Required Application Instructions

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

Part 1. Overview Information
Part 2. Full Text of the Announcement

Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

The primary objective of this cooperative agreement is to improve and standardize HbA1c measurements and data interpretation across clinical systems and national harmonization programs as well as to standardize C-peptide measurements. The reduction in complication risk with improved HbA1c demonstrated in the Diabetes Control and Complications Trial (DCCT) and the United Kingdom Prospective Diabetes Study (UKPDS) underscores the need to measure HbA1c with sufficient reliability such that clinical laboratory results can be directly related to these studies and, therefore, to the risk for development or progression of diabetes-related chronic complications. Because clinical care providers are adjusting medical therapy based on HbA1c measurement and excessive or inadequate therapy can harm patients, it is imperative that the accuracy of this key test as performed for clinical care continue to improve. In the research sphere, the measurement of C-peptide used to monitor endogenous insulin production is the basis for identifying successful therapeutics to delay the progression of type 1 diabetes. There is increasing evidence, including data from the DCCT study, that preservation of even a low level of endogenous insulin production in people with type 1 diabetes is associated with significantly fewer diabetes complications over the longer term. This Funding Opportunity Announcement will provide support for a Central Primary Reference Laboratory (CPRL) to standardize and improve the measurement of HbA1c and C-peptide.

Diabetes mellitus is a chronic disorder characterized by insulin deficiency, hyperglycemia, and high risk for development of complications of the eyes, kidneys, peripheral nerves, heart and blood vessels. The disease is highly prevalent, affecting over 29 million people in the U.S. The disease comes in two major well characterized forms, type 1 diabetes, characterized by autoimmune-mediated destruction of insulin producing pancreatic beta cells, and occurring mainly in children and young adults, and type 2 diabetes, characterized by insulin resistance and associated with obesity, primarily in adults. It is estimated that approximately 1 in every 7 health care dollars spent in the U.S. goes to diabetes care - mostly for treatment of the chronic complications which occur in both forms of the disease. In the U.S., diabetes is the most common cause of blindness in working age adults, kidney failure, and non-traumatic limb amputation.

The landmark nine-year Diabetes Control and Complications Trial (DCCT), completed in 1993, showed conclusively that the risk for development and progression of the chronic complications in patients with type 1 diabetes mellitus could be dramatically reduced with improved blood glucose control as assessed by serial glycohemoglobin [GHB or hemoglobin A1c (HbA1c)] determinations. HbA1c has been shown to be a reliable index of average blood glucose during the previous 2-3 months that is used routinely to monitor glycemic control in individuals with diabetes. Based on the DCCT results, the American Diabetes Association (ADA) and other professional groups have developed a series of specific diabetes treatment guidelines using HbA1c as a measure of mean blood glucose. However, lack of standardization of HbA1c assay methods among different laboratories prevented optimal use of the test in the clinical setting. Efforts to reduce complications of diabetes through improved glycemic control required standardization of clinical HbA1c assays so that tests done for medical care of people with diabetes would be comparable to the levels of HbA1c proven to reduce complications in the

DCCT. Subsequent studies showed the feasibility of standardizing HbA1c assays, and a candidate reference method for HbA1c was proposed. Early efforts to standardize HbA1c values among clinical laboratories by using a "universal calibrator" proved feasible for some assay methods. Later studies showed, however, that such an approach, although relatively simple, did not work for some methods currently in use in the clinic. Thus, it was decided that the best way to proceed with the standardization of the assay across clinical labs to the DCCT reference values was to start at the manufacturing level, with the verification of method standardization using fresh sample comparisons with the Reference Method.

HbA1c measurement standardization has become even more important in recent years. There is increased use of the test, with rising rates of diabetes. The FDA has utilized improvements in HbA1c as an outcome measure for approval of new therapies for diabetes. In 2010, the ADA sanctioned the use of HbA1c as one option for diagnosis of diabetes and pre-diabetes. Thus, there is now a critical need for accuracy and precision near the normal range in addition to the clinical target range for diabetes treatment.

In an effort to standardize these methods and to reduce the variation among them, the American Association for Clinical Chemistry established the National Glycohemoglobin Standardization Program (NGSP). The NGSP evaluates, sets accuracy standards, and certifies methods for the measurement of HbA1c with the goal of standardizing the glycohemoglobin test. This initiative has resulted in a substantial improvement in the comparability, reliability, and precision of assay methods. The International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) work group on Standardization of HbA1c then developed a reference measurement procedure that has been approved by all IFCC member societies. The fact that HbA1c is now recommended for diagnosis of diabetes and prediabetes reinforces the requirement that HbA1c results be accurate. More specifically, constant monitoring of the analytical performance of the assay and quality control is needed to achieve the goals of intra-laboratory CV <2% and inter-laboratory CV <3.5%.

The DCCT established the importance of another key laboratory measurement in type 1 diabetes. C-peptide is a stable and detectable non-functional cleavage product of insulin found in serum. Measurement of C-peptide is used to monitor endogenous insulin production in people with diabetes who are receiving exogenous insulin as therapy. There is increasing evidence, including data from the DCCT study, that preservation of even a low level of endogenous insulin production in people with type 1 diabetes is associated with significantly fewer diabetes complications. DCCT participants with measureable C-peptide were able to achieve better glycemic control with less risk of hypoglycemia and had fewer long term complications of diabetes. These data suggest that functional preservation of endogenous insulin production as assessed by C-peptide has clinical benefit. Typically, the new onset type 1 diabetes patient can expect to see their endogenous insulin production (as measured by mixed meal-stimulated C-peptide) decline over the first 1-2 years after diagnosis, as residual insulin producing beta cells are lost to autoimmune destruction. Therefore, recent trials of clinical interventions in new onset subjects are designed to delay progression of beta cell loss and preserve C-peptide production or to delay its decline over 1 to 2 years. Preservation of C-peptide production at 1 or 2 years as a clinical trial endpoint has been accepted by the FDA.

Measuring C-peptide levels with highly sensitive and standardized methods is therefore important now to accurately implement and interpret clinical trials to identify therapeutic interventions capable of reversing or delaying progression of the disease at onset. Improving, harmonizing, and standardizing C-peptide measurements could be even more important in the future as additional interventions and combination of agents are tested for clinical benefit.

To assist in C-peptide assay harmonization, an ADA endorsed C-peptide standardization committee was established and international C-peptide comparison studies were conducted. As a result of many years of comparison studies using pure C-peptide standards and patient samples, the committee concluded that patient samples work best to improve comparability and calibration among assays, and to reduce variability. More recently, a LC/MS reference method for C-peptide was developed and used to improve comparability of results. A second reference laboratory procedure is also underway to fulfill the requirements of manufacturer acceptability to list the reference method with the Joint Commission on Traceability in Laboratory Medicine.

a) The laboratory is responsible for establishing and maintaining the DCCT primary reference method that analyzes HbA1c by high performance liquid chromatography (HPLC) using Bio-Rex 70 resin.

b) The laboratory is responsible for establishing a network of reference laboratories, all of which maintain reference methods, or precise methods traceable to the reference method.

c) The laboratory is responsible for monitoring the Network Laboratories.

d) The laboratory is responsible for interacting with manufacturers of HbA1c methods, providing assistance in standardizing their methods and then providing comparison data for certification of traceability to the DCCT.

e) The laboratory is responsible for providing fresh whole-blood specimens, in the clinical range of 4-14% Hb1Ac, for use in comparison studies and monitoring laboratory performance for this project.

f) The laboratory is responsible for providing assessment of effectiveness of the program through evaluation of independent Proficiency Testing data from the College of American Pathologists (CAP).

g) The laboratory is responsible for providing data to validate and improve the use of HbA1c as an official diagnostic measure for diabetic disease.

h) The laboratory is responsible for maintaining a public website providing information on the quality of HbA1c assays and methods as well as information on the suitability of assays and methods for particular populations (e.g. hemoglobin variants).

i) The laboratory will foster continuous improvement in the accuracy and reliability of clinical HbA1c assays in use in the U.S., including analyses of inferences based on rare variants and other factors.

j) The laboratory will convene regular meetings to foster harmonization efforts in the U.S. with international efforts to improve and standardize HbA1c measurement.

k) The laboratory is responsible for establishing and maintaining a C-peptide standardization program for select laboratories, particularly those serving major NIH supported clinical research projects.

l) The laboratory is responsible for coordinating the establishment and maintenance of two reference method laboratories for C-peptide and conducting the manufacturer re-calibration studies.

m) The laboratory is responsible for external Quality Control (QC) and/or Proficiency Testing (PT).

n) The laboratory is responsible for receiving, managing, and analyzing data obtained from the primary and secondary reference laboratories for HbA1c and C-peptide.

o) The laboratory PD/PI will be a member of the CPRL Steering Committee (SC). The SC is the main governing body of the network, and works with the NIDDK to oversee the implementation of the program. The laboratory will be working closely with all the other laboratories involved in a collaborative and interactive manner.

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.

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)
• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

Other

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

Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are not allowed.

Applicant Organizations

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

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

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

All PD(s)/PI(s) must have an eRA Commons account. 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).

Applicants must obtain 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:

Michele L. Barnard, Ph.D.
NIDDK Scientific Review Branch
6707 Democracy Boulevard, Room 7353
Bethesda, MD 20892
Telephone: (301) 594-8898
Fax: (301) 480-3505
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.

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:

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.

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

When conducting clinical research, follow all instructions for completing 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.

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

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

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

For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically. 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? Do the PD(s)/PI(s) have a track record in leading and implementing laboratory harmonization or standardization programs with global reach and with applications and importance for both clinical care and research in the diabetes field?

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:

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

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 OMB administrative guidelines, HHS 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, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement UC4, 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:

• Awardee will be primarily responsible for defining the objectives and approaches, planning, conduct, analysis, and publication of results, interpretations, and conclusions of studies conducted under the terms and conditions of the cooperative agreement award.
• The Program Director/Principal Investigator will assume responsibility and accountability to the applicant organization officials and to the NIH for the performance and proper conduct of the research supported under this Funding Opportunity Announcement in accordance with the terms and conditions of award, as well as all pertinent laws, regulations and policies.
• Awardee will retain custody of and have primary rights to the data and software developed under these awards, subject to Government policies regarding rights of access consistent with current HHS, PHS, and NIH policies.
• All staff of the Awardee will maintain the confidentiality of the information developed by the investigations, including, without limitation, study protocols, data analysis, conclusions, etc. per policies approved by the Steering Committee (see below for composition of the Steering Committee) as well as any confidential information received by third party collaborators.
• Awardee must analyze, publish and/or publicly release and disseminate results, data and other products of the study in a timely manner, concordant with the approved plan for making quality-assured data and materials available to the scientific community and the NIH, consistent with NIH policies and achieving the goals of the FOA.
• All staff of the Awardee will be required to participate in a cooperative and interactive manner with NIH staff, one another and with the Steering Committee.
• Awardee must share data, materials, models, methods, information and unique research resources that are generated by the projects in concordance with consortium policies as well as NIDDK policies.
• Awardee agrees to establish agreements with collaborators that address the following issues: (1) procedures for data sharing with industry partners; (2) procedures for safeguarding confidential information, including without limitation, any data generated by the consortium as well as information and/or data received from external collaborators; (3) procedures for addressing ownership of intellectual property that result from aggregate multi-party data; (4) procedures for sharing biospecimens under an overarching MTA amongst collaborators that operationalizes material transfer in an efficient and expeditious manner; (5) procedures for reviewing publications, determining authorship, and industry access to publications.
• Awardees must be in accordance with processes and goals as delineated in the Funding Opportunity Announcement.
• Upon completion or termination of the research project(s), the awardee is responsible for making all study materials and procedures broadly available (e.g., putting into the public domain) or making them accessible to the research community according to the NIH-approved plan submitted for each project, for making data and materials available to the scientific community and the NIH for the conduct of research. The data sharing plan should include a plan to accomplish this at the end of the study.
• Awardee agrees to the governance of the study through the established Steering Committee (defined below).

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

The NIDDK will designate program staff, including a Program Officer and a Grants Management Specialist to provide normal program stewardship and administrative oversight of the cooperative agreement. The Program Officer and Grants Management Specialist will be named in the Notice of Grant Award.

The NIDDK will consult External Experts with relevant scientific expertise to review the progress of the research projects and to advise NIH staff of scientific developments and opportunities that may enhance the achievement of the study goals.

An NIH IC Project Scientist will be substantially involved in this project above and beyond the normal stewardship of an NIH IC Program Official as follows:

• The NIH Project Scientist will coordinate and facilitate the research projects, attend and participate in all meetings of the Steering Committee, and act as liaisons between the Awardee, Steering Committee, and the External Experts.
• The NIH Project Scientist will be a member of the Steering Committee and, as determined by that committee, Subcommittees as needed. Only one NIH Project Scientist will vote on the Steering Committee. Other designated NIH program staff attending the steering committee meetings will be an ex officio (non-voting) member(s).
• The NIH Project Scientist, and other designated NIH program staff will help the Steering Committee develop and draft operating policies.
• The NIH Project Scientist and Program Officer will review the scientific progress, cooperation in carrying out research, and maintenance of high quality research, review the project(s) for compliance with operating policies developed by the Steering Committee, and may recommend to the NIH to continue funding; withhold support or restrict an award for lack of scientific progress or failure to adhere to policies established by the Steering Committee. Review of progress may include regular communications with the Program Director/Principal Investigator and NIH staff, periodic site visits for discussions with awardee research teams, fiscal review, and other relevant matters. The NIH retains the option of periodic external review of progress.
• The NIDDK reserves the right to terminate or curtail any study or any individual award in the event of (a) substantial shortfall in data collection or submission, quality control, or other major breach or a study protocol or policy and procedure, (b) substantive changes in a study protocol that are not in keeping with the objectives of the RFA, and/or a human subject ethical issues that may dictate a premature termination.
• The NIH will name additional scientific consultants as necessary from within the NIH whose function will be to assist the Project Scientists and the Steering Committee in carrying out the goals and aims of the approved studies. The NIH will have one vote for any key committees, regardless of the number of NIH personnel involved.
• The NIH Project Scientist serves as a resource with respect to other ongoing NIH activities to facilitate compatibility and avoid unnecessary duplication of effort.
• The NIH Project Scientist may coordinate activities among awardees by assisting in the design, development, and coordination of (a) common research protocol(s) and statistical evaluations of data and in the publication of results.
• The NIH Project Scientist may review procedures for assessing data quality and monitor study performance.
• The NIH Project Scientist may be a co-author on study publications. In general, to warrant co-authorship, the NIH staff must have contributed to one or more of 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.

Areas of Joint Responsibility include:

Through the Awardee, Steering Committee and NIH staff, the study members will cooperatively develop and implement processes to submit information and data, determine criteria and processes for quality control of information and data to be posted for the research community, refine scientific objectives, and implement research advances to facilitate the goals of the study, consistent with NIH policies and achieving the goals of the program as described in the Funding Opportunity Announcement.

Steering Committee

• The Steering Committee (SC) will meet annually or more often if necessary and will be composed of:
• The Program Director/Principal Investigator, or contact Program Director/Principal Investigator
• The NIH Project Scientist
• Representatives of stakeholders and interested parties, for example, the American Diabetes Association, research consortia leaders, laboratory heads.
• Composition and terms of service on the SC is reviewed and determined by consensus at the first meeting following each new funding cycle. Each full member will have one vote.

This SC will operate to develop collaborative protocols, identify impediments to success and strategies to overcome them, develop shared tools for disseminating information about the projects, and identify opportunities for sharing techniques, materials, information and tools.

• NIDDK staff, in concert with the Steering Committee, will have the option to redirect research activities if it is considered beneficial to the overall program.
• The Steering Committee may, as it deems necessary, invite additional, non-voting scientific consultants to meetings at which research priorities and opportunities are discussed.
• The NIH reserves the right to augment the expertise of the Steering Committee with non-voting External Experts when necessary.
• A Steering Committee Chairperson will be chosen by the NIH. The Chairperson is responsible for coordinating and chairing the Steering Committee meetings.

External Experts

• External Experts may be invited to attend Steering Committee meetings. If deemed necessary by the NIDDK, or at least once per funding cycle, the External Experts may review interim progress of the program and report to NIDDK staff.

Dispute Resolution

Disagreements that may arise in scientific/technical matter or programmatic matters (within the scope of the award) between award recipient and the NIH may be brought to arbitration after first attempting to resolve the issue through the Steering Committee or its subcommittees, as appropriate. An Arbitration Panel composed of three members will be convened. It will have three members: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedures in no way affect the awardee's right to appeal an adverse action in accordance with PHS regulations at 42 CFR Part 50, Subpart D, and HHS regulations at 45 CFR Part 16.

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

A final progress report, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.

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

eRA 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 CenterTelephone: 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

Lisa M. Spain, Ph. D.
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone: 301-451-9871
Email: spainl@mail.nih.gov

Najma Begum, Ph.D.
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone: 301-594-8894
Email: begumn@mail.nih.gov

Christine Gill
National Institute of Diabetes, Digestive & Kidney Diseases (NIDDK)
Telephone: 301-435-2816
Email: gillc@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. This FOA is supported under the authority of P.L. 114-10, "The Medicare Access and CHIP Reauthorization Act of 2015; Section 213. Extension of special diabetes program for type I diabetes and for Indians.