National Institutes of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Funding Opportunity Title
Continuation of the Clinical Centers for the Drug Induced Liver Injury Network [DILIN] (U01)
U01 Research Project – Cooperative Agreements
Reissue of RFA-DK-07-012
Funding Opportunity Announcement (FOA) Number
Companion Funding Opportunity
Catalog of Federal Domestic Assistance (CFDA) Number(s)
Funding Opportunity Purpose
The purpose of this Funding Opportunity Announcement (FOA) is to encourage applications from qualified investigators from clinical centers for the continuation of the Drug-induced Liver Injury Network (DILIN). This network will consist of up to 5 clinical center sites and a single data coordinating center.
Drug-induced liver injury 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.
Since its establishment in 2003, the NIDDK DILIN, has brought together an outstanding cadre of clinicians and investigators with expertise in drug-induced liver injury able to identify cases from a diverse demographic background and a wide geographic distribution. The Network has collected over one thousand cases of liver toxicities due to prescription and nonprescription drugs, Herbal and Dietary supplements. In addition the group has contributed extensively to the development of case definition, standard terminology, minimal elements for causality assessment and development of a clinically practical causality instrument. Furthermore the group has made inroads in the characterization of potential mechanisms of drug induced liver injury (DILI), both genetic and immunological. The Network has made major contribution to the characterization of DILI: its clinical presentation, natural history and outcomes as well as pathogenesis. The DILIN represents the only organized and systematic effort to study DILI in the US and has established collaborations with international investigators. The core group of DILI is well position to expand and accomplice new objectives:
December 20, 2012
Open Date (Earliest Submission Date)
January 27, 2013
Letter of Intent Due Date(s)
January 27, 2013
Application Due Date(s)
February 27, 2013, by 5:00 PM local time of applicant organization.
AIDS Application Due Date(s)
Scientific Merit Review
Advisory Council Review
Earliest Start Date
February 28, 2013
Due Dates for E.O. 12372
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.
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
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 and expand the Drug-Induced Liver Injury Network (DILIN) established by NIDDK in 2003 (http://dilin.dcri.duke.edu/index.html).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). RFA-DK-13-003 will seek the continuation of DILIN 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 up to 5 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. It is expected that the clinical centers will be a single site, with direct access to eligible patients and able to develop strategies to identify eligible DILI patients during the acute phase of the injury. Once the new Network is formed, an invitation to all academic medical centers in the US will be issued to identify and capture cases of DILI at their sites, using an online case report system developed by the DILIN investigators, NIDDK and the National Library of Medicine.
This FOA encourages applications for up to five Clinical Centers (through an open competition); applications for the Data Coordinating Center have been requested through a separate limited competition FOA, RFA-DK-13-502"Limited Competition for the Continuation of the DILIN Data Coordinating Center (U01)".
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 a particular 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. Some investigators have postulated the importance of reactive metabolites or aberrant host metabolism and immune responses in the pathogenesis of DILI but the precise molecular mechanism(s) involved are largely unknown. 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. Among the many thousands of drugs available today, several hundred have been linked to liver injury. But the clinical pattern of liver injury is diverse and complex, and drug-induced liver injury can mimic virtually any form of liver disease, from acute to chronic hepatitis, biliary obstruction to venous obstruction, acute fatty liver disease and even massive hepatic necrosis. To keep track of which drugs cause liver injury and what pattern is typical of which agent is challenging even for the most dedicated sub-specialist in the area. Furthermore, the literature on drug-induced liver disease is large and dispersed to publications in a great many disciplines – including hepatology, gastroenterology, pharmacology, internal medicine, pediatrics, and surgery. Publications on drug-induced liver disease appear in many journals, in multiple languages and often as short reports or letters to the editor whose validity is difficult to assess. 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 plan 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 induced liver injury (HDS-ILI) have steadily increased, representing the second most commonly recorded class of hepatotoxicity causing products in DILIN.
This FOA seeks to continue the Drug Induced Liver Injury Network in order to:
The Network will continue the current Drug Induced Liver Injury Network (DILIN) (http://dilin.dcri.duke.edu/index.html). The organization will be a cooperative network of up to 5 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, obtaining biosamples for repository storage and disseminating research findings. All individual CCs will be required to participate in a cooperative and interactive manner with one another and with the DCC in all aspects of the Drug Induced Liver Injury Network.
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.
A Steering Committee will be the main governing body of the Drug Induced Liver Injury Network. At a minimum, the Steering Committee will be composed of the Program Directors/Principal Investigators (PDs/PIs) of each Clinical Center in the Network, the PDs/PIs of the DCC and the NIDDK Project Scientist. The first meeting of the Steering Committee will be convened by the NIDDK Project Scientist in conjunction with the PD/PI of the DCC. By the end of the first or second meeting of the Committee, the NIDDK will name study Chairpersons from the Clinical Centers to oversee and guide Steering Committee activities. The Steering Committee will meet as often as three to four times per year. All major scientific decisions will be determined by a majority vote of the Steering Committee. Each Clinical Center, the DCC, and the NIDDK Project Scientist will have one vote. The Steering Committee will have primary responsibility for the general organization of the Drug Induced Liver Injury Network, finalizing common clinical protocols, facilitating the development of a standardized nomenclature, diagnostic criteria, histological definitions, and necessary components to the common database on patients. The Steering Committee will be responsible for the conduct and monitoring of studies and reporting study results.
All Clinical Center PDs/PIs will be strongly encouraged to fully commit their center resources and efforts to the Network protocols.
Other subcommittees of the Steering Committee will be established as necessary. Clinical protocols must be approved by local Institutional Review Boards and the Drug Induced Liver Injury Network Steering Committee before initiation.
The Drug Induced Liver Injury Network investigators will be encouraged to seek out separate funding for special projects and to develop collaboration with laboratory and basic research investigators to draw upon the resources (clinical data, serum, tissue, DNA) made available by the Drug Induced Liver Injury Database.
Any specific collaboration involving the resources of the Drug Induced Liver Injury Network will require approval by the Steering Committee.
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
The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.
Funds Available and Anticipated Number of Awards
The NIDDK intends to commit a minimum of $2.33 million in total costs in FY 2013 to fund up to 5 Clinical Center applications.
Although the financial plans of the ICs 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.
The awards to each Clinical Center will be approximately $250,000 in direct costs ($390,000 in total costs). Restricted Patient Care Cost, administered by the DCC for all the CC will be approximately $250,000 per year. Application budgets are not limited, but need to reflect actual needs of 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 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.
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
Non-domestic (non-U.S.) Entities (Foreign Institutions) are
not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are not allowed.
Applicant organizations must complete the following registrations as described in the SF424 (R&R) Application Guide to be eligible to apply for or receive an award. Applicants must have a valid Dun and Bradstreet Universal Numbering System (DUNS) number in order to begin each of the following registrations.
All Program Directors/Principal Investigators (PD(s)/PI(s))
must also work with their institutional officials to register with the eRA
Commons or ensure their existing eRA Commons account is affiliated with the eRA
Commons account of the applicant organization.
All registrations must be completed by the application due date. Applicant organizations are strongly encouraged to start the registration process at least 6 weeks prior to the application due date.
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.
This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.
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:
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.
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.
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 should be sent to:
Francisco O. Calvo, Ph.D.
Chief, Review Branch
National Institute of Diabetes and Digestive and Kidney Diseases
National Institutes of Health
6707 Democracy Boulevard, Room 752, MSC 5452
Bethesda, MD 20892-5452
(Courier use 20817)
The forms package associated with this FOA includes all applicable components, mandatory 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.
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:
All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:
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, with the following modifications:
Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.
Part I. Overview Information contains information about Key Dates. Applicants are encouraged to submit applications before the deadline to ensure they have time to make any application corrections that might be necessary for successful submission.
Organizations must submit applications via 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.
Applicants are responsible for viewing their application before the deadline 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.
This initiative is not subject to intergovernmental review.
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.
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.
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.
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 Award for Management (SAM). 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 by the Center for Scientific Review and responsiveness by components of participating organizations, NIH. Applications that are incomplete and/or nonresponsive will not be reviewed.
In order to expedite review, applicants are requested to notify the NIDDK Referral Office by email at email@example.com when the application has been submitted. Please include the FOA number and title, PD/PI name, and title of the application.
Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-10-115.
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.
Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).
Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.
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?
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?
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?
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?
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?
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.
FOA-Specific Review Criteria
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.
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.
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.
For Renewals, the committee will consider the progress made in the last funding period.
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
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.
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:
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.
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.
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 Program Directors/Principal Investigators (for studies involving multiple coordinated awards) 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, by the Steering Committee. 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 awards, 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. The awardee(s) will retain custody of and have primary rights to the data developed under these awards, subject to the Government rights of access consistent with current HHS, 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 archival 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,
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 applicable, the PI 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
NIH staff have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:
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, participation 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. Serving 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. 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 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) participate in analysis and interpretation of study results and (d) preparation and authorship of pertinent manuscripts.
In addition, a separate NIDDK Program Official identified in the Notice of Grant Award will be responsible for the normal stewardship and monitoring of the award including review and approval of all progress reports and all budgetary decisions. Additional responsibilities include.
Interacting 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.
Reviewing and approving protocols prior to implementation to insure they are within the scope of peer review, for safety considerations, as required by Federal regulations.
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; and (f) 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.
Making 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.
Appointment of 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 Responsibility 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 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. 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 (see item D2 below) 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. The Data and Safety Monitoring Board will review interim results periodically and provide guidance to the NIDDK.
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.
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.
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and welcome the opportunity to answer questions from potential applicants.
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Phone: 301-402-7469 or 866-504-9552 (Toll Free)
Jose Serrano M.D., Ph.D.
Division of Digestive Diseases and Nutrition
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Francisco O. Calvo, Ph.D.
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Helen Hunter Cox, M.H.S.
Commander, U.S. Public Health Service
Grants Management Specialist
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Bethesda, MD 20892-5456
Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.
Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Parts 74 and 92.
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