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 Data Coordinating Center for Type 1 Diabetes TrialNet (UC4)
Activity Code	UC4 High Impact Research and Research Infrastructure - Cooperative Agreement Programs
Announcement Type	New
Related Notices	None
Funding Opportunity Announcement (FOA) Number	RFA-DK-13-508
Companion Funding Opportunity	None
Number of Applications	See Section III. 3. Additional Information on Eligibility.
Catalog of Federal Domestic Assistance (CFDA) Number(s)	93.847
Funding Opportunity Purpose	This Funding Opportunity Announcement (FOA) invites one Research Project Cooperative Agreement application (UC4) from the Program Director/Principal Investigator of the TrialNet Data Coordinating Center (TNCC). The mission of TrialNet is to conduct clinical trials aimed at the prevention of type 1 diabetes. This is a one-time FOA to provide funds to the TNCC to conduct 2 new clinical trials or studies, as part of an ongoing consortium of TrialNet investigators, for a maximum of five years, contingent on satisfactory performance. To support the conduct of these trials, TNCC will manage and support a complex network of Clinical Centers, Affiliate Centers, Core Laboratories, Central Pharmacy, and other TrialNet contractors. The TNCC will provide for biostatistical design and analysis, data and sample management, including standardized acquisition, quality control, dissemination, and public accessibility.

Posted Date	November 7, 2013
Open Date (Earliest Submission Date)	January 19, 2014
Letter of Intent Due Date(s)	January 19, 2014
Application Due Date(s)	February 19, 2014, by 5:00 PM local time of applicant organization. Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.
AIDS Application Due Date(s)	Not Applicable
Scientific Merit Review	June/July 2014
Advisory Council Review	October 2014
Earliest Start Date	December 2014
Expiration Date	February 20, 2014
Due Dates for E.O. 12372	Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

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 Diabetes Prevention Trial-Type 1 (DPT-1, initiated in 1993), tested whether two separate interventions involving insulin could prevent progression from autoimmunity to T1D: (1) Parenteral insulin in subjects with projected 5-year T1D risk of greater than 50%, and (2) oral insulin in subjects with projected 5-year T1D risk of 25-50%. Although protective effects of insulin were not demonstrated, DPT-1 did show, in a very large cohort, that: (1) the diabetes risk (over 5-10 years) of relatives of people with T1D could be accurately predicted based on genetic evaluation, tests of autoantibodies in blood, and metabolic status; and (2) trials requiring massive screening efforts to identify eligible subjects and involving intensive treatment regimens could be efficiently accomplished.

Following on from DPT-1, TrialNet was established to provide a large and complex, highly collaborative, clinical trials network. The TrialNet partnership consists of 14 North American Clinical Centers (funded by NIDDK U01 grants) and four international Clinical Centers (infrastructure funded by Juvenile Diabetes Research Foundation [JDRF]), and a Data Coordinating Center (the TNCC) (funded by NIDDK contract and grants). The TNCC provides network scientific leadership in study design, study monitoring, and performs data processing, biostatistical analyses, and administrative operations. The TrialNet Chair and Vice Chair offices, subcontractors of the TNCC, provide scientific and medical leadership, protocol/consent/volunteer handbook development, and oversight of the receipt and review of applications for future TrialNet studies. In addition, TrialNet has 220 Affiliate Sites. Affiliate Sites, supported by regional Clinical Centers, screen T1D family members for autoimmunity and eligibility for TrialNet studies. Some Affiliate Sites conduct trials and follow subjects in addition to screening for risk. The Network is supported by 20 central laboratories and support units (all TNCC subcontractors).

TrialNet studies that have been developed, implemented, and or completed are as follows (data as of August 27, 2013):

TrialNet Studies
Title	Enrollment	Launch	Completion
Effects of Oral Insulin in Relatives of Individuals with T1D in the Diabetes Prevention Trial-Type 1	Target: 372 Final: 372	1994	2003
Improving Metabolic Assessments in T1D Clinical Trials Comparison of the Reliability of Mixed Meal Tolerance Test and Glucagon Stimulation Test	Target: 120 Final: 148	2004	2005
Comparative Study Between the Cytokine, ELIspot, Tetramer, Immunoblot and T Cell Proliferation Assays Using Fresh Blood Samples from Subjects with Recent Onset T1D	Target: 60-100 Final: 96	2005	2007
Pathway to Prevention Natural History Study of the Development of T1D (Phase 1 Screening, Phase 2/3 Enrollment) The primary purpose of TrialNet screening is to identify potential subjects for prevention trials, but also to generate data on contributors of disease risk, and provide samples for mechanistic studies.	Ongoing To date screening: 114,879 To date at risk: 3,334	2004	Ongoing
New Onset T1D Mycophenolate Mofetil/Daclizumab Clinical Trial	Target: 120 Final: 126	2004	Enrollment: 2007 Outcome: 2009
Effects of Rituximab on the Progression of T1D in New Onset Subjects	Target: 66 Final: 87	2006	Enrollment: 2007 Outcome: 2008
Oral Insulin for Prevention of Diabetes in Relatives At Risk for T1D Testing prediction from DPT-1 Oral Trial	Target: N/A* To Date: 257 (1 stratum) 368 (all strata)	2007	Enrollment: 2015 Outcome: 2017
Nutritional Intervention to Prevent T1D Pilot Trial	Target: 90 To Date: 123	2006	Enrollment: 2008 Outcome: 2009
Effects of CTLA-4 Ig (Abatacept) on the Progression of T1D in New Onset Subjects	Target: 108 Final: 112	2008	Enrollment: 2009 Outcome: 2011
Effects of Recombinant Human Glutamic Acid Decarboxylase (rhGAD65) Formulated in Alum (GAD-alum) on the Progression of T1D in New Onset Subjects	Target: 126 Final: 146	2008	Enrollment: 2009 Outcome: 2011
Effect of Metabolic Control at Onset of Diabetes on Progression of T1D**	Target: 72 Final: 71	2009	Enrollment: 2011 Outcome: 2012
Effects of Canakinumab on the Progression of Type 1 Diabetes in New Onset Subjects	Target: 66 Final: 71	2010	Enrollment: 2011 Outcome: 2012
Anti-CD3 (Teplizumab) for Prevention of Diabetes in Relatives At Risk for T1D	Target: 140-170 To Date: 30	2011	Enrollment: 2016 Outcome: 2018
Long-Term Investigative Follow-Up Trial (LIFT)	Target: TBD	2012	Ongoing
Effects of CTLA-4 Ig (Abatacept) for Prevention of Glucose Tolerance in Relatives at Risk for T1D	Target: 206 To Date: 23	2013	Enrollment: 2017 Outcome: 2019

*Study uses a maximum information design so there is not an exact enrollment target. Enrollment will be complete when the necessary number of events occurs.

**Trial performed jointly with DirecNet at TrialNet Centers.

***Immune Tolerance Network (ITN) studies reviewed and approved by TrialNet and conducted at TrialNet Centers include: 1) Treatment of Recent Onset T1D with AntiCD3 Monoclonal Antibody; 2) Thymoglobulin for New Onset T1D; and 3) A Phase I Trial of Proleukin and Rapamune in Recent Onset T1D.

TrialNet’s primary objective is to delay or prevent the development of T1D in persons at risk. Large numbers of relatives must be screened to identify those with at least moderate (~35% over 5 years) risk of clinical disease. The goal of TrialNet is to test safe and potentially effective interventions aimed at disease prevention to all subjects with moderate to high risk.

In addition to prevention trials, TrialNet’s goal is to test interventions aimed at decreasing β-cell destruction and/or enhancing β-cell survival in persons with T1D and residual β-cell function. This goal is now approached through collaborations with partners such as the Immune Tolerance Network (NIAID funded) and the pharmaceutical industry. Long-term studies have demonstrated that the longer patients with T1D maintain β-cell function, as measured by stimulated C-peptide production, the better protected they are from serious diabetes complications (DCCT/EDIC); thus it is anticipated that intervention studies in this population will also provide clinical benefits to participants. With a T1D incidence of 30,000 persons per year in the United States, the pool of subjects eligible for new onset trials is relatively small, and is further limited by age restrictions and a requirement for enrollment within weeks after diagnosis. TrialNet plays a vital role in providing supported Clinical Centers to accomplish effective recruiting, conduct and follow-up of treatment trials. TrialNet's prevention trials also benefit from the Network's participation in new onset trials. Families interested in enrolling their newly-diagnosed member in a treatment trial will often also be interested in screening family members for potential T1D risk and prevention trial participation. In addition, TrialNet strives to leverage ongoing clinical studies to generate information to improve understanding of the pathophysiology of T1D. This will facilitate the identification of biomarkers to serve as intermediate study endpoints, enabling intervention earlier in the disease process as well as shorter trials using fewer subjects.

TrialNet is currently developing new trials to prevent the progression of diabetes risk in relatives of people with type 1 diabetes. For example, it is known that in relatives whose blood samples are positive for a single diabetes-relevant autoantibody specificity, their risk of disease increases substantially if they progress to positivity for multiple autoantibody specificities. TrialNet is planning to conduct a clinical trial to test whether agents can interrupt autoimmune progression prior to metabolic dysfunction. Interventions tested in this subject cohort will have to be very safe and well tolerated, easy to administer, and subjects will need to be followed for many years since risk of progression is fairly low in single autoantibody positive individuals. However, since it is early in disease course, it is expected that interventions could be highly effective. Possible interventions include but are not limited to Trichuris suis ova.

Since TrialNet intensively follows subjects with elevated risk, subjects are often identified who have increased blood glucose levels before they have overt clinical symptoms ( Silent Diabetes ).  TrialNet is planning to conduct studies to determine optimal management of Silent Diabetes and/or whether early intervention can slow or even reverse the disease course in these individuals. Possible interventions for this cohort include but are not limited to approaches to initiation of insulin and/or use of insulin sensitizers such as metformin. Pilot studies to inform optimal trial design may also be proposed including but not limited to characterization of beta cell function and/or of progression from silent to overt type 1 diabetes.  The identification of individuals with Silent Diabetes requires frequent testing of genetically at risk individuals, therefore recruitment is from the pool of subjects already enrolled in observational studies. To increase the number of potentially eligible subjects, TrialNet will collaborate with other consortia such as TEDDY (The Environmental Determinants of Diabetes in the Young,  http://teddy.epi.usf.edu/ ) and TRIGR (Trial to Reduce IDDM in the Genetically at Risk, http://trigr.epi.usf.edu/ ) to identify and enroll subjects into Silent Diabetes studies.

Funding Instrument	Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, NIH scientific or program staff will assist, guide, coordinate, or participate in project activities.
Application Types Allowed	New The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.
Funds Available and Anticipated Number of Awards	NIH intends to commit $25,000,000 for one award in Fiscal Year 2014.
Award Budget	Application budgets should not exceed $25,000,000 in total costs and must reflect the actual needs of the proposed project.
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.

Only the current awardee of the grant for the TrialNet Data Coordinating Center is eligible to apply to this Funding Opportunity Announcement.

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

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

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH 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 and should work with their organizational officials to either create a new account or to affiliate an existing account with the applicant organization’s eRA Commons account. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Only the PD/PI of the current TrialNet Coordinating Center may apply.

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:

• To an RFA of an application that was submitted previously as an investigator-initiated application but not paid;
• Of an investigator-initiated application that was originally submitted to an RFA but not paid; or
• Of an application with a changed grant activity code.

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:

• 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 (preferably electronic) should be sent to:

Francisco O. Calvo, Ph.D.
Chief, Review Branch
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
6707 Democracy Boulevard, Room 752
Bethesda, MD 20892-5452
(for express/courier service: Bethesda, MD 20817)
Telephone: (301) 594-8897
FAX: (301) 480-4126
Email: [email protected]

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.

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

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.

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

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

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

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

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

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

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

Research Strategy: The TNCC applicant must describe plans including, but not limited to, the following items. The applicant is encouraged to use a specific example for each trial, but should discuss how the plans could be adapted for other possible interventions using the same population of subjects:

1. Trial to prevent or delay progression of T1D risk:

• Applicant should describe preliminary analyses of data from TrialNet or DPT-1 cohorts to show that changes in risk biomarkers, such as increases in the number of distinct autoantibody specificities, result in increased risk for ultimate progression to type 1 diabetes.
• Applicant should describe preliminary data and analyses that support the feasibility of a clinical trial to test an agent to prevent or delay risk progression, including recruitment potential, variability of endpoint determinations, treatment parameters, etc.,
• Applicant should describe trial planning parameters and statistical design, making note of any innovations.

2. Studies to determine optimal management of Silent Diabetes and/or whether early intervention can slow or even reverse the disease course in these individuals:

• Applicant should provide preliminary data pertaining to the definition of Silent Diabetes, such as blood glucose measurements after oral glucose challenge, HbA1c measurements, fasting blood sugars, etc.
• Applicant should provide preliminary data and analyses that support the feasibility of a Silent Diabetes trial or study, focusing on recruiting opportunities, number of subjects available and number likely to agree to be studied, variability of endpoint determinations, treatment parameters, etc.
• Applicant should describe trial or study planning parameters and statistical design, making note of any innovations.

Applicant should describe plans or provide information as requested in the following sections:

3. Implementation and upgrading (as needed) for communication, data collection, editing, processing, analysis, and reporting;

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

5. Implementation and upgrading (as needed) of procedures to ensure the safety and confidentiality of all records; and

6. Implementation and upgrading of procedures for coordinating submission of samples and data from the participating Clinical and Affiliate Centers to the TrialNet Central Laboratories and NIDDK Repository.

7. A summary of all active TrialNet Study Protocols should be included.

Letters of Support: Applicant should provide letters of support from participating consortia (TEDDY, TRIGR), steering or executive committees as appropriate,that state willingness to assist in recruiting subjects for the Silent Diabetes clinical trial or study.

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 modification:

• The TNCC application is expected to include an overall sharing plan for data generated during the funding of TrialNet, according to the NIDDK Data Sharing Policy. The plan should specifically indicate what will be shared, with whom it will be shared (including the NIDDK Data Repository), when it will be shared, by what means it will be shared, and the conditions that will apply to recipients of shared data. This plan must be approved by the NIDDK before the award will be issued under this FOA.

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

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

When conducting clinical research, follow all instructions for completing Cumulative Inclusion Enrollment Report 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 due date to ensure they have time to make any application corrections that might be necessary for successful submission.

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

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

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

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.

Since these awards will be issued with a 5-year budget and project period from the same fiscal year, the grantee will not have any authority for an automatic extension, nor will one be permitted with NIH prior approval. Funds will not be available for expenditure beyond September 30th of the 5th fiscal year after the period of availability. Thus, extensions of the budget/project period will not be allowed.

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.

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 by the Center for Scientific Review and responsiveness by NIDDK, 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 protected] 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-13-030.

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.

Significance

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

Investigator(s)

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

Innovation

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

Approach

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

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of children, justified in terms of the scientific goals and research strategy proposed?

Environment

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

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

Biohazards

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

Resubmissions

Not Applicable

Renewals

Not Applicable

Revisions

Not Applicable

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) 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:

• 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. 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:

• 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.

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) of the network, including the Clinical Center U01, the Clinical Network Hub U01, and the Data Coordinating Center, 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 Principal Investigators/Program Directors (for studies involving multiple protocols) shall designate a single Protocol Chairperson (if the Principal Investigator/Program Director does not assume this role) for each protocol to be carried out by the study group. The Protocol Chairperson shall function as the scientific coordinator for the protocol and shall assume responsibility for obtaining approval to implement the protocol from the Steering Committee and for developing and monitoring the protocol. Significant modifications to approved protocols must be approved by the Steering Committee.

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

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

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

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

8. Reporting of the study findings. Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies. The awardee must also be adherent to Study Publication and Presentation Policy. The NIDDK will have access to and may periodically review all data generated under an award. NIDDK staff may co-author publications of findings with awardees consistent with NIH and study policies.

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

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

11. Maintaining confidentiality of information: The awardee(s) will maintain the confidentiality of the information developed by the investigators (i.e., protocols, data analysis, conclusions, etc.) as well as proprietary information of a company collaborating with the study.

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

archiving and storage of data and biosamples collected in large, multi-site studies funded by NIDDK. The 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).

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

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

An NIDDK Project Scientist will 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, participate in the Steering Committee that oversees study conduct. The NIDDK Project Scientist or designee will be a full participant and voting member of the Steering Committee and, if applicable, subcommittees.

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

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

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

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

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

d. The NIDDK Project Scientist or designee may be co-authors on study publications. In general, to warrant co-authorship, NIDDK staff must have contributed to the following areas: (a) design of the concepts or experiments being tested; (b) performance of significant portions of the activity; (c) participation in analysis and interpretation of study results and (d) preparation and authorship of pertinent manuscripts.

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

1. Interact with the Principal Investigator(s)/Program Director(s) on a regular basis to monitor study progress. Monitoring may include: regular communications with the Principal Investigator/Program Director and staff, periodic site visits, observation of field data collection and management techniques, quality control, fiscal review, and other relevant matters; as well as attendance at Steering Committee, data safety and monitoring board, and related meetings. The NIDDK retains, as an option, periodic review of progress by researchers not involved with the study.

2. Review and approve protocols prior to implementation to insure they are within the scope of peer review, for safety considerations, as required by Federal regulations.

3. The NIDDK Program Official will monitor protocol progress, and may request that a protocol study be closed to accrual for reasons including: (a) accrual rate insufficient to complete study in a timely fashion; (b) accrual goals met early; (c) poor protocol performance; (d) patient safety and regulatory concerns; (e) study results that are already conclusive; (f) low likelihood of showing a benefit of the intervention (futility); and (g) emergence of new information that diminishes the scientific importance of the study question. The NIDDK will not permit further expenditures of NIDDK funds for a study after requesting closure except as specifically approved by the NIDDK.

4. Make recommendations for continued funding based on: a) overall study progress, including sufficient patient and/or data accrual; b) cooperation in carrying out the research (e.g., attendance at Steering Committee meetings, implementation of group decisions, compliance with the terms of award and reporting requirements); and/or c) maintenance of a high quality of research, which will allow pooling of data and comparisons across multiple cooperative agreement awards for common data elements.

5. Appoint a Data and Safety Monitoring Board (DSMB) as appropriate; the NIDDK Program Official or their designee will serve as the Executive Secretary and/or NIDDK program representative on the DSMB.

Areas of Joint 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 Principal Investigator(s)/Program Director(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 and by interacting closely with the awardees during protocol development and implementation.

2. External Study Oversight.

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

Dispute Resolution:

Any disagreement that may arise on scientific/programmatic matters (within the scope of the award), between award recipients and the NIDDK may be brought to dispute resolution. A dispute resolution panel will be composed of three members --one selected by the awardee (or the Steering Committee, with the NIDDK member not voting), a second member selected by NIDDK, and the third member elected by the two prior selected members. These special dispute resolution procedures in no way affect the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulations at 42 CFR Part 50, Subpart D, and HHS regulations at 45 CR Part 16.

Progress reports for multi-year funded awards are due annually on or before the anniversary of the budget/project period start date of award. The reporting period for multi-year funded award progress report is the calendar year preceding the anniversary date of the award. Information on the content of the progress report and instructions on how to submit the report are posted at http://grants.nih.gov/grants/policy/myf.htm.

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.

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

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

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GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
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Ellen Leschek, M.D.
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone: 301-402-8291
Email: [email protected]

Francisco Calvo, Ph.D.
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone: 301-594-8897
Email: [email protected]

Diana O'Donovan
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone: 301-594-8868
Email: [email protected]

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.