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 National Institute of Diabetes and Digestive and Kidney Diseases seeks to accelerate the pace of scientific research towards more effective treatment and prevention of type 1 diabetes and its complications. To this end, NIDDK is committed to providing access to research resources including biosamples repositories and databases from type 1 diabetes clinical trials.  This activity will support investigations on non-renewable (non-DNA) samples generated by selected studies and clinical trials. Potential applicants are strongly advised to read this notice carefully and to contact Scientific/Research staff prior to preparing an application. To assist applicants for this and other related funding opportunity announcements, two webinars are planned. Applicants should visit http://www.niddk.nih.gov/research-funding/Pages/default.aspx for more information about registering for one of these informational webinars.

For examples of projects funded under similar FOAs, use the NIH Research Portfolio Online Reporting Tool (RePORTER). Enter the FOA designations (PAR-13-003 or PAR-11-350, as separate queries) in the field labeled FOA in the "Project Details" section, clear the Fiscal Years field in the top right corner of the query page, and run the query to view descriptions of awarded grants.

There are two ways to access samples. One is through the NIDDK Central Repository (www.niddkrepository.org) which contains samples from the following type 1 diabetes clinical trials: Type 1 Diabetes Prevention Trial- 1 (DPT-1), Genetics of Kidneys in Diabetes (GoKinD), and Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC samples collected though 2006). The second way to access samples is through one of the following NIDDK-funded consortia, which are summarized in detail below.

This opportunity is limited to research using samples from the clinical trials or studies listed herein. Funding or access to samples will not be provided for assay development or exploratory animal models research. Investigators should propose to test scientifically meritorious hypotheses related to the clinical trial’s goals.

Studies using NIDDK Repository-held samples (DPT-1, GoKind, some DCCT/EDIC samples) will be reviewed both for access approval and funding at the same time through this FOA.  Applicants must visit the NIDDK Repository https://www.niddkrepository.org/home/, register for a login and password, and make a preliminary application for access to samples. The Repository will then provide a standardized report which will indicate that samples are present in sufficient number and quantity or volume for the study.

Applications that propose to use consortium-controlled samples (TrialNet, some DCCT/EDIC samples, ITN, TRIGR) must document that the consortium has granted approval for access to the samples. See Section IV.2 below for specific instructions on the required documentation.

The FOA is expected to promote scientific discoveries on disease mechanisms, disease pathogenic processes, and biomarkers of disease progression or clinical responses.  This FOA will provide funding to support scientific collaboration among assay providers from outside of the clinical trials networks and clinical and laboratory scientists and biostatisticians within NIDDK’s consortia listed above. Consortia member scientists are encouraged to submit applications, but they must also have documented access to consortium-controlled samples through the relevant process.

Applicants are expected to return data derived from analysis of samples to the data coordinating center for the relevant NIDDK consortium, or the NIDDK Data Repository, along with appropriate quality measures. Applicants are also expected to return the data and unused samples to the relevant NIDDK consortium or repository by one year after the period of award of this project.

The following is a brief description of clinical trials and studies with opportunities for samples access and testing.

1. The Diabetes Control and Complications Trial (DCCT) recruited 1,441 type 1 diabetic participants who were randomly assigned to 2 treatment groups, intensive and conventional, for an average of 6.5 years of randomized treatment time. The DCCT ended in 1993 after demonstrating conclusively that intensive treatment reduced the development and progression of diabetic retinopathy, nephropathy and neuropathy, compared to conventional treatment.  Subsequently, the Epidemiology of Diabetes Interventions and Complications Study (EDIC) recruited 96 percent of the living participants from DCCT for regular observational follow-up of metabolic and complications status, using similar methods as in the DCCT. The former intensive treatment group continues to exhibit some of the same reduction in the risks of diabetic complications, starting from a new baseline. This carry-over effect of prior glycemic exposure on the later course of complications (superimposed on the effect of concurrent glycemic exposure) has been called "metabolic memory". Serum, plasma and urine samples have been obtained annually since the DCCT baseline and stored frozen at -70 C. Samples collected through 2006 are available through the NIDDK Repository and may be applied for under this FOA. A data set is available and applicants are urged to obtain and review the data to assist in their preparation of the application. Information for obtaining data and a samples availability report from this study is available on the NIDDK Repository Website: https://www.niddkrepository.org/home/ .

The ongoing DCCT/EDIC research group also welcomes applications for collaborative studies from any investigator who believes he/she has a research idea that could utilize some of the stored sample collection (serum, plasma and urine) and clinical phenotypic data in an ancillary study. Any proposal would receive initial review by the relevant DCCT/EDIC committees, and would have to abide by the policies and procedures for data sharing and publications described here:  https://portal.bsc.gwu.edu/web/edic/edic-potential-collaborators;jsessionid=32B284622ED88E1076CA7BD54176116C.ajp13 849

Possible research topics for DCCT/EDIC biosamples include, but are not limited to:

• Analysis of blood or urine samples for validation of biomarkers (metabolomic, proteomic, etc.) associated with susceptibility (or resistance) to T1D complications.
• Analysis of blood or urine samples for validation of biomarkers associated with the DCCT intervention.
• Primary outcome data relevant to the planned analysis of 100 cardiovascular events is expected to be available after December 2014. Projects that seek to use cardiovascular outcomes data as part of their ancillary study may apply but should plan to do that analysis after December 2014.

2. GoKinD: The Genetics of Kidneys in Diabetes collection was created to facilitate research into Type 1 diabetes and the genetic basis of diabetic kidney disease by providing access to data and samples for genotyping. GoKinD created a repository of DNA and clinical information from adults with long-term Type 1 diabetes, with or without kidney disease. Probands had diabetic nephropathy (persistent proteinuria or end stage renal disease) caused by Type 1 diabetes, had Type 1 diabetes for at least 10 years, were diagnosed before age 31, and received insulin therapy without interruption. Controls had persistent normoalbuminuria despite having type 1 diabetes at least 15 years, did not take antihypertensives and had never been treated with ACE inhibitors. All participants contributed DNA, plasma, serum, and urine samples.  For 268 of the 930 probands and for 318 of the 939 controls, the equivalent clinical information and saved biological samples are also available for both the mother and father as well as for the probands. A clinical data set is available along with GWAS data and applicants are urged to obtain and review the data to assist in their preparation of the application. Information for obtaining data and a samples availability report, and samples access data sharing policies, is available on the NIDDK Repository Website: https://www.niddkrepository.org/home/  .

Possible research topics for GoKinD biosamples include, but are not limited to:

• Analysis of blood or urine samples for new biomarkers (metabolomic, proteomic, etc.) associated with susceptibility (or resistance) to diabetic kidney disease.
• Analysis of blood or urine samples to further characterize the role of molecules implicated in the development of diabetic kidney disease.

3. DPT-1: The Diabetes Prevention Type 1 (DPT-1) trial was a multi-center randomized clinical trial to determine if treatment with a common beta-cell auto-antigen (insulin) can delay the onset of Type 1 Diabetes Mellitus (Type 1 DM) in relatives of persons with type 1 diabetes.  The protocol for high risk subjects used daily subcutaneous insulin injections and an annual course of intravenous insulin treatment), while the protocol for intermediate risk subjects used daily doses of insulin or placebo administered orally. There were over 100,000 relatives of persons with type 1 diabetes screened, and 711 subjects entered either the parenteral or oral arm of the study.  Serum samples were collected and will be available from subjects who enrolled in the trial(s), some of whom later developed type 1 diabetes.   Samples from a selection of subjects (over 10,000) who were autoantibody negative at screening are also available.   A data set is available and applicants are urged to obtain and review the data to assist in their preparation of the application.  Information for obtaining data and a samples availability report, and samples access data sharing policies, is available on the NIDDK Repository Website: https://www.niddkrepository.org/home/ .

Possible research topics for DPT-1 serum samples include, but are not limited to:

• Analysis of serum for new biomarkers (metabolomic, proteomic, etc.) associated with parenteral or oral treatment with insulin in the DPT-1 trial, with the goal to better understand the effects of treatment on autoimmune responses.
• Analysis of serum for new biomarkers (metabolomic, proteomic, etc.) associated with diabetes risk progression, disease protection, or progression to disease (such as conversion from single to multiple autoantibody status, or from normal to abnormal (pre-diabetic) glucose tolerance), or samples from subjects with risk who were extensively followed with no disease progression.

5. The Type 1 Diabetes TrialNet is an international network of investigators, clinical centers, and core support facilities that recruits patients and conducts research to advance knowledge about type 1 diabetes and to test strategies for its prevention and early treatment. TrialNet supports the development and implementation of clinical trials of agents aimed at preventing the disease in at-risk patients and slowing the progression of type 1 diabetes in new onset patients. The network’s Pathway To Prevention enhances understanding of how the disease develops in individuals at risk and thus helps in the formulation of future trials. The study provides the basis for risk assessment and recruitment of at-risk subjects into clinical trials aimed at preventing the disease in susceptible individuals, see weblink for publications from TrialNet:

(http://www.diabetestrialnet.org/publications/publications.htm). TrialNet samples available under this FOA are described below. Applicants must apply for access to samples using ancillary studies application procedures: http://www.diabetestrialnet.org/ancillary/. See also TrialNet policies for access to samples from the archive: http://www.diabetestrialnet.org/documents/ancillary/1ANSARCHIVEACCESSANCILLARYPOLICYfinal.pdf

a) The TrialNet Pathway To Prevention Study collects serum, RNA, plasma, and peripheral blood mononuclear cells (PBMC) every 6 months from enrolled subjects at risk for disease, and a smaller number of control subjects. Samples from selected subjects within the study will be made available. Check the TrialNet website (link above) for specific information about the available collection, and for instructions on how to apply for access.

Scientific questions that can be addressed using this collection include some of those described above for the DPT-1 collection, but in addition allow explorations of cellular functional phenoptypes since living cells were collected (see TrialNet website for details).

Possible research topics for Pathway To Prevention serum samples include, but are not limited to:

• Analysis of peripheral blood cells, serum, blood RNA, and plasma for new biomarkers (metabolomic, proteomic, etc.) associated with diabetes risk progression, disease protection, or progression to disease (such as conversion from single to multiple autoantibody status, or from normal to abnormal (pre-diabetic) glucose tolerance), or samples from subjects with risk who were extensively followed with no disease progression.

b) The TrialNet Mycophenolate Mofetil-Daclizumab (MMF/DZB) clinical trial tested whether two immunosuppressive drugs used in combination, MMF and DZB, could stop the ongoing destruction of beta cells in new onset type 1 diabetes patients, relative to MMF alone or placebo control.  The clinical trial was stopped early when it became clear that the drugs were not able to stop the decline in C-peptide production Samples that potential collaborators may apply for include PBMC, whole blood RNA, and serum. Check the TrialNet website for specific information about the available collection (samples may be limited), and for instructions on how to apply for access.

Possible research topics include, but are not limited to:

• investigations of correlates of disease progression after diagnosis,
• biomarkers that may have been altered by drug treatment, yet did not impact the disease process sufficiently to delay or prevent C-peptide decline.

c) The TrialNet Anti-CD20 trial tested the effects of the drug rituximab (anti-CD20) on progression of type 1 diabetes in new onset patients. This randomized, double-blind study used rituximab to deplete B cells and tracked the decline in C-peptide over 2 years (primary endpoint at 1 year). The study showed a statistically significant maintenance of C-peptide production at 1 year in type 1 diabetes patients that received the active drug compared to, although the effect waned at the two years. Samples that potential collaborators may apply for include serum, plasma, PBMC and whole blood RNA. Check the TrialNet website for specific information about the available collection, (samples may be limited), and for instructions on how to apply for access.

Possible research topics include, but are not limited to:

• Investigations of correlates of response to rituximab (i.e., B cell depletion and recovery, C-peptide preservation), as well as biomarkers that may be affected by drug treatment and yet did not impact C-peptide preservation.
• In the rituximab study, some subjects in the drug-treated group were seen to preserve their C-peptide production better than others. Assays that could predict or explain the responder/non-responder phenotype could be valuable for understanding the trial and designing more effective interventions.

d) The TrialNet CTLA-4-Ig trial tested the effects of the agent "abatacept" (CTLA-4-Ig, Orencia) on progression of type 1 diabetes in new onset patients. Abatacept interferes with the activation of T cells by binding to the molecules CD80/86 (expressed on antigen presenting cells) and blocking their interaction with the co-stimulatory receptor CD28 (expressed on T cells). This double-blinded, placebo control trial showed that abatacept, given monthly, delayed the decline of C-peptide (a measure of beta cell function) relative to placebo controls . Samples that potential collaborators may apply for include serum, plasma, PBMC and whole blood RNA. Check the TrialNet website for specific information about the available collection, and for instructions on how to apply for access.

Possible research topics include, but are not limited to:

• Investigations of correlates of response to abatacept (i.e., C-peptide preservation, or measures of co-stimulatory blockade), as well as biomarkers that may be affected by drug treatment and that did or did not correlate with C-peptide preservation in individual subjects. 

e) The TrialNet GAD-alum trial (randomized, blinded, and placebo controlled) tested whether 2 or 3 spaced vaccinations using GAD protein in alum, relative to alum alone,  could delay C-peptide decline in new onset subjects . GAD-alum was predicted to modulate the antigen-specific immune response to GAD antigen, through either response type skewing or induced regulation, and to thereby interfere with pathogenesis. The study showed no difference between either of the active drug dosing arms, and the placebo, in the primary or secondary outcome measures at 12 months (Lancet. 2011 Jun 28). Samples that potential collaborators may apply for include serum, plasma, PBMC and whole blood RNA. Check the TrialNet website for specific information about the available collection, and for instructions on how to apply for access. 

Possible research topics include, but are not limited to:

• Investigations of correlates of response to GAD, (i.e, immune responses to GAD), as well as biomarkers that may be affected by drug treatment and that did or did not correlate with C-peptide changes in individual subjects.

f)  The TrialNet Anti-IL-1 beta (canakinumab trial) showed that inhibition of the IL-1 inflammatory pathway could not delay the decline of C-peptide in new onset T1D patients at 1 year. Samples that potential collaborators may apply for include serum, plasma, PBMC and whole blood RNA. Check the TrialNet website for specific information about the available collection, and for instructions on how to apply for access. 

Possible research topics include, but are not limited to:

• Investigations of correlates of response to canakinumab (i.e., measures of inflammation), as well as biomarkers that may be affected by drug treatment and that did or did not correlate with C-peptide changes in individual subjects. 

6. The Immune Tolerance Network (ITN) is an international consortium dedicated to advancement of tolerance-inducing therapies for the treatment of autoimmune diseases, asthma and allergic diseases, and for the prevention of graft rejection following kidney, liver, and pancreatic islet transplantation.  The ITN develops and conducts phase I III clinical trials of novel tolerance strategies that investigate safety and efficacy, as well as the basic biological features and potential biomarkers of clinical tolerance, through mechanistic studies integrated into each trial.

The major goals of the ITN with respect to T1D are:

• To develop and test novel immune therapies to prevent and treat T1D through the induction of robust and long-lasting immunological tolerance.  Several of these first in class studies have led to new investigational approaches to the treatment of T1D both at time of onset and in the islet transplantation setting.  One ITN goal is to continue these cutting edge proof-of-principle studies in order to bridge the basic science with pharmaceutical industry efforts.
• To develop and validate assays to monitor the impact of these therapies on T1D disease progression, leading to new biomarkers that can be correlated with tolerance.  Such assays include molecular and cell-based measures of the status of the immune system and the nature of antigen-specific responses of immune cells in type 1 diabetes.
• To gain new understanding of the immunologic mechanisms involved in the natural history and progression of type 1 diabetes and to use such information to formulate new treatment approaches, including combinations of therapeutics that target distinct immunological pathways associated with T1D.
• To develop bioinformatics and data analysis strategies for the interpretation of complex clinical and mechanistic data across type 1 diabetes trials and to define common features of immunity that may be shared between this and other autoimmune disorders.

Relevant T1D clinical trials with samples available under this FOA are briefly described below:

a)  ITN007AI. Phase II Multiple dose Treatment of Type 1 Diabetes Mellitus with hOKT3γ1 (Ala-Ala) . A 2-arm study, open label phase II trial over the first year of disease in participants with new onset T1D.  

b)  ITN017AI. Evaluation of Tolerability, Safety, and Pharmacokinetics of hOKT3γ1(Ala-Ala) in Participants with Type 1 Diabetes Mellitus . Safety and pharmacokinetics of hOKT3γ1 (Ala-Ala) in participants diagnosed with Type 1 Diabetes Mellitus within 12 months.

c)  ITN018AI. A Phase I Trial of Proleukin and Rapamune in Recent-onset Type 1 Diabetes Mellitus . A phase I trial in individuals who have been diagnosed with type 1 diabetes within 3-48 months prior to enrollment. The sample size for this study is 10 subjects aged 18-35 years.

d)  ITN027AI. Autoimmunity-Blocking Antibody for Tolerance in Recently Diagnosed Type 1 Diabetes . In this Phase II protocol, two courses of the hOKT3gamma1 (Ala-Ala) was administered 1 year apart. The purpose of this study was to determine whether hOKT3gamma1 (Ala-Ala) can halt the progression of type 1 diabetes in patients diagnosed within the past 60 days.

e)  ITN005CT.  Islet Transplantation in Type I Diabetic Patients using the Edmonton Protocol of Steroid-Free Immunosuppression . This was a single-arm, Phase I study, the primary objective of which was to cure diabetes mellitus by an injection of cellular graft into the liver.

f)   ITN012AI. Autoantigen Vaccination in Human Type 1 Newly Diagnosed Diabetes Mellitus . This was a pilot study to investigate the safety and the immunologic mechanisms of human insulin B-chain in incomplete Freund’s adjuvant (IFA) in humans. The ultimate goal of the intervention is to prevent or delay further loss of beta cell mass after the clinical onset of Type 1 diabetes mellitus.

g)  ITN028AI. Effect of Antithymocyte Globulin on Preserving Beta-cell Function in New-onset Type 1 Diabetes Mellitus . This was an early phase II study of the safety and efficacy of the rabbit polyclonal anti-thymocyte globulin Thymoglobulin (Thymo) in new onset T1D to determine if this treatment can induce tolerance and thereby prolong endogenous insulin secretion in affected individuals. Eligible subjects have T1D of < 3 months duration, aged 12-35 years.

Complete trial and sample information such as type of specimen available, specimen collection schedule and schedule of assessments can be found on the ITN website: https://www.itntrialshare.org. Sample availability may vary by trial and might include plasma, serum, whole blood RNA/DNA and PBMC.  Applicants must first apply for access to the ITN samples using ancillary studies application procedures as described on the ITN web page: http://www.immunetolerance.org/professionals/research/policies . All sample requests will be reviewed by the ITN Central Institutional Review Board.

Possible research topics might include, but are not limited to:

• Investigations of tolerance mechanisms induced by drug treatment
• Biomarkers/Assays correlating with responder/non responder status
• Biomarkers/Assays related to disease progression

7. Trial to Reduce IDDM in the Genetically at Risk Trial (TRIGR)

The incidence of type 1 diabetes is rising among children younger than 5 years of age. A relatively short duration of breast-feeding and early exposure to complex dietary proteins have been implicated as risk factors for advanced beta-cell autoimmunity or clinical type 1 diabetes. Early nutritional intervention may help to prevent type 1 diabetes and has been reported to be successful in experimental models of autoimmune diabetes, although the data are not consistent. Preliminary data indicated that among children at increased risk for type 1 diabetes, weaning to a highly hydrolyzed formula decreased the cumulative incidence of islet-cell antibodies and the cumulative incidence of at least one autoantibody during a mean observation period of 4.7 years. Therefore, the TRIGR consortium developed a clinical trial to determine whether exposure to formula could impact type 1 diabetes autoimmunity and incidence. In 2007, TRIGR randomized the last of 2,159 eligible infants to receive either test (extensively hydrolyzed) or control formulas when mothers decide to wean from exclusive breastfeeding. The participants are being monitored up to the age of 10 years (last subject visit in 2017) for the appearance of diabetes-predictive autoantibodies and clinical type 1 diabetes. This trial is being conducted in clinical centers throughout North America, Europe, and Australia.

The ongoing TRIGR research group welcomes applications for collaborative studies from any investigator who believes he/she has a research idea that could utilize some of the stored sample collection (serum, plasma, and frozen PBMCs, details about available samples may be found on the TRIGR website http://trigr.epi.usf.edu/ ) and associated clinical phenotypic data, in an ancillary study. Any proposal would receive initial review by the relevant TRIGR committees (request for access must be received by TRIGR at least 6 weeks prior to the grant receipt date, details about how to submit can be found here http://trigr.epi.usf.edu/ ). Successful applicants are expected to abide by the policies and procedures for data sharing and publications described on the TRIGR website http://trigr.epi.usf.edu/ .

Possible research topics for TRIGR biosamples include, but are not limited to:

• Analysis of serum or plasma samples for new biomarkers (lipidomics/metabolomics, proteomics, etc.) associated with nutritional status, diabetes risk progression, disease protection, or progression to disease (such as conversion from single to multiple autoantibody status, or from normal to abnormal (pre-diabetic) glucose tolerance),
• Primary outcome data relevant to the planned analysis is expected to be available after April 30, 2017. Projects that seek to use outcome data as part of their ancillary study may apply but should plan to do that analysis after April 30, 2017.

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)

Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Applicant Organizations

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

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

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

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

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

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

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

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

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

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

In addition, the NIH will not accept a resubmission (A1) application that is submitted later than 37 months after submission of the new (A0) application that it follows.  The NIH will accept submission:

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

Applicants must download the SF424 (R&R) application package associated with this funding opportunity using the Apply for Grant Electronically button in this FOA or following the directions provided at Grants.gov.

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

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

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

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

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

The letter of intent, preferably electronic, should be sent to:

Dianne M. Camp, Ph.D.
Scientific Review Officer, Review Branch
National Institute of Diabetes and Digestive and Kidney Diseases
Fax: 301-480-3505
Email: campdm@mail.nih.gov

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

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

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

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

Estimated Project Funding: Enter the budget request here. This number should include total costs (direct and indirect) for the entire project period. Note that a detailed budget cannot be accepted in the application; it will be requested after the initial review as part of Just In Time.

It is expected that applications will span a wide range of budgetary requirements, from small studies utilizing few subjects to larger studies with more expensive testing.  Small exploratory studies are encouraged. 

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: Background and rationale for request of these limited, irreplaceable, and valuable clinical samples are required. Applications should provide a strong scientific justification, evidence of assay validation and support for laboratory performance at the highest quality standards. The question being posed by the investigator must be appropriate to the source of the biospecimens, how they were collected, prepared, analyzed, and stored, their age, and the phenotypic and other accompanying data.  Include detailed information about which samples are requested (use the available data to specify samples characteristics).  If projects will be combining the results from the proposed study with those obtained from other samples, applications should explain how the additional samples will fit in with the overall study design. Funding for analysis of additional samples from other studies is allowed if it is well justified and important for understanding the specific clinical studies listed below.   

Specific objectives, including how the results would be integrated with other study results, and the impact of the results on understanding disease progression or response to treatment should be described.

The application must include assay details and methodology, including amounts and type of samples (applicants should request the minimum volume required for their assay), assay variability and quality control, expected effect sizes and group differences, a statistical plan with calculations to show that the available and requested samples should be sufficient to answer the question.  Provide a detailed plan for data analysis. Include a brief summary of the team’s expertise and experience and evidence that they can handle the analysis proposed. Plans for sample management, including return to the NIDDK repository of any unused specimens should be provided.  

Letters of Support:  Applicants must apply to the consortium through the relevant ancillary studies application process with sufficient time for consortium review prior to the application due date for the FOA (at least 6 weeks prior to due date). Documentation from the relevant clinical consortia confirming that access to samples has been approved, consisting of a letter or email from the clinical consortium's Ancillary studies Chair or other official as designated in the consortium, should be included as a Letter of Support. 

For NIDDK Repository-held samples, applicants must visit the NIDDK Repository website:  https://www.niddkrepository.org/home/ , register for a login and password, and make a preliminary application for access to samples. The Repository will then provide a standardized report which will indicate that samples are present in sufficient number and quantity or volume for the study. This report must be included with the grant application (in the Letters of Support section) or the application will be considered incomplete and will be not be reviewed.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS)) as provided in the SF424 (R&R) Application Guide, with the following modification:

• All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan. Applicants are expected to return data derived from analysis of samples to the data coordinating center for the relevant NIDDK consortium, or the NIDDK Data Repository, along with appropriate quality measures. The plan should acknowledge the expectation to follow NIDDK instructions to return the data and unused samples to the relevant NIDDK consortium or repository by one year after the period of award of this project.

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

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

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

Foreign (non-U.S.) institutions must follow policies described in the NIH Grants Policy Statement, and procedures for foreign institutions described throughout the SF424 (R&R) Application Guide.

Part I. Overview Information contains information about Key Dates. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission.

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

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

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

This initiative is not subject to intergovernmental review.

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

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

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

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

For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically.

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

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

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness by the Center for Scientific Review, NIH. Applications that are incomplete will not be reviewed.

In order to expedite review, applicants are requested to notify the NIDDK Referral Office by email at calvof@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.

Significance

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

Investigator(s)

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

Innovation

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

Approach

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

Did applicants justify use of these limited, irreplaceable, and valuable clinical samples? Does the study take full advantage of the unique characteristics of these particular samples?

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

Environment

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

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

Protections for Human Subjects

For research that involves human subjects but does not involve one of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.

Inclusion of Women, Minorities, and Children 

When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of children to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

Vertebrate Animals

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

Biohazards

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

Resubmissions

Not Applicable

Renewals

Not Applicable

Revisions

Not Applicable

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

Applications from Foreign Organizations

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

Select Agent Research

Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Resource Sharing Plans

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

Budget and Period of Support

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

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by 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.

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications. Following initial peer review, recommended applications will receive a second level of review by the National Diabetes and Digestive and Kidney Diseases Advisory Council. The following will be considered in making funding decisions:

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

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

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

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

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

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.      

Any application awarded in response to this FOA will be subject to the DUNS, SAM Registration, and Transparency Act requirements as noted on the Award Conditions and Information for NIH Grants website.

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

Cooperative Agreement Terms and Conditions of Award

Not Applicable

When multiple years are involved, awardees will be required to submit the annual Non-Competing Progress Report (PHS 2590 or RPPR) and financial statements as required in the NIH Grants Policy Statement.

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

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

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

eRA Commons Help Desk (Questions regarding eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)
Finding Help Online: http://grants.nih.gov/support/index.html
TTY: 301-451-5939
Email: commons@od.nih.gov

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

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone: 301-710-0267
TTY 301-451-5936
Email: GrantsInfo@nih.gov

For TrialNet and DPT-1:

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

For GOKIND:

Rebekah Rasooly, Ph.D.
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone: 301-594-6007
Email: rasoolyr@mail.nih.gov

For ITN:

Katarzyna Bourcier, Ph.D.
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 301-451-3205
Email: bourcierkd@niaid.nih.gov

For DCCT/EDIC:

Catherine C. Cowie, Ph.D., MPH 
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone:  301-594-8804
Email:  cowie@nih.gov

For TRIGR:

Gilman Grave, M.D.
Eunice Kennedy Shriver National Institute Of Child Health and Human Development (NICHD)
Telephone: 301-496-5593
Email: gg37v@nih.gov

Dianne M. Camp, Ph.D.
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone: 301-594-7682
Email: campdm@mail.nih.gov

Todd Le
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone: 301-594-7794
Email: toddle@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 Parts 74 and 92. This FOA is supported under a Special Statutory Program for Type 1 Diabetes Research via PL 113-93 (Section 204), "The Protecting Access to Medicare Act of 2014.