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

This FOA invites an application from the current awardee of the Diabetes Prevention Program Outcomes Study (DPPOS) Biostatistics Research Center to undertake continued research on the DPPOS cohort. The application submitted under this FOA is linked toRFA-DK-15-503, which will support the DPPOS Clinical Centers.

Initiated in 1996, the Diabetes Prevention Program (DPP) was a landmark study which demonstrated that an intensive lifestyle intervention or the drug metformin could significantly prevent or delay the development of type 2 diabetes in high risk individuals. Twenty-two sites recruited over 3200 individuals to participate in DPP, which sought to prevent or delay the onset of type 2 diabetes in high risk individuals (i.e., defined as having impaired glucose tolerance and being overweight or obese). Participants were randomized to an intensive lifestyle intervention, metformin, or placebo. The average age at randomization was 50 years, with 20% of the cohort being older than 60 years of age. The cohort was ethnically diverse (20% African American, 16% Hispanic American, 5% American Indian and 4% Asian/Pacific Islander). After an average treatment duration of 2.8 years, there was a 58% reduction in the development of diabetes with lifestyle intervention and a 31% reduction with metformin, each compared with placebo (p<0.001). Interventions were effective across gender and race/ethnicity.

DPPOS represents the longitudinal follow-up of the DPP cohort.

Although the DPP convincingly demonstrated that type 2 diabetes could be delayed in high-risk individuals, questions remained about the long-term effects of these interventions. To answer these questions, the cohort has been followed longitudinally for an additional 11 years, through the DPPOS. Following the termination of the DPP, the metformin and placebo groups received a modified lifestyle intervention. In the DPPOS, the metformin group has continued on open-label metformin treatment, and the lifestyle participants receive an intervention to help maintain their lifestyle changes. All groups have also been offered lifestyle refresher classes. Participants are seen twice per year to assess glycemia and other outcomes are assessed annually. When participants develop type 2 diabetes, they continue to be followed for measurement of outcomes, but are referred to their physician for treatment of their diabetes. The long-term goals of the ongoing DPPOS have been to determine whether 1) The decreased development of diabetes seen with lifestyle or metformin would be sustained over time; and 2) Delay/prevention of diabetes would translate into decreased microvascular outcomes. Because of limited numbers of events, there has not previously been adequate power to examine cardiovascular outcomes.

This FOA invites an application from the existing DPPOS Biostatistics Research Center to support continued research through longer term follow up of the DPPOS cohort, focusing on a comparative effectiveness study to determine the benefits on CVD and cancer of early initiation of metformin treatment in individuals who have pre-diabetes versus waiting to begin metformin until needed for treatment of diabetes. Efficacy of early metformin may also be compared with early intensive lifestyle change (ILS) in reducing CVD or cancer. This comparative effectiveness study is of enormous public health importance since nearly 26 million individuals in the U.S. have type 2 diabetes and an additional 79 million (35% of the U.S. population over the age of 20 years) have pre-diabetes. There is substantial epidemiologic evidence that suggests that individuals treated with metformin for type 2 diabetes have lower CVD and cancer rates. The mechanism of this putative effective of metformin on CVD and cancer is unclear and may be mediated by glycemic control, weight loss or other mechanisms.

Continued research on and follow-up of the DPPOS cohort may also: 1) provide long-term information on the impact of delaying the development of diabetes on microvascular outcomes; and 2) lead to improved understanding of the modern day continuum of dysglycemia, as the DPP/DPPOS cohort represents the only large-scale cohort of individuals with a known time of diabetes diagnosis.

The DPPOS study group, consisting of the investigators from the Clinical Centers and the Biostatistics Research Center, will collaboratively develop the study design and develop plans for implementing the protocol. The study group will jointly analyze data from the study, and disseminate this information through presentations at scientific meetings and manuscripts in scholarly, peer-reviewed journals. The study group has also developed mechanisms through which investigators outside of the study group may collaborate with the study investigators to test novel hypotheses using the DPPOS cohort or DPPOS samples and/or data.

1. Biostatistics Research Center (BRC)

There will be a single BRC. 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 is will also be responsible for establishing all scientific collaborations for specialized outcomes measuring complications of diabetes and co-morbidities.

The DPPOS study group will have exclusive access to data from the DPPOS study population for a defined period, according to NIDDK data sharing policies. All study data analyzed for publication of the primary study outcome(s) are expected to be provided to the NIDDK Repository so that it can be shared within six months of the publication date for the primary outcome publication or within two years of the date that the database is locked for analysis, whichever occurs first, as appropriate and consistent with achieving the goals of the program. All data analyzed for publication of the secondary outcome(s) are expected to be provided to the Repository so that it can be shared within two years of the date that the database for these outcomes is locked for analysis, consistent with achieving the goals of this program. The DPPOS Steering Committee has already established policies under which ancillary studies may be conducted while the study is ongoing, consistent with applicable laws, regulations, and policies.

In addition to conducting the research described above, the BRC is responsible for the collection and management of all clinical and laboratory data. The BRC will be responsible for ensuring subject 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. The BRC will coordinate communication among and with the CC.

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

The BRC will prepare appropriately detailed reports to the Steering Committee and to the DPPOS 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.

2. Clinical Centers (CC) (RFA-DK-15-503)

The clinical centers are responsible for 1) continuing to provide metformin to those participants who were originally randomized to the metformin arm and who have not developed type 2 diabetes and 2) collecting outcomes in all consented participants.

The CC will be expected to implement the protocol. The CC will collect data in accordance with established study procedures and submit all samples and data to the BRC and central laboratory and central reading centers, as appropriate and required by the protocol.

3. Steering Committee

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

The Steering Committee will continue to develop policies and procedures for the DPPOS 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.

4. Project Scientist

The NIDDK Project Scientist will continue to assist the Steering Committee in carrying out the DPPOS 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.

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.

This FOA is limited to the current awardee of the Diabetes Prevention Program Outcomes Study (DPPOS) Biostatistics Research Center.

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.

Applicant Organizations

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

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

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

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

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

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

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

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

The NIH will not accept duplicate or highly overlapping applications under review at the same time. This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101).

In addition, the NIH will not accept a resubmission (A1) application that is submitted later than 37 months after submission of the new (A0) application that it follows. The NIH will accept 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, including Supplemental Grant Application Instructions except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

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

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 electronically, should be sent to:

Dr. Francisco Calvo
Chief, Review Branch
6707 Democracy Boulevard, Room 752
Bethesda, MD 20892-5452
(for express/courier service: Bethesda, MD 20817)
Telephone: (301) 594-8897
Fax: (301) 480-3505
Email: [email protected]

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

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, with the following additional instructions.

Descriptive Title of Applicant's Project: To allow NIH to identify a group of applications as a related set of collaborative applications, the titles for each application in the set must have the following format: a "1/N indicator + identical Title (e.g., 1/3 where the 1/3 means this is site 1 of 3 sites in the set. The other sites will be labeled 2/3, etc.). A set of applications is defined as all applications submitted in response to this FOA as well as the associated FOA (RFA-DK-15-503). Titles of all collaborative applications must be identical except as follows: Applications submitted in response to this FOA must include "Research Project" at the end of the title; the application submitted in response to RFA-DK-15-505 should include "Biostatistics Center" at the end of the title. The numbering order of the collaborative applications in the consortium is at the discretion of the applicants. Titles may not exceed 200 characters in length, including the tag (e.g., 1/3) at the beginning of the title.

Cover Letter Attachment: The Cover Letter is one pdf file only. The following collaborative information is required in the Cover Letter: a listing of all the applications that are part of the set of collaborative applications being submitted, including for each: 1) the PD/PI(s) name(s); 2) the Title (including the tag, e.g., "1/3"); and 3) the Applicant Institution. Each site should submit an identical listing.

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.

Other Attachments

The following items should be included as attachments under "Other Attachments."

1. Clinical Protocol Synopsis

The file name "Clinical Protocol Synopsis.pdf" should be used and will be reflected in the final image bookmarking for easy access for reviewers.

The clinical protocol synopsis must include the following information:

• A description of the study population, in aggregate for the entire study, including subject eligibility and inclusion/exclusion criteria;
• A table showing the demographics of the available population at every site should be included;
• Approaches to be used for retention, cooperation and follow-up of subjects and to address any anticipated changes in the composition of the study population over the course of the study, for example, due to aging of the population under study;
• Methods of assignment of subjects to study groups and of randomization, if applicable;
• A description of how data from the site(s) will be obtained, managed, and protected;
• Descriptions of all clinical, laboratory, physiological, and/or behavioral tests to enable the research questions to be answered; and
• A description of the data management and quality control plan, including methods for monitoring the quality and consistency of the intervention(s) and data collection; policies and methods for ensuring blinding of study results; and data confidentiality and subject privacy.

Applications that lack the Clinical Protocol Synopsis are incomplete and will not be peer reviewed.

2. Statistical Analysis Plan

The filename "Statistical Analysis Plan.pdf" should be used and will be reflected in the final image bookmarking for easy access for reviewers.

The applicant should describe the statistical methods to be used, including the sample size and power calculations, plans for the primary and secondary analyses, and 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. To maintain the integrity of the DPPOS study, the clinical site investigators should continue to be blinded to event rates by original DPP randomization group. Therefore, the clinical center applications submitted to RFA DK-15-503 will contain a briefer discussion of power, which may include discussion of the event rate in the placebo group. The coordinating center application, submitted by the unblinded study biostatistician, should include a more detailed power analysis based on actual event rates to date in the DPPOS. Although applicants may only request 5 years of funding, power calculations may be provided for more than 5 years of follow up, if appropriate. If optimal power would be achieved with longer follow-up, the coordinating center should provide plans for a futility analysis as soon as possible and no later than at the end of year 3 of the project period that would allow NIDDK to make a determination about whether to request applications to extend the follow up for an additional project period.

Applications that lack the Statistical Analysis Plan are incomplete and will not be peer reviewed.

3. Data and Safety Monitoring Plan (DSMP)

The filename "Data and Safety Monitoring Plan.pdf" should be used and will be reflected in the final image bookmarking for easy access for reviewers.

The DSMP should be commensurate with the risk level of the proposed clinical research and must be included for all clinical trials (see http://grants.nih.gov/grants/guide/notice-files/not98-084.html ) and multi-center clinical studies. 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 or study protocols 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 Data and Safety Monitoring Board (if one is used).

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.

Applications that lack the DSMP are incomplete and will not be peer reviewed.

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:

Specific Aims:

The Specific Aims must be identical in each of the applications that are linked as a collaborative set.

Research Strategy: Each application must contain a Research Strategy that clearly describes those aspects of the project that are common to all sites of the collaboration. The Research Strategy must be identical across the linked U01 applications, with the exception of the section under the header "Elements Unique to This Site." All variations in the Research Strategy, no matter how minor, should be highlighted in this subsection. In this subsection, the BRC PD/PIs should describe their unique contribution(s) to the study, such as statistical analyses.

The common Research Strategy section should include:

• A discussion of the significance of the problem being studied, the need for the trial, and the potential impact of the results of the trial, as well as how the trial will test the hypothesis(es) proposed;
• A concise description of the overall strategy, methodology and analyses to be used to accomplish the goals and specific aims of the trial;
• A description of and rationale for the proposed study design;
• A description of the intervention to be tested and the protocol to be followed in each arm of the trial, including a discussion of potential biases or challenges in the protocol and how they will be addressed;
• Statistical methods that are appropriate for the study design, including sample size and power calculations and the underlying assumptions (and data) used to link these calculations to the endpoints and to the hypothesis(es) being tested; A discussion of studies that led to the proposed clinical trial and information or data from preliminary studies that address the need for and the feasibility of the trial; and
• A brief acknowledgement of the responsibilities as part of a multi-center collaborative project.

The unique BRC section should include 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; the oversight, responsibilities, and coordination of all clinical sites and any sites or cores proposed as subcontracts to the coordinating center.

In this section, there should be sufficient description of the items listed above to permit thorough evaluation of the proposed trial. Technical details contained in the clinical trial synopsis, statistical analysis plan, and data and safety monitoring plan can be referenced from within the Research Strategy section, in order to avoid duplicating text.

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

• All applications submitted for the January 25, 2015 due date or after are expected to comply with the NIH Genomic Data Sharing Policy as detailed in NOT-OD-14-111, as applicable.
• 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 (http://www.niddk.nih.gov/research-funding/process/human-subjects-research/Documents/PublicversionNIDDKdatasharingpolicy2013July2013.pdf)

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. The protocol and informed consent templates may be submitted as appendices.

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.

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

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

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

Important reminders:

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

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

See more tips for avoiding common errors.

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

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.

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

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

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

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

If the project involves 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?

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.

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.

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.

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

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

Not Applicable

For Renewals, the committee will consider the progress made in the last funding period.

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.

Not Applicable

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 Wide Association Studies (GWAS) /Genomic Data Sharing Plan.

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 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 submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the National Diabetes and Digestive and Kidney Diseases (NDDK) Advisory Council. 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 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.

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Parts 74 and 92 (Part 92 is applicable when State and local Governments are eligible to apply), and other HHS, PHS, and NIH grant administration policies.

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

The PD(s)/PI(s) will have the primary responsibility for:
1. Developing the research design and study protocol, including definition of objectives and approaches, sample size and power calculations, and establishing procedures for participant recruitment and follow-up, data collection, quality control, interim data and safety monitoring, final data analysis and interpretation, and publication of results.

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

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

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

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

6. Submitting interim progress reports, when requested, 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, consistent with achieving the goals of the program. 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://icmje.org/recommendations/browse/publishing-and-editorial-issues/clinical-trial-registration.html).

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

An NIDDK Project Scientist with substantial involvement will:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Areas of Joint Responsibility

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

A Chairperson of the Steering Committee, other than the NIDDK Project Scientist, will be selected by the NIDDK. The Chairperson provides leadership to the Committee by conducting the Steering Committee meetings, representing the study group to the External Oversight Committee established by the NIDDK (see item D2 below) and by interacting closely with the awardees during protocol development and implementation.

2. External Study Oversight.

An independent Data and Safety Monitoring Board will be established by the NIDDK for Phase III clinical trials or other high risk studies as appropriate. 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.

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

A final 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)
Finding Help Online: http://grants.nih.gov/support/index.html
Email: [email protected]

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact CenterTelephone: 800-518-4726
Web ticketing system: https://grants-portal.psc.gov/ContactUs.aspx
Email: [email protected]

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone: 301-710-0267
Email: [email protected]

Karen Teff, Ph.D.
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone: 301-594-8803
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.