DILIN study and describe the implementation of a plan to include key personnel with qualifications to alternatively and effectively carry out the function of the Program Director/Principal investigator for the DCC.

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, with the following modification:

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

Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

PHS Inclusion Enrollment Report

When conducting clinical research, follow all instructions for completing PHS Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.

PHS Assignment Request Form

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

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

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

4. Submission Dates and Times

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

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

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

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

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

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

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

7. Other Submission Requirements and Information

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

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

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

Important reminders:

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

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

See more tips for avoiding common errors.

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

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

Investigator(s)

Are the PD(s)/PI(s) and other personnel well suited to their roles in the Center? Do they have appropriate experience and training, and have they demonstrated experience and an ongoing record of accomplishments in managing complex research? Do the investigators demonstrate significant experience with coordinating collaborative clinical research? If the Center is multi-PD/PI, do the investigators have complementary and integrated expertise and skills; are their leadership approach and organizational structure appropriate for the Center? Does the applicant have experience overseeing selection and management of subawards, if needed?  

Innovation

Does the application propose novel management strategies in coordinating the research of the DILIN the Center will serve? Are the concepts, strategies, or instrumentation novel to one type of research program or applicable in a broad sense? Is a refinement, improvement, or new application of organizational concepts proposed?   

Approach

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

Environment

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

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.

Protections for Human Subjects

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

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

Inclusion of Women, Minorities, and Children 

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

Vertebrate Animals

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

Biohazards

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

Resubmissions

Not Applicable

Renewals

For Renewals, the committee will consider the progress 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

            Not Applicable

Select Agent Research

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

Resource Sharing Plans

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

Authentication of Key Biological and/or Chemical Resources:

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

Budget and Period of Support

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

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) 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:

  • May undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score.
  • Will receive a written critique.

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 (NIDDKAC). 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 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.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 FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website.  This includes any recent legislation and policy applicable to awards that is highlighted on this website.

2. Administrative and National Policy Requirements

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.

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

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

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

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 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 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 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 awardees/sites. Such reports are in addition to the required annual noncompeting continuation progress report.

7. 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.

8. Any involvement of a third party in the study, including access to any study data; study results; using the name of the study; or the name of the NIH or NIDDK, is permitted only after concurrence by the NIDDK Program Official who may consult with others at NIH including the NIDDK Technology Advancement Office.

9. 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.

10. 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.

11. 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 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 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 ), as well as the NIDDK policy for data sharing in multi-center and large single-center clinical studies

http://www.niddk.nih.gov/research-funding/process/human-subjects­research/Documents/PublicversionNIDDKdatasharingpolicy2013July2013.pdf.

12. 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://icmje.org/recommendations/browse/publishing-and-editorial-issues/clinical-trial­registration.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 Project Coordinator, 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 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 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 NIDDK Project Scientist or Project Coordinator 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 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 Awardees 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 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 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.

A Chairperson of the Steering Committee, other than the NIDDK Project Scientist, will be selected by the NIDDK, in consultation with the Steering Committee. 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.

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 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.

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

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

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 Service Desk (Questions regarding ASSIST, eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

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

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-945-7573

Scientific/Research Contact(s)

Jose Serrano M.D., Ph.D.
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Phone 301- 594-8871
Email: serranoj@mail.nih.gov

Peer Review Contact(s)

Maria Elena Bloom, Ph.D.
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone: 301-594-7637
Email: davilabloomm@mail.nih.gov

Financial/Grants Management Contact(s)

Carey M. Beckley
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Tel 301-594-8833
Email: beckleyc@mail.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 Part 75.

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