Part 1. Overview Information

Key Dates

All applications are due by 5:00 PM local time of applicant organization. All types of non-AIDS applications allowed for this funding opportunity announcement are due on the listed date(s).

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

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

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

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

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

Background

Type 1 Diabetes Mellitus (T1DM) is characterized by an absolute insulin deficiency caused by T-cell mediated autoimmune destruction of pancreatic -cells via one or more autoantibodies. The rate of -cell destruction varies, generally occurring more rapidly at younger ages. Epidemiological data from Scotland and Australia suggest that people with T1DM have lifespans that are 8-13 years shorter than the general population (Bjornstad P et al 2018). For both men and women, this is primarily attributable to premature atherosclerotic cardiovascular disease; more than 70% of men and 50% of women with T1DM have developed coronary artery calcification (CAC) by the age of 45 years (Schofield J et al 2019). Accelerated atherosclerosis in T1DM is thought to result from many pathways including effects from inflammation, dyslipidaemia, hypertension and nephropathy whereby these known risk factors may operate differently in Type 2 Diabetes Mellitus (T2DM), suggesting a difference in the pathophysiology of cardiovascular disease (CVD).

Recent studies have documented a 2-5% increase in T1DM incidence worldwide; suggesting an environmental or genetic/environmental interaction since this is too short a time period for genetic shifts (Maahs DM et al 2014). The SEARCH for Diabetes in Youth (SEARCH) study estimated that there were ~175,000 youth with T1DM in the United States in 2010; with a 21.1% rise in the prevalence of T1DM from 2001 to 2009 in youth aged 0 through 19 years, with increases observed in all sex, age, and race/ethnic subgroups except those with the lowest prevalence (0 4 years old and American Indians) (Dablea et al 2014). A significant proportion of adolescents (13-19 years old) with T1DM have clinical CVD risk factors (38% have an low-density lipoprotein-cholesterol >100 mg/dL, 22% have blood pressure above the 90th percentile for age, sex, and height, and 39% have a body mass index >85th percentile for age and sex). Although T1DM is more common among non-Hispanic white (NHW) youth, minority youth with T1DM are reported to have poorer glucose control (only 14% of non-Hispanic Black participants currently meet the ADA’s HbA1c target compared with 34% and 28% in NHW and Hispanic participants, respectively), more diabetes related complications (e.g., diabetic ketoacidosis, kidney disease, CVD risk factors), and higher mortality (Maahs DM et al 2014). In addition, there are significant gender disparities in T1DM-related CVD. Women with T1DM have at least a four-fold increased risk of CVD compared to women without T1DM, as opposed to a doubling of risk in men with T1DM compared to men without T1DM. Adolescent girls with T1DM had a significantly worse CVD risk profile compared to girls without T1DM and boys with T1DM (Brown et al 2016). However, the excess relative risk in women with T1DM is not explained by changes in known cardiovascular risk factors among adolescent or adult populations. Therefore, the presence of T1DM eliminates the gender-related CV protection seen among populations without diabetes

The Diabetes Control and Complications Trial Epidemiology of Diabetes Complications (DCCT/EDIC) trial showed that intensive insulin treatment reduced the risk of nonfatal myocardial infarction, stroke, or CVD death by 57% in the intensively managed compared with the conventional arm after 17 years of follow-up (DCCT/EDIC 2005) in people with T1DM. Improved management of traditional CVD risk factors has led to 29% reduction in the relative risk of death of T1DM participants over a 10-year period in a Swedish cohort (Rawshani A et al 2017); however the overall relative risk for CVD remains elevated at 2.3 for men and 3.0 for women as ascertained in a Scottish registry study (Livingstone SJ et al 2012). Furthermore, existing risk calculators may underestimate the risk of CVD in T1DM; risk calculators do not usually account for glycemic control, the duration of diabetes, or presence of microvascular complications. This suggests that though traditional approaches in CVD prevention and treatment are having some benefit in this population, the persistent elevated CVD risk among men and women with T1DM shows that much more effective prevention and management strategies are needed. Such strategies may include earlier and more refined CVD risk assessment and earlier and more potent lifestyle modification and pharmacologic interventions to address CVD risk factors coupled with superior glycemic control. Furthermore, a number of recent developments has created new opportunities for CVD prevention among T1DM including drugs that target new pathways (e.g., PCSK9 inhibitors) and agents that reduce glycemia, improve CVD risk factors and have favorable cardiac and renal protection in T2DM (e.g., SGLT-2 inhibitors). Hence, there may be an opportunity to offer more potent reductions in risk factors and/or novel cardioprotective effects as well as better ways of addressing subclinical atherosclerosis rather than only vascular dysfunction.

Because T1DM typically occurs in youth, many of these individuals have evidence of significant clinical CVD risk factors by adolescence and young adulthood as previously noted. Several of the challenges and opportunities for addressing CVD among youth with T1DM were also raised during the NHLBI workshop on CVD prevention among young adults including: long follow-up needed for hard outcomes (note the 17 year follow-up required in DCCT/EDIC) resulting in a reliance on surrogate markers and subclinical outcomes in clinical trials; challenges with recruitment and consent; low engagement with health care and adherence during this life stage.

The National Heart, Lung, and Blood Institute Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents provides recommendations for lifestyle and pharmacologic management of CV risk factors. However, current data suggests suboptimal risk factor management among youth with T1DM. There is a need to overcome the reluctance of clinicians to initiate pharmacotherapy for CVD risk factors; this reluctance may be due to current guidelines being informed by adult studies of T2DM due to lack of clinical trial evidence in youth and T1DM. Data about the appropriate timing of initiation of hypertension and dyslipidemia treatment in individuals with T1DM are limited; current recommendations are based primarily on expert opinion and adult and pediatric guidelines differ on recommended age range/approach for initiating pharmacotherapy for hypertension and dyslipidemia for individuals with T1DM. All guidelines agree on the importance of intensive glucose control, healthy diet, and exercise.

Purpose

This purpose of this FOA is to support human-based research to advance our understanding of the pathophysiology, risk factors, early detection and treatment of CVD in T1DM in the following areas:

Human-based research Ancillary studies that use data, biosamples, post-mortem tissue or new diagnostic testing in established cohorts of T1DM are encouraged because of their wealth of longitudinal data. The research could also establish a new cohort or comparator group and include participants across the lifespan, from young adults to the elderly. Large databases of electronic health records may be a useful resource and could include research on developing algorithms to accurately identify patients with T1DM. The research does not need to meet the definition of Human Subjects research if the study uses only de-identified samples. Hypotheses to be tested may be based on pre-clinical research, but no animal research is allowed for this FOA. It is expected that applications proposing an ancillary study to an existing clinical study must include a letter of support from the clinical study indicating that the proposed research is feasible given the availability of resources of the existing clinical study. It is expected that applications proposing to use data and/or biospecimens available through BioLINCC must include a Letter of Availability submitted as a Letter of Support. Applications that propose use of the NIDDK Central Repository samples are expected to include a standardized report submitted as a Letter of Support from the Repository that indicates that samples are present in sufficient number and quantity or volume for the study, and will report by how much the study (if approved) will deplete the sample collection.

Pathophysiology Atherosclerosis is a disease of decades. For individuals with T1DM, years of high and variable glucose levels accelerate the pace of the long journey toward clinical vascular disease. Some mechanisms for atherosclerosis may be unique to T1DM, whereas other mechanisms may also be apparent among those with T2DM and/or no diabetes. New findings suggest a role of insulin deficiency in altering a lipoprotein, APOC3 to promote vascular disease and conversely, a role for a subtype of high density lipoprotein (HDL) particles and an associated protein HDL Paraoxonase 1 to protect from vascular disease. A conundrum in T1DM research has been the observation that a period of poor glucose control can have long-term consequences on the development of diabetes complications. This effect, termed metabolic memory, is recently shown to be strongly associated with epigenetic changes on specific genes including several differentially-methylated sites near Thioredoxin Interacting Protein (TXNIP). This FOA supports proposed translational research that will elucidate mechanisms by which the metabolic abnormalities and autoimmunity of T1DM alter the development of atherosclerosis, cardiomyopathy and other conditions of CVD.

Risk factors Epidemiological studies indicate that standard CV risk factors only partially explain the increased CVD risk in people with T1DM, so the use of clinical guidelines for T2DM may be insufficient for risk stratification in T1DM. For example, the T1DM co-morbidities of obesity and diabetic kidney disease (DKD) could affect the T1DM CV risk profile. Traditionally, T1DM was a condition of lean individuals, yet the prevalence of overweight and obesity in T1DM has increased significantly and though obesity is a known independent risk factor for CVD in nondiabetic populations, the impact of obesity in T1DM has not been fully elucidated. Obesity may contribute to insulin resistance in T1DM in addition to the existing autoimmune-mediated insulin deficiency. DKD, including albuminuria and reduced glomerular filtration rate is a complication of T1DM that is strongly linked to CVD. It is unclear if this is due to shared risk factors (e.g., hypertension, dysglycemia, dyslipidemia and obesity) or the potentiation of these factors via fluid retention and renin-angiotensin-aldosterone system activation. Applications to this FOA could propose studies to develop CVD risk-prediction algorithms specifically for patients with T1DM. This research could involve measurement of new potential biomarkers or analysis of existing data.

Early detection The major obstacle for CVD prevention trials in T1DM is the lack of a validated surrogate endpoint. Trials to assess an intervention are not feasible because of the long duration required to reach a cardiovascular event as the outcome measure. A validated measure of early atherosclerotic CVD would reflect disease extent, refine trial entry criteria to high risk participants and quantify changes secondary to the intervention. This FOA encourages research on the analysis of cardiac imaging studies on T1DM cohorts who subsequently developed cardiovascular events. It would also support testing cutting-edge cardiac imaging specifically on T1DM participants. Other areas of interest are: biomarkers, including imaging, for cardiomyopathy and heart failure with preserved ejection fraction (HFpEF) to understand the disease process and permit clinical studies; and wearable sensors or other devices for facile detection of cardiac autonomic neuropathy to increase the awareness and diagnosis of this diabetes complication that is a significant contributor to CVD morbidity and mortality.

Treatment The significant progress in therapeutics for CVD in T2DM, such as SGLT2 inhibitors and GLP1 agonists, have not translated to T1DM, where the mainstay of treatment remains control of glucose, lipids, blood pressure and weight. This FOA supports research on a wide-range of interventions and disease targets to improve the outcomes for the CVD of T1DM. Examples are: behavioral techniques to improve adherence to risk factor modification; proof-of-concept trials for a new treatment supported by strong pre-clinical data; pilot studies in T1DM for repurposing drugs approved for a CVD or other indication or for a different patient population; and acute intervention trials to reduce tissue damage during a myocardial infarction or stroke.

CVD The metabolic effects of beta cell loss in T1DM lead to molecular and cellular damage at all levels of the vascular system from capillaries to the major vessels and cardiac parenchyma. Research on diabetes complications traditionally bifurcates between the microvasculature and macrovasculature. The focus of this FOA is on macrovascular disease that includes outcomes of myocardial infarction, stroke, peripheral artery disease, heart failure, cardiomyopathy, cardiac arrythmias and cardiac autonomic neuropathy and/or the study of coronary arteries, cerebral arteries, large peripheral arteries, cardiac tissue, atherosclerosis, thrombosis and lipoprotein metabolism. Research can include the effect of microvascular disease on the development of macrovascular disease, e.g., DKD, but the emphasis must be on CVD. Therefore, applications that focus on primary outcomes related to cognitive impairment, vision, wound healing, kidney and nerve function (excluding cardiac autonomic neuropathy) would not be responsive to this FOA and such applications would be withdrawn.

T1DM Research projects supported by this FOA are expected to have a strong focus on participants with T1DM and the results must be relevant to this patient population. The studies could include groups with T2DM or no diabetes for comparison and the results could also be relevant to them. The application will be expected to describe the criteria used to determine T1DM for the cohort or samples to be studied.

Supported Research Activities

Responsive applications must propose projects that focus on macrovascular CVD in T1DM that includes outcomes of myocardial infarction, stroke, peripheral artery disease, heart failure, cardiomyopathy, cardiac arrythmias and cardiac autonomic neuropathy and/or the study of coronary arteries, cerebral arteries, large peripheral arteries, cardiac tissue, atherosclerosis, thrombosis and lipoprotein metabolism. Research can include the effect of microvascular disease on the development of macrovascular disease, e.g., DKD, but the emphasis must be on CVD.

Selected examples of possible projects supported by this FOA include, but are not limited to:

• Studies that propose to develop CVD risk-prediction algorithms specifically for patients with T1DM involving measurement of new potential biomarkers or analysis of existing data.
• Studies that include analysis of cardiac imaging studies on T1DM cohorts who subsequently developed cardiovascular events, or testing cutting-edge cardiac imaging specifically in T1DM cohorts to evaluate risk prediction of cardiovascular events
• Studies that evaluate behavioral techniques to improve adherence to cardiovascular risk factor reduction
• Studies that propose proof-of-concept trials for a new treatment supported by strong pre-clinical data or for evaluating existing treatments that are approved for non-cardiovascular indications and/or non T1DM to be evaluated within in T1DM cohorts

The following types of research will be considered non-responsive to this FOA and will not proceed to peer review:

• Applications proposing only animal studies
• Applications that do not include data and/or biospecimens from individuals with T1DM, and/or do not include participants with T1DM as the primary focus of the study
• Applications that focus on primary outcomes related to cognitive impairment, vision, wound healing, kidney and nerve function (excluding cardiac autonomic neuropathy)
• If using data and/or biospecimens available through other clinical studies or biorepositories (including NIDDK and/or NHLBI biorepositories), applications that do not include a Letter of Support affirming the availability of the required resource

Potential applicants are strongly encouraged to consult with the Scientific/Research Contact(s) listed in this FOA prior to submission. Early contact is encouraged as it provides an opportunity for NIH staff to discuss the scope and goals of the project and to provide guidance to applicants.

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

Section II. Award Information

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

Section III. Eligibility Information

1. Eligible Applicants

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Local Governments

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

Federal Governments

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

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations
• 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) 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 to register in eRA Commons. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration, but all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov Applicants must have an active 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.

2. Cost Sharing

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

3. Additional Information on Eligibility

Number of Applications

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

The NIH will not accept duplicate or highly overlapping applications under review at the same time. 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)

Section IV. Application and Submission Information

1. Requesting an Application Package

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

2. Content and Form of Application Submission

Letter of Intent

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

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

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

The letter of intent should be sent to:

Director, Office of Scientific Review
National Heart, Lung, and Blood Institute
Email: [email protected]

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

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

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

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.

R&R or Modular Budget

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

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

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

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

Specific Aims

Present clear statements describing specific aims with a strong focus on participants with T1DM and how the expected research results are expected to be relevant to this patient population. Comparator groups (e.g., obese patients, those with Type 2 diabetes, etc.) are permissible and the results could also be relevant to them. Responsive applications must also focus primarily on macrovascular CVD in T1DM. Research can include the effects of microvascular disease on the development of macrovascular disease, e.g., DKD, but the emphasis must be on CVD.

Research Strategy

Applications must describe the following:

• The cohort or samples (postmortem tissue, new diagnostic test results in established cohorts, biosamples, etc.) to be used for the proposed research and the selection criteria that will be used to determine the diagnosis of T1DM
• Plans for inclusion of participants across the lifespan
• If only patient samples will be utilized, the planned de-identification process that will be used
• If utilizing electronic health records, plans for development of algorithms for selecting patients and comparator groups
• For studies involving new participants, the expected recruitment plan and milestones for attaining adequate numbers of participants, biosamples, electronic health records, or access to study data for analyses
• Plans for ensuring the availability of resources needed for the proposed research project, (cohorts, biosamples or data)
• The regulatory status (IND or IDE) for any proposed intervention or diagnostic
• For projects proposing translational research, the approach that will be used to elucidate mechanisms by which the metabolic abnormalities and autoimmunity of T1DM alter the development of conditions of CVD such as atherosclerosis or cardiomyopathy
• For projects that propose studies to develop CVD risk-prediction algorithms for patients with T1DM, the rationale for the study cohort selection criteria, planned measures, and expected approach that would be used in building the risk-prediction model. Identify how proposed measurements would be used to estimate the likelihood of developing CVD in T1DM patients, the prediction timepoint(s) in the lifespan, the observation window(s), the potential approach to developing evaluation metrics, and how the outcomes could be utilized for possible prevention, early detection, or intervention. This research could involve measurement of new potential biomarkers or analysis of existing data.
• If proposing measurement of new potential biomarkers, evidence that supports employing these biomarkers for risk prediction
• Resources (e.g., data and/or biosamples) needed for the study and, if not owned by the applicant institution, the availability of the resources to the investigative team

Note for Applications Proposing the involvement of Human Subjects and/or Clinical Trials: Use the Research Strategy section to discuss the overall strategy, methodology, and analyses of your proposed research, but do not duplicate information collected in the PHS Human Subjects and Clinical Trial Information Form. The PHS Human Subjects and Clinical Trial Information Form will capture detailed study information, including eligibility criteria; inclusion of women, minorities, and individuals across the lifespan; protection and monitoring plans; and statistical design and power. NHLBI policies regarding accrual, inclusion, and monitoring of human subjects are described in NHLBI Accrual of Human Subjects (Milestones) Policy, NHLBI Policy for Inclusion of Women and Minorities in Clinical Research, and NHLBI Policy for Data and Safety Monitoring of Extramural Clinical Studies.

Letter(s) of Support

All instructions in the SF424 (R&R) Application Guide must be followed. In addition, include letters of support to confirm the availability of and access to resources if the resources are not owned by the applicant institution.

Ancillary Studies

Applications proposing an ancillary study to an existing clinical study must include a letter of support from the clinical study indicating that the proposed research is feasible given the resources of the existing clinical study. This letter should be from the appropriate committee or person (e.g., Ancillary Study Committee or Chair of the Steering Committee) indicating that the parent study is willing to provide the study investigators with access to participants, samples and/or data, and there is adequate time remaining in the parent study to complete the ancillary research project as scientifically and technically appropriate. The letter should indicate that the proposed ancillary study will not interfere with the parent study or unduly burden participants, and that all approved procedures and policies of the parent study will be followed. If the proposed ancillary study will extend beyond the project period of the parent study, the letter of support must include a commitment from the collaborating parent study PDs/PIs regarding continuity of the collaboration and available resources beyond the parent study period of support. The letter must also address the agreement between the parent and ancillary study regarding sample sharing, data harmonization and sharing, and communication between the investigators involved in the ancillary study and parent study. Applications that do not include letter(s) from the appropriate committee(s) or person(s) demonstrating the approval and cooperation of the parent study for the proposed ancillary research in response to this FOA will be considered nonresponsive and will not be peer reviewed. Documentation of approval from the clinical study may be submitted no later than 30 days after the receipt date if it is not available at the time of application submission. Approval letters submitted as post-submission material must be provided as a PDF emailed directly to the Peer Review contact by the appropriate institutional representative.

Biorepositories

The NIDDK Central Repository has data and biosamples from the DCCT/EDIC study and other NIDDK-funded trials that may be relevant to this research. Applicants should contact the NIDDK Central Repository in advance to determine the quantity of samples for the proposed study. In addition, applicants must consult with the Repository to determine whether the proposed use of samples is consistent with the limitations of the subjects informed consents. If the applicant plans on using the NIDDK Central Repository samples, the application must include a standardized report from the Repository that indicates that samples are present in sufficient number and quantity or volume for the study, and will report by how much the study (if approved) will deplete the sample collection. This report must be included in the application as a Letter of Support or the application will be considered non-responsive and will not be peer reviewed. The review of applications to this RFA will be considered by the NIH in determining access to the samples.

The NHLBI Biorepository has served as a valuable scientific resource for nearly four decades by acquiring unique biospecimen collections from NHLBI-funded clinical studies and distributing samples to qualified investigators at no fee beyond the cost of shipping. Richly phenotyped biospecimens from many NHLBI-funded clinical studies are stored in the NHLBI Biorepository and are open to the scientific community through NHLBI Biospecimen and Data Repository Information Coordinating Center (BioLINCC) website atwww.biolincc.nhlbi.nih.gov. The number of collections available through BioLINCC continues to grow each year. If the applicant plans on using data and/or biospecimens available through BioLINCC, the application must include a Letter of Availability that must be included in the application as a Letter of Support or the application will not be reviewed. Applicants may request a consultation with the BioLINCC and NHLBI Biorepository team prior to, or during, the biospecimen search to discuss which biospecimen material types and/or study collections may be considered for their proposed research protocol. Requests for a consultation prior to submitting a search request may be made using the "Contact Us" link on the BioLINCC home page. The request to search for biospecimens from a specific collection(s) available through BioLINCC can be initiated at any time but must be initiated at least 21 days prior to the FOA Application Due Date that the applicant proposes to use. Given that the time to complete a search and provide a Letter of Availability varies due to the complexity of a search and/or the necessity to perform additional searches, applicants should ensure they allow adequate time for a search to be performed and confirmed.

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

The following modifications also apply:

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

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

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

Study Record: PHS Human Subjects and Clinical Trials Information

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

Section 2 - Study Population Characteristics

2.4 Inclusion of Women and Minorities has the following additional instructions:

Justify the anticipated or projected sample size for the overall cohort and for any relevant subgroups (i.e., demonstrate whether the sample size is sufficiently powered to address the study's aims).

2.5 Recruitment and Retention Plan has the following additional instructions:

Describe contingency plans to manage potential delays or barriers with participant recruitment in the overall cohort as well as in key subgroups.

2.7 Study Timeline has the following additional instructions:

Applicants must include both a description and a table or graph of the overall study timeline and key milestones. Include the following milestones from receipt of award to the key milestone in the study timeline, as applicable:

• IRB approval(s) of final protocol and informed consent
• Study registration in ClinicalTrials.gov no later than 21 days following enrollment of the first study participant
• Finalized standard operating procedures (SOPs), operations manuals, data collection protocols, and informed consent/assent document(s)
• Anticipated start and end dates for participant recruitment and data collection(s)
• Study initiation
• Enrollment of the first participant
• Enrollment of 25%, 50%, 75% and 100% of the projected recruitment for all study participants, including women, minorities and children (as appropriate)
• Collection of data related to primary and secondary endpoints and database lock
• Submission of primary manuscript to peer-reviewed scientific journal(s) and dissemination of results
• Submission of study results to ClinicalTrials.gov within 12 months of the primary completion date

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

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

Foreign Institutions

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.

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

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

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

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

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

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

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

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

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential 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.

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

Documentation of approval by the Steering Committee for an ancillary study to a clinical study and/or use of data and/or biospecimens from a repository may be submitted no later than 30 days after the receipt date if it is not available at the time of application submission. Approval letters submitted as post-submission material must be provided as a PDF emailed directly to the Peer Review contact by the appropriate institutional representative. Applications that do not include letter(s) from the appropriate committee(s) or person(s) demonstrating the approval and cooperation of the parent study for the proposed ancillary research, and/or use of data and/or biospecimens from a repository, in response to this FOA will be considered noncompliant and will not be peer reviewed.

Section V. Application Review Information

1. Criteria

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

In addition, for applications involving clinical trials

A proposed Clinical Trial application may include study design, methods, and intervention that are not by themselves innovative but address important questions or unmet needs. Additionally, the results of the clinical trial may indicate that further clinical development of the intervention is unwarranted or lead to new avenues of scientific investigation.

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? Is the prior research that serves as the key support for the proposed project rigorous? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

In addition, for applications involving clinical trials

Are the scientific rationale and need for a clinical trial to test the proposed hypothesis or intervention well supported by preliminary data, clinical and/or preclinical studies, or information in the literature or knowledge of biological mechanisms? For trials focusing on clinical or public health endpoints, is this clinical trial necessary for testing the safety, efficacy or effectiveness of an intervention that could lead to a change in clinical practice, community behaviors or health care policy? For trials focusing on mechanistic, behavioral, physiological, biochemical, or other biomedical endpoints, is this trial needed to advance scientific understanding?

Specific to this FOA: To what extent does the proposed research focus on macrovascular CVD T1DM? How relevant are the proposed selection criteria for determining the T1DM cohort or study samples? How significant will the proposed research be to the current understanding of the pathophysiology, risk factors, early detection or treatment of cardiovascular disease in T1DM?

Investigator(s)

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

In addition, for applications involving clinical trials

With regard to the proposed leadership for the project, do the PD/PI(s) and key personnel have the expertise, experience, and ability to organize, manage and implement the proposed clinical trial and meet milestones and timelines? Do they have appropriate expertise in study coordination, data management and statistics? For a multicenter trial, is the organizational structure appropriate and does the application identify a core of potential center investigators and staffing for a coordinating center?

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?

In addition, for applications involving clinical trials
Does the design/research plan include innovative elements, as appropriate, that enhance its sensitivity, potential for information or potential to advance scientific knowledge or clinical practice?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

In addition, for applications involving clinical trials

Does the application adequately address the following, if applicable

Study Design

Is the study design justified and appropriate to address primary and secondary outcome variable(s)/endpoints that will be clear, informative and relevant to the hypothesis being tested? Is the scientific rationale/premise of the study based on previously well-designed preclinical and/or clinical research? Given the methods used to assign participants and deliver interventions, is the study design adequately powered to answer the research question(s), test the proposed hypothesis/hypotheses, and provide interpretable results? Is the trial appropriately designed to conduct the research efficiently? Are the study populations (size, gender, age, demographic group), proposed intervention arms/dose, and duration of the trial, appropriate and well justified?

Are potential ethical issues adequately addressed? Is the process for obtaining informed consent or assent appropriate? Is the eligible population available? Are the plans for recruitment outreach, enrollment, retention, handling dropouts, missed visits, and losses to follow-up appropriate to ensure robust data collection? Are the planned recruitment timelines feasible and is the plan to monitor accrual adequate? Has the need for randomization (or not), masking (if appropriate), controls, and inclusion/exclusion criteria been addressed? Are differences addressed, if applicable, in the intervention effect due to sex/gender and race/ethnicity?

Are the plans to standardize, assure quality of, and monitor adherence to, the trial protocol and data collection or distribution guidelines appropriate? Is there a plan to obtain required study agent(s)? Does the application propose to use existing available resources, as applicable?

Data Management and Statistical Analysis

Are planned analyses and statistical approach appropriate for the proposed study design and methods used to assign participants and deliver interventions? Are the procedures for data management and quality control of data adequate at clinical site(s) or at center laboratories, as applicable? Have the methods for standardization of procedures for data management to assess the effect of the intervention and quality control been addressed? Is there a plan to complete data analysis within the proposed period of the award?

Specific to this FOA:

How consistent are the stated research cohort or sample selection criteria with a diagnosis of T1DM in the proposed research strategy?

To what extent is it likely that the access to the proposed participants, cohorts, biosamples and/or data will be available for the proposed research? If utilizing resources from another clinical study, how well-suited are the parent study research design and cohort to be able to provide appropriate resources for the proposed study? If recruitment of new participants is proposed, how adequate are the plans for recruitment? Is the proposed milestones and/or timeline appropriate for the goals of the project? How strong are the proposed contingency plans in the event that there is inadequate progress towards achieving the milestones? If applicable, is the extension of the proposed study beyond the parent study well justified? If the proposed study will continue after the parent study ends, is (are) there sufficient resource(s) to support the continuation and completion of the proposed study?

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

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?

In addition, for applications involving clinical trials

If proposed, are the administrative, data coordinating, enrollment and laboratory/testing centers, appropriate for the trial proposed?

Does the application adequately address the capability and ability to conduct the trial at the proposed site(s) or centers? Are the plans to add or drop enrollment centers, as needed, appropriate?

If international site(s) is/are proposed, does the application adequately address the complexity of executing the clinical trial?

If multi-sites/centers, is there evidence of the ability of the individual site or center to: (1) enroll the proposed numbers; (2) adhere to the protocol; (3) collect and transmit data in an accurate and timely fashion; and, (4) operate within the proposed organizational structure?

Specific to this FOA: If the application indicates that the project will utilize data and/or biosamples from an existing clinical study or other resource (e.g., BioLINCC or NIDDK Central Repository), to what extent will the parent study have the capacity to support the activities of the proposed project? Is there a clear commitment of the parent study or other outside resource to support the conduct of the proposed study; in particular, what assurances are provided that the proposed project will have access to the data and or biosamples from the existing clinical study or other resources (e.g., BioLINCC or NIDDK Central Repository)?

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.

Study Timeline

Specific to applications involving clinical trials

Is the study timeline described in detail, taking into account start-up activities, the anticipated rate of enrollment, and planned follow-up assessment? Is the projected timeline feasible and well justified? Does the project incorporate efficiencies and utilize existing resources (e.g., CTSAs, practice-based research networks, electronic medical records, administrative database, or patient registries) to increase the efficiency of participant enrollment and data collection, as appropriate?

Are potential challenges and corresponding solutions discussed (e.g., strategies that can be implemented in the event of enrollment shortfalls)?

Protections for Human Subjects

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

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

Inclusion of Women, Minorities, and Individuals Across the Lifespan

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

Vertebrate Animals

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.

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

For Resubmissions, the committee will evaluate the application as now presented, taking into consideration the responses to comments from the previous scientific review group and changes made to the project.

Renewals

Not Applicable

Revisions

For Revisions, the committee will consider the appropriateness of the proposed expansion of the scope of the project. If the Revision application relates to a specific line of investigation presented in the original application that was not recommended for approval by the committee, then the committee will consider whether the responses to comments from the previous scientific review group are adequate and whether substantial changes are clearly evident.

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) Genomic Data Sharing Plan (GDS).

Authentication of Key Biological and/or Chemical Resources:

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.

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.

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by NHLBI, in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

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

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

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

Applications will 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 National Heart, Lung, and Blood 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.

3. Anticipated Announcement and Award Dates

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

Section VI. Award Administration Information

1. Award Notices

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.

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

ClinicalTrials.gov: If an award provides for one or more clinical trials. By law (Title VIII, Section 801 of Public Law 110-85), the \\"responsible party\\" must register and submit results information for certain applicable clinical trials on the ClinicalTrials.gov Protocol Registration and Results System Information Website (https://register.clinicaltrials.gov). NIH expects registration and results reporting of all trials whether required under the law or not. For more information, see https://grants.nih.gov/policy/clinical-trials/reporting/index.htm

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

Monitoring Requirements: The NIH policy for data and safety monitoring requires oversight and monitoring of all NIH-conducted or -supported human biomedical and behavioral intervention studies (clinical trials) to ensure the safety of participants and the validity and integrity of the data. Further information concerning these requirements is found at http://grants.nih.gov/grants/policy/hs/data_safety.htm and in the application instructions (SF424 (R&R) and PHS 398).

Investigational New Drug or Investigational Device Exemption Requirements: Consistent with federal regulations, clinical research projects involving the use of investigational therapeutics, vaccines, or other medical interventions (including licensed products and devices for a purpose other than that for which they were licensed) in humans under a research protocol must be performed under a Food and Drug Administration (FDA) investigational new drug (IND) or investigational device exemption (IDE).

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, 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 laws that prohibit discrimination on the basis of race, color, national origin, disability, age and, in some circumstances, religion, conscience, and sex. This includes ensuring programs are accessible to persons with limited English proficiency. The HHS Office for Civil Rights provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-providers/provider-obligations/index.html and http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html.

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

• Recipients of FFA must ensure that their programs are accessible to persons with limited English proficiency. HHS provides 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 https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/fact-sheet-guidance/index.html and https://www.lep.gov. 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 https://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

• 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.

• HHS funded health and education programs must be administered in an environment free of sexual harassment. Please see https://www.hhs.gov/civil-rights/for-individuals/sex-discrimination/index.html; https://www2.ed.gov/about/offices/list/ocr/docs/shguide.html; and https://www.eeoc.gov/eeoc/publications/upload/fs-sex.pdf. For information about NIH's commitment to supporting a safe and respectful work environment, who to contact with questions or concerns, and what NIH's expectations are for institutions and the individuals supported on NIH-funded awards, please see https://grants.nih.gov/grants/policy/harassment.htm.

• Recipients of FFA must also administer their programs in compliance with applicable federal religious nondiscrimination laws and applicable federal conscience protection and associated anti-discrimination laws. Collectively, these laws prohibit exclusion, adverse treatment, coercion, or other discrimination against persons or entities on the basis of their consciences, religious beliefs, or moral convictions. Please see https://www.hhs.gov/conscience/conscience-protections/index.html and https://www.hhs.gov/conscience/religious-freedom/index.html.

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

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

Not Applicable

3. Reporting

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

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

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

Section VII. Agency Contacts

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, application errors and warnings, documenting system problems that threaten submission by the due date, and post-submission issues)

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

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: [email protected] (preferred method of contact)
Telephone: 301-945-7573

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: [email protected]

Nicole Redmond, MD, PhD, MPH
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0379
Email: [email protected]

Teresa L.Z. Jones, M.D.
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Phone: 301-435-2996
E-mail:[email protected]

Director, Office of Scientific Review
National Heart, Lung, and Blood Institute
Email: [email protected]

Fatima Kamara
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-7916
Email: [email protected]

Mary K. Rosenberg
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone: 301-594-8891
Email: [email protected]

Section VIII. Other Information

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

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. 116-260, Consolidated Appropriations Act, 2021; Section 302. Diabetes Programs.