It is critical that applicants follow the instructions in the Research Instructions for 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 a cooperative agreement application from the existing GRADE awardees to continue to treat type 2 diabetes and measure outcomes in those individuals recruited into the GRADE study, in order to complete the study according to the approved protocol. GRADE is a pragmatic, unmasked clinical trial to compare commonly used diabetes medications, when combined with metformin, on long-term glucose-lowering effectiveness, with the main goal of providing guidance to clinicians about the most appropriate medications to treat type 2 diabetes.

The epidemic of type 2 diabetes is a major public health problem, expected to affect up to one in three Americans if current trends continue. The most recent estimates in the US include a prevalence of more than 27 million persons with type 2 diabetes, with an incidence of approximately 1.7 million new cases per year. Cardiovascular disease is increased 2-5 fold in type 2 diabetes and is the leading cause of premature death. In addition, there are major human and economic costs related to the development of long-term microvascular complications that cause more cases of blindness, renal failure, and non-traumatic amputations than any other disease. High quality clinical trials have established the importance of lowering glucose with a variety of medications to reduce the long-term complications. One of the major challenges for practitioners is to choose, from the considerable armamentarium of glucose-lowering medications at their disposal, the optimal approach to achieving and then maintaining good glycemic control for as long as possible. Evidence supporting the choice of one versus another agent as the second drug added to metformin, the consensus initial treatment for type 2 diabetes, is lacking. Comparative effectiveness research is a high priority both to improve public health and to maximize cost-effectiveness in the management of type 2 diabetes. Moreover, efforts to individualize therapies and determine whether some therapies work better in individuals with particular characteristics compared to others are needed, and the differential effects of various therapies on the physiology of glucose metabolism also remain unknown.

In response to these concerns, NIDDK funded the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) Study in 2012. GRADE is a pragmatic, randomized clinical trial in patients with <10 years duration of diagnosed type 2 diabetes that will compare the metabolic effects of four common anti-diabetic drugs when combined with metformin. The four randomly assigned medications are the sulfonylurea glimepiride, the DPP-4 inhibitor sitagliptin, the GLP-1 agonist liraglutide, and the basal insulin glargine. A total of 5000 patients who are within 10 years of diagnosis of their type 2 diabetes and are being treated with metformin at the time of recruitment are being enrolled. These subjects are randomly assigned to one of the four drugs, which are added to metformin, to compare the effects among these four combinations. The study compares the drug combinations over a clinically meaningful duration, with a mean follow-up of 4.8 years.

Given a substantial lag in recruitment at the start of the study, it will require 3.5 years (rather than the originally planned 3 years) to complete recruitment; at the current randomization rate, it is anticipated that recruitment will be accomplished by April 2017. The GRADE Data and Safety Monitoring Board (DSMB) has recommended and NIDDK has approved a six-month extension of recruitment and six month extension of follow-up, such that the last participant visit will occur in April 2021.

Continued follow-up of the GRADE cohort is required to have adequate power to answer the questions delineated in the protocol, which has been approved by all participating IRBs and the DSMB.

The primary metabolic outcome is the time to primary failure defined as a hemoglobin A1c (HbA1c) greater than or equal to 7%, subsequently confirmed, after having been treated with maximally tolerated doses of both metformin (up to 2000 mg per day) and the randomly assigned second medication (intention-to-treat). A secondary metabolic outcome is the time to an HbA1c >7.5%, confirmed. At that time, basal insulin rescue therapy is added for the participants assigned to drugs other than insulin, and insulin therapy is intensified for those assigned to basal insulin. Another metabolic outcome is the time to tertiary metabolic failure defined as the time to another HbA1c >7.5%, confirmed, after treatment with basal insulin together with metformin and the randomly assigned second medication, at which time more intensive insulin therapy is initiated. Other metabolic outcomes being studied include the mean HbA1c and measures of insulin secretion and resistance over the entire study duration and at intermediate time points. Other important attributes of the four drug combinations being assessed include adverse effects such as weight gain and hypoglycemia, effects on cardiovascular disease (CVD) risk factors, tolerability and quality-of-life, and cost and cost-effectiveness. Although the GRADE study is not primarily a clinical outcomes study, selected measures of microvascular disease are included as secondary outcomes and clinical cardiovascular outcomes are being recorded. The study also plans to examine the phenotypic and, resources permitting, the genotypic characteristics that are associated with metabolic response to and/or failure of the individual medication combinations. Mechanistic studies of the pathophysiology contributing to success or failure of individual combinations are also part of the trial.

Under this FOA, one award will be made to the Biostatistics Research Center, which will include subcontracts to each of the 36 clinical sites recruiting, treating and following GRADE participants, and to the central laboratory, reading centers, and scientific cores.

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

1. Clinical Center (CCs)

The Clinical Centers are responsible for retention and treatment of GRADE participants and for collecting outcomes.

The CCs are expected to implement the protocol. The CCs treat participants' type 2 diabetes and collect data in accordance with established study procedures and submit all samples and data to the Biostatistics Research Center (BRC) and central laboratory and reading centers, as appropriate and required by the protocol.

Investigators at the CCs conduct analyses in conjunction with the BRC. The GRADE study group will have exclusive access to data from the GRADE 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. All data analyzed for publication of the secondary outcomes 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. The GRADE study group has already established policies under which ancillary studies may be conducted while the study is ongoing.

2. Biostatistics Research Center (BRC)

There will be a single BRC. The BRC biostatisticians work with the Clinical Center investigators to develop the design of the study. The BRC investigators 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 provides biostatistical and analytic expertise and conducts analysis and interpretation of the laboratory and clinical data in conjunction with the investigators at the Clinical Centers. The BRC is 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.

In addition to conducting the research described above, the BRC is responsible for the oversight and coordination of CC activities. The BRC continues to be responsible for overseeing and facilitating communication between the Drug Distribution Center and the CCs, to ensure the timely supply of medications, according to the protocol. The BRC oversees the collection and management of all clinical and laboratory data. The BRC continues to be responsible for ensuring subject confidentiality and safety, and quality control. The BRC conducts training and certification of study staff, and maintains and updates the manual of operations. The BRC continues to oversee implementation of and adherence to the study protocol. The BRC coordinates communication among and with the CCs.

The BRC continues to be responsible for the movement of biologic samples from the CCs to the central laboratory and, subsequently, to the NIDDK Repository, where samples will be stored for future analysis. The BRC similarly continues to ensure the flow of radiographic tests and other collected data to the appropriate central reading center. The BRC also collaborates with the NIDDK Data Repository to prepare all GRADE data to eventual archiving and distribution, according to the timeline described above.

The BRC continues to prepare appropriately detailed reports to the Steering Committee and to the GRADE DSMB, and to the NIDDK staff at regular intervals. The BRC is responsible for the planning and logistics of meetings of the Steering Committee and its subcommittees, and assists NIDDK with the logistics of the DSMB meetings.

3. Steering Committee

The primary governing body of the study continues to be the Steering Committee, comprised of the Program Directors/Principal Investigators of the BRC and each CC, and the NIDDK Project Scientist.

The Steering Committee continues to develop policies and procedures for the GRADE study group, and ensures that these policies are properly implemented. These may include procedures for modification of study design, use of study data and samples, approval of ancillary studies, publication and presentation of study findings, monitoring of study progress, determining completeness and quality of data collection, and other performance measures.

4. Project Scientist

The NIDDK Project Scientist continues to assist the Steering Committee in carrying out the GRADE study. The Project Scientist provides 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.

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 a limited competition for the continuation of the GRADE study, which was previously funded under PAR-11-157. Only the currently funded Biostatistics Research Center (BRC) is eligible to apply. Only the currently funded Clinical Centers (CCs) are eligible to be CCs as subcontracts to the BRC.

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).

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

It is critical that applicants follow the instructions in the Research Instructions for 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:

Michele L. Barnard, Ph.D.
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
6707 Democracy Boulevard, Room 7353
Bethesda, MD 20892-5452
(for express/courier service: Bethesda, MD 20817)
Telephone: 301-594-8898
Email: NIDDKLetterofIntent@mail.nih.gov

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.

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

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

Other Attachments: The application must include the following documents, uploaded as separate pdf files with the names indicated below.

1. Clinical Protocol Synopsis

The filename "Clinical Protocol Synopsis.pdf" should be used.

The synopsis is meant to supplement the information provided in the Research Strategy and should include the following information:

• A description of the study population, including GRADE subject eligibility and inclusion/exclusion criteria;
• A discussion of the participants at each center; a table showing the demographics of the population at each site and overall should be included;
• Approaches to be used for retention, addressing any anticipated changes in the composition of the study population over the course of the study; a table should show past retention at each site and overall;
• A description of all primary and secondary outcomes measures;
• A timeline of study activities.

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.

The Statistical Analysis Plan is meant to supplement the information provided in the Research Strategy. The applicant(s) should describe the statistical methods to be used, including the sample size and power calculations, plans for the primary and secondary analyses, and any pre-specified interim analyses. The plan is critical to knowing whether applicants have selected the correct cohort size and/or are using the most appropriate methods to analyze the data and make the correct conclusions at the end of the study.

Applications that lack the Statistical Analysis Plan 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:

Research Strategy: The Research Strategy should include:

• A discussion of the significance of the problem being studied, the need for the study, and the potential impact of the results of the study, as well as how the study will test the hypotheses proposed;
• A concise description of the overall strategy, methodology and analyses to be used to accomplish the goals and specific aims of the study;
• A description of and rationale for the proposed study design;
• A description of the outcomes to be assessed and how they will be measured, including a discussion of potential biases or challenges in the protocol and how they will be addressed;
• 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 study, as well as the oversight, responsibilities, and coordinating of any sites or cores. The description of the study organization should also indicate who will be responsible for preparation of various reports and of meetings needed for the management of a complex study.

In this section, there should be sufficient description of the items listed above to permit thorough evaluation of the proposed study. Technical details contained in the clinical protocol synopsis, statistical analysis plan, and the 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:

The NIDDK has established Central Biosample, Genetic and Data Repositories for the archiving and storage of data and biosamples in large, multi-site studies funded by NIDDK. The investigators 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 ).

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

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 study protocol may be attached as an appendix.

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

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

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

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.

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. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

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

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

See more tips for avoiding common errors.

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

In order to expedite review, applicants are requested to notify the NIDDK Referral Office by email at NIDDKLetterofIntent@mail.nih.gov 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? Is there a strong scientific premise for the project? 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? 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 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 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

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 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.

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 Advisory Council (NDDKAC). The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons. 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.

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.

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

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

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

Cooperative Agreement Terms and Conditions of Award

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

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

The PD(s)/PI(s) will have the primary responsibility for:

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

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

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

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

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

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

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

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

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

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

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

12. The NIDDK has established Central Biosample, Genetic, and Data Repositories for the archiving and storage of data and biosamples collected in large, multi-site studies funded by NIDDK. The PI or his/her designee will coordinate with the NIDDK Data Repository to prepare the collected data for eventual archiving and distribution. In addition, if applicable, the PI or his/her designee will work with the NIDDK Biosample Repository to coordinate procedures for coding, shipping, processing, receipt, and storage of study samples that are to be maintained in the Repository. All samples and data transferred to the Repositories will be under the custodianship of the NIDDK, although the study’s Steering Committee will have proprietary control of and exclusive access to the samples and data for an agreed-upon period of time. Subsequently samples and data will be available to the wider scientific community in accordance with the NIH policy on Data Sharing (https://grants.nih.gov/grants/policy/data_sharing/data_sharing_guidance.htm),

as well as the NIDDK policy for data sharing in multi-center and large single-center clinical studies http://www.niddk.nih.gov/research-funding/process/human-subjects-research/Documents/PublicversionNIDDKdatasharingpolicy2013July2013.pdf.

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

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

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

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

Areas of Joint Responsibility include:

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

1. Steering Committee.

A Steering Committee organized by the study investigator(s) will be the main governing body of the study.

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

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

The frequency of Steering Committee meetings will be dictated by a vote of the members of the Steering Committee.

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

2. External Study Oversight.

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

Dispute Resolution

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

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.

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

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

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

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

Email: support@grants.gov

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

Barbara Linder, M.D., Ph.D.
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone: 301-594-0021
Email: linderb@mail.nih.gov

Michele Barnard, Ph.D.
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone: 301-594-9989
Email: barnardm@mail.nih.gov

Christina Coriz
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone: 301-594-8848
Email: corizc@mail.nih.gov

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 Part 75.