Department of Health and Human Services

Part 1. Overview Information

Participating Organization(s)

National Institutes of Health (NIH)

Components of Participating Organizations

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

Funding Opportunity Title
Elucidating the heterogeneity of impaired awareness of hypoglycemia in Type 1 Diabetes (T1D) - Biostatistics Research Center (U01 Clinical Trial Not Allowed)
Activity Code

U01 Research Project – Cooperative Agreements

Announcement Type
New
Related Notices

  • January 21, 2022 - Notice of Change to Award Information for RFA-DK-21-036. See Notice NOT-DK-22-011.

Funding Opportunity Announcement (FOA) Number
RFA-DK-21-036
Companion Funding Opportunity
RFA-DK-21-020 , U01 Research Project (Cooperative Agreements)
Assistance Listing Number(s)
93.847
Funding Opportunity Purpose

This FOA invites applications for a Biostatistics Research Center (BRC) to participate in a clinical consortium to determine the factors that contribute to the heterogeneity in the restoration of impaired awareness of hypoglycemia (IAH) and improved counter-regulatory responses in adult individuals with Type 1 Diabetes (T1D) and impaired awareness of hypoglycemia (IAH). A separate FOA (RFA-DK-21-020) invites Clinical Centers to: 1) determine if the most up-to-date diabetes technology to optimize HbA1c while minimizing hypoglycemia can restore awareness of hypoglycemia and improve counter-regulatory responses in individuals with T1D and IAH; 2) identify the magnitude and duration of time in range (TIR), time spent in hypoglycemia or other CGM metrics that are associated with restoration of awareness of hypoglycemia; and 3) determine the association of current or newly developed self-reported measures of IAH with counter-regulatory responses to elucidate the heterogeneity in restoration of hypoglycemia awareness.

All awardees will form a cooperative research consortium in conjunction with NIDDK to design and implement a uniform protocol across what is expected to be 10 Clinical Centers and the BRC. Findings from this clinical trial are expected to make a significant contribution to our understanding of the physiological factors which contribute to restoration of impaired awareness of hypoglycemia and be used to tailor treatment regimens for adult individuals with T1D and IAH.

Key Dates

Posted Date
January 04, 2022
Open Date (Earliest Submission Date)
March 01, 2022
Letter of Intent Due Date(s)

March 01, 2022

Application Due Dates Review and Award Cycles
New Renewal / Resubmission / Revision (as allowed) AIDS Scientific Merit Review Advisory Council Review Earliest Start Date
March 31, 2022 Not Applicable Not Applicable July 2022 October 2022 December 2022

All applications are due by 5:00 PM local time of applicant organization. 

Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

Expiration Date
April 01, 2022
Due Dates for E.O. 12372

Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in the Research (R) Instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from NIH Guide for Grants and Contracts).

Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions.

Applications that do not comply with these instructions may be delayed or not accepted for review.

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

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

  3. Use Grants.gov Workspace to prepare and submit your application and eRA Commons to track your application.


  4. Table of Contents

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

This FOA invites applications for a single Biostatistics Research Center to collaborate with Clinical Centers to determine the factors that contribute to the heterogeneity in the restoration of impaired awareness of hypoglycemia (IAH) and improved counter-regulatory responses in adult individuals with Type 1 Diabetes (T1D) and IAH. All awardees selected to participate must agree to be part of a consortium that will collaboratively develop and implement a uniform protocol.

Individuals with IAH are often excluded from clinical trials and this omission contributes greatly to a lack of knowledge regarding the clinical characteristics which determine or predict an individual’s ability to restore hypoglycemic awareness.  

New technologies including continuous glucose monitors (CGM) and artificial pancreas devices alert patients to declining levels of glucose and can reduce hypoglycemic events and restore awareness of hypoglycemia. However, evidence is emerging that even with CGM usage and a reduction in hypoglycemic events, a large proportion of individuals can still be classified as having IAH based on self-reported measures such as the Gold or Clarke scales. Contributing to the problem is that many individuals with T1D are not able or willing to take advantage of these technologies or may not use the CGM consistently.

Identification of the presence or absence of impaired awareness of hypoglycemia within individuals for classification into clinical trials is typically based on scores of > 4 in self-reported measures such as the Gold or Clarke questionnaires. Both questionnaires were originally validated in the 1990s before the common use of CGMs and the development of the artificial pancreas. While these existing questionnaires may adequately identify IAH, there are limitations associated with each and neither was designed to tease out the heterogeneity of an individual’s ability to restore awareness and relate this to physiological responses during hypoglycemia. None of the current questionnaires address the important clinical issue of nocturnal hypoglycemia. New patient reported outcome measures such as the HypoA-Q are promising but cut-off points for the presence or absence of IAH have yet to be identified. Therefore, composite metrics of existing questionnaires or new reliable and meaningful self-report questionnaires may need to be developed. Reliable self-reported measures of hypoglycemia awareness that could identify an individual’s ability to restore awareness and associated counter-regulatory responses would facilitate conduct of future clinical trials.

The goals of the clinical consortium will be to 1) determine if the most up-to-date diabetes technology to optimize HbA1c while minimizing hypoglycemia can restore awareness of hypoglycemia and improve counter-regulatory responses in individuals with T1D; 2) identify the magnitude and duration of time in range (TIR), time spent in hypoglycemia or other CGM metrics that are associated with restoration of awareness of hypoglycemia; and 3) determine the association of self-reported (current or newly developed) measures of IAH with counter-regulatory responses to elucidate the heterogeneity in restoration of hypoglycemia awareness. It is expected that state of the art metabolic assessments such as hypoglycemic, hyperinsulinemic clamps (with or without stable isotopes) for the measurement of counter-regulatory responses (CRR) will be utilized to determine the association among improved CRR, restoration of awareness and self-report assessments.

This FOA invites applications for a Biostatistics Research Center (BRC) to collaborate with investigators at the Clinical Centers (CC) in designing a study that will accomplish the scientific aims described above. A separate FOA (RFA-DK-21-020) will provide support for the Clinical Centers, which will recruit and study individuals with T1D and IAH and if appropriate, a control group to be determined upon formation of the consortium.  Detailed explanation of NIDDKs Regulatory Policies and Guidance on BRCs can be found in Policies for Clinical Researchers.  The BRC is expected to contribute expertise to the development of the consensus protocol, to oversee the implementation of the study across Clinical Centers and to analyze and interpret the data. Although the ultimate design of the study is not known, it is anticipated that each participant will undergo a hypoglycemic, hyperinsulinemic clamp at baseline and yearly over a two-year period. Repeated CGM glycemic profiles and metrics will be collected at intervals determined by the study team as well as collection of self-reported questionnaires on hypoglycemic awareness and possibly cognitive and psychological measures. Therefore, applicants to this FOA are required to understand these different outcome variables (counter-regulatory responses, CGM metrics, questionnaires) which will be used to generate primary and secondary outcomes. Furthermore, it is expected that a specific core will be formed under the umbrella of the BRC which will be responsible for the development, evaluation and validation of new composite measures, psychometrics, or questionnaires associated with identification of IAH by self-report. The lead of this core should have relevant experience in developing these tools and training in health psychology, psychology or other applicable expertise. If expertise is not available within the BRC, a sub-contract may need to be established.

.As part of the development of the common protocol, the BRC is expected to oversee and plan meaningful stakeholder engagement which entails active and relevant involvement of patients, caregivers, family members, clinicians, healthcare systems, advocacy groups, and other relevant stakeholders in the development, design and execution of the study.

Peer review will consider both the scientific merit of the application, as well as the ability of the applicant to conduct, oversee and coordinate the study.

The Awardees (i.e., the CC and the BRC) will assemble to form a Steering Committee (see below) which will meet to develop a common protocol and manual(s) of procedures. The submitted applications will serve as a starting point for the Steering Committee's deliberations. The Biostatistics Research Center will take the lead to coordinate study design and protocol development, protocol implementation, and data analysis.

It is expected that the Steering Committee will meet a minimum of two times at the NIH and have frequent contact by telephone during the planning phase, which is expected to take at least nine months.

Consortium Organization

1. Clinical Centers

Clinical Centers (CC) will recruit individuals with T1D and impaired awareness of hypoglycemia as well as a control group to be decided by the consortium. The population recruited should have racial and ethnic diversity.

The PD/PI and key co-investigators at each CC will be expected to collaborate in designing and implementing the uniform study protocol. Centers must not only have the requisite number of patients but also proven experience in recruiting and retaining individuals with T1D as well as experience in conducting hypoglycemic, hyperinsulinemic clamps. Centers must also have expertise in utilizing the most up to date diabetes technologies including CGM. The CC will collect data in accordance with established study procedures and submit all samples and data to the Biostatistics Research Center (BRC) and central laboratory and central reading centers, as appropriate and required by the protocol.

Investigators at the CC will conduct analyses in conjunction with the BRC. The study group will have exclusive access to data from the study population for a defined period, according to NIDDK and NIH data sharing policies. All study data analyzed for publication of the primary and secondary study outcome(s) are expected to be provided to the NIDDK Central Repository so that it can be shared as appropriate per NIDDK policy and consistent with achieving the goals of the program. The Steering Committee (see below) will establish policies under which ancillary studies may be conducted while the study is ongoing, consistent with applicable laws, regulations, and policies.

2. Biostatistics Research Center (BRC)

There will be a single BRC, which will have scientific as well as coordination responsibilities. The BRC biostatisticians will work with the Clinical Center investigators to develop the scientific design of the study. The BRC investigators will have primary responsibility for ensuring that the design of the study, including the primary outcome, is scientifically sound and is supported by appropriate power calculations. The BRC will also provide biostatistical and analytic expertise and conduct analysis and interpretation of the laboratory and clinical data in conjunction with investigators at the Clinical Centers. The BRC will be responsible for guiding development of the statistical analysis plan for the study as a whole and for each manuscript reporting pre-specified primary and secondary outcomes. The BRC will also be responsible for establishing all scientific collaborations for specialized outcomes. As it is anticipated that the study will utilize repeated measures of the counter-regulatory responses derived from the clamp and CGM measurements to characterize glycemia, the BRC must have the scientific expertise to analyze and interpret these data.

In addition to these research functions, the BRC is responsible for the collection, management and analysis of all clinical and laboratory data, including establishment of any central laboratories or cores needed. The BRC is expected to provide specific and appropriate expertise for a core responsible for the development, evaluation and validation of new composite measures, psychometrics, or questionnaires associated with identification of IAH. The lead of this core should have relevant experience developing these tools and training in health psychology, psychology or other applicable expertise. If expertise is not available within the BRC, a sub-contract may need to be established.

The BRC will be responsible for ensuring participant confidentiality and safety, and quality control. The BRC will conduct training and certification of study staff, and maintain and update the manual of operations. The BRC will oversee implementation of and adherence to the study protocol including training of research coordinators. The BRC will coordinate communication among and with the CC. The BRC will also be responsible for establishing and managing activities related to the single IRB. In addition, the BRC will develop procedures to require study investigators and other relevant personnel associated with the study to identify and manage financial and other conflicts of interest at least annually and share this information with NIDDK staff.

If additional sites are needed to recruit adequate numbers of patients, subcontracts may be added to individual study sites or the BRC. The BRC will be responsible for recruitment of additional sites.

The BRC will also be responsible for organizing and supporting stakeholder engagement efforts for the consortium during the planning period as well as during the conduct of the study.

The BRC will coordinate the movement of biologic samples from the CC to the central laboratory and, subsequently, to the NIDDK Central Repository, where samples will be stored for future analysis. The BRC will similarly coordinate with the CC to ensure the flow of collected data to the appropriate central reading center. The BRC will also coordinate work with the NIDDK Central Repository to prepare all study data for eventual archiving and distribution.

The BRC will prepare appropriately detailed reports to the Steering Committee and to the Data Safety Monitoring Board (DSMB), and to the NIDDK staff at regular intervals. The BRC will be responsible for the planning and logistics of meetings of the Steering Committee and its subcommittees, and will assist NIDDK with the logistics for DSMB meetings.

To support the consortium organization, the BRC will identify fixed and variable costs and establish procedures for negotiation of third party agreements or selection of subcontractors (i.e., manufacturers of artificial pancreas and CGM, clinical sites, clinical/investigational pharmacies, clinical/research laboratories, biospecimen repositories, etc.), and develop processes to efficiently administer and manage these entities throughout the project.

The NIDDK Technology Advancement Office must be consulted early in the process when an NIDDK-funded study enters into a collaboration agreement. These consults will be facilitated by the NIDDK Program Official. Applicants should also refer to the Policies for Clinical Researchers | NIDDK to set the expectation for BRC roles and responsibilities.

3. Steering Committee

The primary governing body of the study will be the Steering Committee, comprised of the PDs/PIs of the BRC and each CC, and the NIDDK Project Scientist.

The Steering Committee will develop policies and procedures for the study group and ensure that these policies are properly implemented. These may include procedures for modification of study design, use of study samples and data, approval of ancillary studies, publication and presentation of study findings, monitoring study progress, determining completeness and quality of data collection, and other performance measures. NIDDK expects the investigators to develop robust ancillary study policies to provide opportunities for outside investigators to leverage collected data and biospecimens, as well as the recruited cohort, to expand the scientific output of the group.

4. Project Scientist

The NIDDK Project Scientist will assist the Steering Committee in designing and carrying out the study. The Project Scientist will provide scientific support to awardees' activities, including protocol development, quality control, interim data monitoring, final data analysis, preparation of publications, and overall performance monitoring.

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

Section II. Award Information

Funding Instrument

Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, NIH scientific or program staff will assist, guide, coordinate, or participate in project activities. See Section VI.2 for additional information about the substantial involvement for this FOA.

Application Types Allowed
New

The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types. Only those application types listed here are allowed for this FOA.

Clinical Trial?

Not Allowed: Only accepting applications that do not propose clinical trials.

Need help determining whether you are doing a clinical trial?

Funds Available and Anticipated Number of Awards

NIDDK intends to commit $4.72 million in FY 2022 to support this consortium. Future year amounts will depend on appropriations. It is anticipated that awards will be made to 10 Clinical Centers under RFA DK-21-020 and to one Biostatistics Research Center under this FOA.

The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications.

Award Budget

Application budgets need to reflect the actual needs of the proposed project. Application awards are limited to $500,000 Direct Costs in grant year 1; $1,000,000 Direct Costs in grant year 2; $1,000,000 Direct Costs in grant year 3, $1,000,000 Direct Costs in grant year 4 and $1,000,000 in Direct costs in grant year 5.

Award Project Period

The scope of the project should determine the project period. The maximum project period is 5 years.

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

Section III. Eligibility Information

1. Eligible Applicants

Eligible Organizations

Higher Education Institutions

  • Public/State Controlled Institutions of Higher Education
  • Private Institutions of Higher Education

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

  • Hispanic-serving Institutions
  • Historically Black Colleges and Universities (HBCUs)
  • Tribally Controlled Colleges and Universities (TCCUs)
  • Alaska Native and Native Hawaiian Serving Institutions
  • Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

  • Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
  • Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

  • Small Businesses
  • For-Profit Organizations (Other than Small Businesses)

Local Governments

  • State Governments
  • County Governments
  • City or Township Governments
  • Special District Governments
  • Indian/Native American Tribal Governments (Federally Recognized)
  • Indian/Native American Tribal Governments (Other than Federally Recognized)

Federal Governments

  • Eligible Agencies of the Federal Government
  • U.S. Territory or Possession

Other

  • Independent School Districts
  • Public Housing Authorities/Indian Housing Authorities
  • Native American Tribal Organizations (other than Federally recognized tribal governments)
  • Faith-based or Community-based Organizations
  • Regional Organizations
Foreign Institutions

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

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

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

Required Registrations

Applicant organizations

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

  • System for Award Management (SAM) – Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
    • NATO Commercial and Government Entity (NCAGE) Code – Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
    • Unique Entity Identifier (UEI)- A UEI is issued as part of the SAM.gov registration process. SAM registrations prior to fall 2021 were updated to include a UEI. For applications due on or after January 25, 2022, the UEI must be provided on the application forms (e.g., FORMS-G); the same UEI must be used for all registrations, as well as on the grant application.
    • Dun and Bradstreet Universal Numbering System (DUNS) – Organization registrations prior to April 2022 require applicants to obtain a DUNS prior to registering in SAM. By April 2022, the federal government will stop using the DUNS number as an entity identifier and will transition to the Unique Entity Identifier (UEI) issued by SAM. Prior to April 2022, 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.
  • eRA Commons - Once the unique organization identifier (DUNS prior to April 2022; UEI after April 2022) is established, organizations can register with eRA Commons in tandem with completing their full SAM and Grants.gov registrations; all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
  • Grants.gov – Applicants must have an active SAM registration in order to complete the Grants.gov registration.

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

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

Eligible Individuals (Program Director/Principal Investigator)

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

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

2. Cost Sharing

This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.

3. Additional Information on Eligibility

Number of Applications

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

The NIH will not accept duplicate or highly overlapping applications under review at the same time, per 2.3.7.4 Submission of Resubmission Application. This means that the NIH will not accept:

  • A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
  • A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
  • An application that has substantial overlap with another application pending appeal of initial peer review (see 2.3.9.4 Similar, Essentially Identical, or Identical Applications).

Section IV. Application and Submission Information

1. Requesting an Application Package

The application forms package specific to this opportunity must be accessed through ASSIST, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission

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

Letter of Intent

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.

By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:

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

The letter of intent should be sent to:

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

Page Limitations

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed.

Instructions for Application Submission

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

SF424(R&R) Cover

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

SF424(R&R) Project/Performance Site Locations

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

SF424(R&R) Other Project Information

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

Consortium Assurance: The filename "Consortium Assurance.pdf" should be used.

The PD/PI should provide a letter stating his/her willingness to participate in Consortium activities, including sharing the scientific portion of the application, participating in meetings at the NIH and regular conference calls and abiding by approved Consortium policies, and following the common protocol agreed to during the planning phase.

In addition, the PD/PI and an authorized Institutional Official must provide evidence that the Institution is willing to sign a standard reliance agreement and use the single IRB proposed by the BRC as part of its application, in accordance with NIH policy on the use of a single Institutional Review Board for multi-site research,https://grants.nih.gov/grants/guide/notice-files/NOT-OD-17-076.html.

SF424(R&R) Senior/Key Person Profile

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

R&R or Modular Budget

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

The annual budget requested should match the timeline proposed for the project and the scope of the project. The first nine months will be devoted to planning and the budget will cover PI/critical co-investigator effort in protocol and manual of procedures development and travel to Steering Committee meetings. The BRC is expected to organize the planning meetings. After the planning period, the budget should reflect the scientific and coordination efforts of the BRC. The study should be completed before the end of year 5 to allow ample time for data clean-up and analysis. It is anticipated that the BRC will need to start hiring and training staff in advance of the actual initiation of recruitment to complete all preparatory work related to study launch (e.g., development of data entry systems, completion of IRB approval, set-up of a central laboratory and other key cores, as needed, etc.). It should be understood that, in the event of an award, the budget of the BRC will be adjusted from that proposed in the application to reflect the actual needs of the study-developed protocol. Although the exact protocol is not known, the BRC application should include a central laboratory and basic laboratory budget. For laboratory budgeting purposes in this application, the BRC should assume that approximately 200 individuals will undergo hypoglycemic, hyperinsulinemic clamps, three times over a three year period. It is expected that the following measurements will be taken at appropriate time intervals during the clamp: glucose, insulin c-peptide, glucagon, epinephrine, norepinephrine.

It is anticipated that supplemental BRC funding may be required to cover laboratory and other analysis costs that are part of the consensus protocol developed by the consortium. Furthermore, additional funding might be provided if the study needs to add recruitment sites as subcontracts to the BRC. Once the study starts, it is anticipated that there will be two study group meetings in the Washington DC area each year. The BRC will be expected to organize these meetings, as well as support two DSMB meetings each year. Funds should also be included in the final year of the budget for archiving data and biosamples at the NIDDK Central Repository. In addition, the BRC is responsible for the single IRB for the consortium. The budget should also include support for Stakeholder Engagement activities during the planning period as well as during the study period.

R&R Subaward Budget

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

PHS 398 Cover Page Supplement

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

PHS 398 Research Plan

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

Research Strategy: The Clinical Center applications submitted to the companion FOA, RFA-DK-21-020, will propose potential study designs, including the study population, and selection and timing of outcomes. Although the ultimate design of the study is not known and will be decided on by the final consortium during the planning year, it is anticipated that each participant will undergo a hypoglycemic, hyperinsulinemic clamp at baseline and yearly over a two-year period. Repeated CGM glycemic profiles and metrics will be collected at intervals determined by the consortium as well as collection of self-reported questionnaires on hypoglycemic awareness and possibly cognitive and psychological measures. While the BRC is not expected to propose a detailed study design, it is expected that the BRC will provide scientific input to the consortium on how to rigorously accomplish the aims of the study and their approach to evaluating and analyzing these proposed outcomes. The BRC applicant should propose a primary outcome and statistical methods that could be used to analyze the types of data that might be collected to accomplish the aims described in the Funding Opportunity Description (Part 2, Section1 of this FOA). Sample size calculations should be provided based on the proposed primary and secondary outcomes. The applicant should describe the statistical methods to be used in analyzing key data, including any pre-specified interim analyses. This plan is critical to knowing whether applicants have selected the correct cohort size based on proper power calculations and/or are using the most appropriate methods to analyze the resulting data and make correct conclusions at the end of the study. The sample size and statistical power calculations should contain enough detail, including a discussion of assumptions made, so that a reviewer can readily duplicate the sample size projection. Sample size calculations should be based on 90% power and include a discussion of the anticipated rates of follow-up (i.e., drop out/lost to follow up) during key outcome collection contacts. A discussion of how missing data will be handled should be included. Any planned interim analyses should also be described.

The BRC applicant should discuss how individuals with T1D and IAH will be identified and how the restoration of impaired awareness of hypoglycemia will be defined. The BRC should describe the number of individuals with T1D and IAH that would be needed at the end of the study to conduct clinically meaningful analyses, how many participants will need to be followed in the study to achieve this number, and how many potential participants would need to be screened for study eligibility.

The BRC should describe the specific core that will be formed which will be responsible for the development, evaluation and validation of new composite measures, psychometrics, or questionnaires for the identification of IAH by self-report. The BRC should identify a lead of this core with appropriate expertise. The BRC should describe the advantages and disadvantages of current self-report questionnaires used to identify impaired awareness of hypoglycemia.  The BRC should propose alternate, new approaches or composite metrics for identification of IAH and how they would approach validating any new questionnaires or metrics, and test the utility of the questionnaires in elucidating the heterogeneity of IAH and its relationship the counter-regulatory responses.

Letters of Support: A letter of support must be provided from the proposed single IRB.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide.

The following modifications also apply:

  • All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.
  • 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 investigator(s) should be prepared to transfer all data and samples to the Repository at the conclusion of the study. The study group will have exclusive access to data for a defined period, according to NIDDK data sharing policies, https://www.niddk.nih.gov/research-funding/human-subjects-research/policies-clinical-researchers.

Appendix:

Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

  • No publications or other material, with the exception of blank questionnaires or blank surveys, may be included in the Appendix.

PHS Human Subjects and Clinical Trials Information

When involving human subjects research, clinical research, and/or NIH-defined clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered “Yes” to the question “Are Human Subjects Involved?” on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

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

Section 3 - Protection and Monitoring Plans

All parts of Section 3 are required under this FOA.

3.3 Data and Safety Monitoring Plan

In addition to the description of safety monitoring, address plans to monitor study performance, including plans to assure fidelity to the protocol and integrity of the data. Information about Data and Safety Monitoring Plans in available on the NIDDK website: https://www.niddk.nih.gov/research-funding/human-subjects-research/policies-clinical-researchers/data-safety-monitoring-plans.

NIDDK will appoint a Data Safety Monitoring Board (DSMB). While the final details of the DSMP will depend on the final study protocol, this attachment should address processes likely based on the scientific thrust of the study. Information about DSMPs is available on the NIDDK website: http://www.niddk.nih.gov/research-funding/process/human-subjects-research/policies-for-clinical-researchers/data-safety-monitoring-plans/Pages/data-and-safety-monitoring-plans.aspx.

All applications must include a general description of the monitoring plan, policies, procedures, responsible entities, and approaches to identifying, managing and reporting reportable events (adverse events and unanticipated problems), to the applicable regulatory agencies (e.g., Institutional Review Board (IRB)), the Office of Biotechnology Activities (as appropriate), the Office of Human Research Protections, the Food and Drug Administration, and the NIDDK and OSMB.

The DSMP must address the following areas from the perspective of BRC responsibilities:

  • Who will manage and conduct the monitoring;
  • What will be monitored;
  • Proposed monitoring time points;
  • Where the monitoring will occur;
  • How the reportable events will be managed and reported; and
  • How sites/centers, and participating facilities (labs, pharmacies) will be monitored.

3.5 Overall Structure of the Study Team

Organization Plan:

The application should describe how the study will be organized and managed, both for the planning period and for the full study. This should include information on the leadership and staff of the BRC, and the ability of the PD/PI to bring together the necessary study network. The PD/PI should discuss in detail whether he/she, as well as other key members of the team, have experience in the conduct and administration of complex, multi-center studies, including delineation of the success of those studies in terms of recruitment, retention and publications.

Provide a description of the study organization and administration, including, but not limited to: a description of committee structures needed to manage the complexity of the trial, including plans to assure fidelity to the protocol and integrity of the data; policies and methods for ensuring data confidentiality and participant privacy; and the oversight, responsibilities, and coordination of any sites or cores proposed. The BRC should describe how the team will develop processes to efficiently administer and manage these entities throughout the project.The attachment should include a discussion of the proposed single IRB, including the experience of the IRB to oversee multi-center studies.

Describe the process for identification and selection of additional collaborators/Clinical Centers/cores if needed following the planning phase.

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).All instructions in the SF424 (R&R) Application Guide must be followed.

PHS Assignment Request Form

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

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

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

4. Submission Dates and Times

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

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

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

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

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

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

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

7. Other Submission Requirements and Information

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

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

For assistance with your electronic application or for more information on the electronic submission process, visit How to Apply – Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

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

The applicant organization must ensure that the unique entity identifier (DUNS number or UEI as required) provided on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

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

Use of Common Data Elements in NIH-funded Research

Many NIH ICs encourage the use of common data elements (CDEs) in basic, clinical, and applied research, patient registries, and other human subject research to facilitate broader and more effective use of data and advance research across studies. CDEs are data elements that have been identified and defined for use in multiple data sets across different studies. Use of CDEs can facilitate data sharing and standardization to improve data quality and enable data integration from multiple studies and sources, including electronic health records. NIH ICs have identified CDEs for many clinical domains (e.g., neurological disease), types of studies (e.g. genome-wide association studies (GWAS)), types of outcomes (e.g., patient-reported outcomes), and patient registries (e.g., the Global Rare Diseases Patient Registry and Data Repository). NIH has established a “Common Data Element (CDE) Resource Portal" (https://cde.nlm.nih.gov/home) to assist investigators in identifying NIH-supported CDEs when developing protocols, case report forms, and other instruments for data collection. The Portal provides guidance about and access to NIH-supported CDE initiatives and other tools and resources for the appropriate use of CDEs and data standards in NIH-funded research. Investigators are encouraged to consult the Portal and describe in their applications any use they will make of NIH-supported CDEs in their projects.

Post Submission Materials

Applicants are required to follow the instructions for post-submission materials, as described in the policy. Any instructions provided here are in addition to the instructions in the policy.

Section V. Application Review Information

1. Criteria

Only the review criteria described below will be considered in the review process.  Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.

Overall Impact

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).

Scored Review Criteria

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

 

Does the project address an important problem or a critical barrier to progress in the field? Is the prior research that serves as the key support for the proposed project rigorous? 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 those 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?

Specific to this FOA: How appropriate is the expertise of the PI and proposed study team in analyzing and statistically evaluating the proposed outcomes of the clinical trial?  Do they have the expertise to organize, manage and implement the proposed mulitsite clinical trial and meet milestones and timelines? Has expertise been identified to lead a core for the evaluation and validation of self-reported questionnaires to identify impaired awareness of hypoglycemia?

 

 

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? Have the investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? 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? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects? 
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 individuals of all ages (including children and older adults), justified in terms of the scientific goals and research strategy proposed?

Specific to this FOA:

Is the Core's justification for validating and potentially developing new metrics appropriate for the identification of impaired awareness of hypoglycemia in patients with T1D?

Is the study team's approach to integrating and analyzing the multiple types of data appropriate for the information to be collected in this study (measurements of counter-regulatory responses, CGM data and self-report questionnaires).

Is the organizational structure appropriate? Is the organizational plan well described? As described, will the organizational plan support the operational success of a multisite clinical study?

 

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

Additional Review Criteria

As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.

   

For research that involves human subjects but does not involve one of the  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  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.

Specific to this FOA: Does the Data and Safety Monitoring Plan directly address safety concerns related to the proposed intervention and outcomes? Are the inclusion and exclusion criteria for participants clearly delineated? Are mitigation plans described?

 

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 individuals of all ages (including children and older adults) 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.

 

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

 

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.

 

Not Applicable.

 

Not Applicable.

 

Not Applicable.

Additional Review Considerations

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

 

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

 

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).

 

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

 

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

 

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

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by the NIDDK, in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons. Appeals of initial peer review will not be accepted for applications submitted in response to this FOA.

As part of the scientific peer review, all applications will receive a written critique.

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

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

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 Disease 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.

3. Anticipated Announcement and Award Dates

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

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

Section VI. Award Administration Information

1. Award Notices

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the recipient's business official.

Recipients must comply with any funding restrictions described in Section IV.6. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

Any application awarded in response to this FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website.  This includes any recent legislation and policy applicable to awards that is highlighted on this website.

Individual awards are based on the application submitted to, and as approved by the NIH and are subject to the IC-specific terms and conditions identified in the NOA.

Institutional Review Board or Independent Ethics Committee Approval: Recipient institutions must ensure that protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the recipient must provide NIH copies of documents related to all major changes in the status of ongoing protocols.

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Recipients, and Activities, including of note, but not limited to:

If a recipient is successful and receives a Notice of Award, in accepting the award, the recipient agrees that any activities under the award are subject to all provisions currently in effect or implemented during the period of the award, other Department regulations and policies in effect at the time of the award, and applicable statutory provisions.

Should the applicant organization successfully compete for an award, recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights laws that prohibit discrimination on the basis of race, color, national origin, disability, age and, in some circumstances, religion, conscience, and sex (including gender identify, sexual orientation, and pregnancy). This includes ensuring programs are accessible to persons with limited English proficiency and persons with disabilities. The HHS Office for Civil Rights provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-providers/provider-obligations/index.html and https://www.hhs.gov/civil-rights/for-individuals/nondiscrimination/index.html

HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research. For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA.

Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.html or call 1-800-368-1019 or TDD 1-800-537-7697.

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 and 2 CFR Part 200.206 “Federal awarding agency review of risk posed by applicants.” This provision will apply to all NIH grants and cooperative agreements except fellowships.

Cooperative Agreement Terms and Conditions of Award

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 Part 75, and other HHS, PHS, and NIH grant administration policies.

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

The Program Director(s)/Principal Investigator(s) will have the primary responsibility for:

1. Developing the research design and study protocol, including definition of objectives and approaches, sample size and power calculations, and establishing procedures for participant recruitment and follow-up, data collection, quality control, interim data and safety monitoring, final data analysis and interpretation, and publication of results.

2. Establishing a Steering Committee to implement, coordinate and manage the project(s). Recipient(s) will name investigators to serve as members on a Steering Committee and other subcommittees, as appropriate, meeting periodically. Recipients will be required to accept and implement the common protocol(s) and procedures approved by the Steering Committee.

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

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

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

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

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

8. Any third-party collaboration (including but not limited to interactions with organizations from industry, academia, and nonprofit institutions) should be governed by a research collaboration agreement (e.g., Clinical Trial Agreement, Research Collaborative Agreement, etc.) or any third-party contract mechanism(s) with terms that ensure the collaboration is conducted in accordance with the Cooperative Agreement, applicable NIH/NIDDK policies and procedures, and with written approval from NIDDK Program staff. Any relevant proposed third-party agreements related to the network studies between grantee and third-party will be provided to the NIDDK Program staff and NIDDK Technology Advancement Office for review, comment, and approval to assure compliance with NIH/NIDDK policies and network policies. Further, at the request of the NIDDK Program staff, any other network-relevant third-party agreements must be shared with NIDDK. Failure to comply with this term may prompt action in accordance with NIH Grants Policy Statement, Section 8.5 titled: “Special Award Conditions and Remedies for Noncompliance (Special Award Conditions and Enforcement Actions”, and Section 8.5.2, titled: “Remedies for Noncompliance or Enforcement Actions: Suspension, Termination, and Withholding Support”, noncompliance with the terms and conditions of award will be considered by the funding IC for future funding and support decisions and may result in termination of the award.”

9. Any involvement of a third-party (including but not limited to industry, academia, and nonprofit institutions) in the study and network activities that includes access to any network generated resources (i.e., data and biosamples), or study results that are not publicly available, or using the name of the network or study or the name of the NIH or NIDDK, is permitted only after written permission by the NIDDK Program staff who will consult with others at NIH and NIDDK Technology Advancement Office.

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

11. Maintaining confidentiality of information: The recipient(s) will maintain the confidentiality of the information developed by the investigators (i.e., protocols, data analysis, conclusions, etc.) as well as proprietary information of an individual company or other entity collaborating with the study. Any exception requires written approval from NIDDK Program staff.

12. Data Management and Sharing Plan: The NIDDK has established a Central Repository to support the receipt, storage, and distribution of data, biosamples, and other resources generated in clinical studies funded by the NIH/NIDDK. When the NIDDK Central Repository is to be utilized, prior to enrolling participants, the PI or his/her designee will coordinate with the NIDDK Program and Central Repository staff to prepare for eventual archiving and distribution of the study generated resources that are to be maintained in the Central Repository. All resources transferred to the Central Repository will be under the custodianship of the NIDDK. The study’s leadership will have proprietary control of and exclusive access to the resources per the NIDDK approved sharing plan. Subsequently, these resources 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, https://grants.nih.gov/policy/sharing.htm, and http://grants.nih.gov/grants/policy/data_sharing/data_sharing_faqs.htm), as well as the NIDDK policy for resource sharing, NIDDK Data Sharing Policy.

13. Study investigators are required to comply with NIH Policy on the Dissemination of NIH Funded Clinical Trial Information as stated at https://grants.nih.gov/policy/clinical-trials/reporting/understanding/nih-policy.htm. Per policy, the recipient is responsible for meeting the expectations of this policy. Refer to additional information at https://grants.nih.gov/policy/clinical-trials/reporting/index.htm.

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

An NIDDK Project Scientist with substantial involvement will:

1. Serve as the contact point for all facets of the scientific interaction with the recipient (s). As required for the coordination of activities and to expedite progress, NIDDK may designate additional NIDDK staff to provide advice to the recipient on specific scientific and/or analytic issues. Such staff may include another Project Scientist or Project Coordinator, who will provide direct technical assistance to the recipients to optimize the conduct and/or analysis of the study; or who may assist in the coordination of activities across multiple sites.

2. For multi-center studies, participate in the Steering Committee that oversees study conduct. The NIDDK Project Scientist or Project Coordinator will be a full participant and voting member of the Steering Committee and, if applicable, subcommittees.

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

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

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

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

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

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

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

  1. Interact with the Program Director(s)/Principal Investigator(s) on a regular basis to monitor study progress. Monitoring may include: regular communications with the Program Director/Principal Investigator and staff, periodic site visits, observation of field data collection and management techniques, quality control, fiscal review, and other relevant matters; as well as attendance at Steering Committee, data safety and monitoring board, and related meetings. The NIDDK retains, as an option, periodic review of progress by researchers not involved with the study.
     
  2. Review and approve protocols prior to implementation to insure they are within the scope of peer review, for safety considerations, as required by Federal regulations.
     
  3. The NIDDK Program Official will monitor protocol progress, and may request that a protocol study be closed to accrual for reasons including: (a) accrual rate insufficient to complete study in a timely fashion; (b) accrual goals met early; (c) poor protocol performance; (d) patient safety and regulatory concerns; (e) study results that are already conclusive; (f) low likelihood of showing a benefit of the intervention (futility); and (g) emergence of new information that diminishes the scientific importance of the study question. The NIDDK will not permit further expenditures of NIDDK funds for a study after requesting closure except as specifically approved by the NIDDK.
     
  4. Make recommendations for continued funding based on: a) overall study progress, including sufficient patient and/or data accrual; b) cooperation in carrying out the research (e.g., attendance at Steering Committee meetings, implementation of group decisions, compliance with the terms of award and reporting requirements); and/or c) maintenance of a high quality of research, which will allow pooling of data and comparisons across multiple cooperative agreement awards for common data elements.
     
  5. Appoint an independent Data and Safety Monitoring Board (DSMB) as appropriate for Phase III clinical trials or other high-risk studies, or an Observational Study Monitoring Board (OSMB) for observational/epidemiologic studies; these Boards will review study progress, safety data, and interim results, as appropriate, and provide guidance to the NIDDK. The NIDDK Program Official or their Project Coordinator will serve as the Executive Secretary and/or NIDDK program representative on the DSMB.


Areas of Joint Responsibility include:

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

Steering Committee

A Steering Committee organized by the study investigator(s) will be the main governing body of the study.
The Steering Committee has primary responsibility to design research activities, establish priorities, develop common protocols and manuals, questionnaires and other data recording forms, establish and maintain quality control among recipients, review progress, monitor patient accrual, coordinate and standardize data management, and cooperate on the publication of results. Major scientific decisions regarding the core data will be determined by the Steering Committee. The Steering Committee will document progress in written reports to the NIDDK Program Official, and will provide periodic supplementary reports upon request.

The Steering Committee will be composed of all Program Director(s)/Principal Investigator(s), (including those of data coordinating /statistical centers, if any) and co-investigators as deemed necessary, and the NIDDK Project Scientist. The final structure of the Steering Committee and voting procedures will be established at the first meeting. The NIDDK Project Scientist will have voting membership on the Steering Committee, and as appropriate, its subcommittees. The frequency of Steering Committee meetings will be dictated by a vote of the members of the Steering Committee.

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

3. Reporting

When multiple years are involved, recipients will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement. NIH FOAs outline intended research goals and objectives. Post award, NIH will review and measure performance based on the details and outcomes that are shared within the RPPR, as described at 45 CFR Part 75.301 and 2 CFR Part 200.301.

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

In accordance with the regulatory requirements provided at 45 CFR 75.113 and 2 CFR Part 200.113 and Appendix XII to 45 CFR Part 75 and 2 CFR Part 200, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period.  The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS).  This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313).  As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available.  Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 and 2 CFR Part 200 – Award Term and Condition for Recipient Integrity and Performance Matters.

Section VII. Agency Contacts

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

Application Submission Contacts

eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten submission by the due date, and post-submission issues)

Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

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

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: support@grants.gov

Scientific/Research Contact(s)

Karen Teff, Ph.D.
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone: 301-594-8803
Email: karen.teff@nih.gov

Peer Review Contact(s)

Michele Barnard, Ph.D.
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone: 301-594-8898
Email: michele.barnard@nih.gov

Financial/Grants Management Contact(s)

Eunica Haynes
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone: 301-827-4018
Email: haynese@mail.nih.gov
 

Section VIII. Other Information

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Authority and Regulations

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75 and 2 CFR Part 200.

This FOA is supported under the authority of P.L. 116-260, Consolidated Appropriations Act, 2021; Section 302. Diabetes Programs.

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