March 11, 2019
April 11, 2019, by 5:00 PM local time of applicant organization. All types of non-AIDS applications allowed for this funding opportunity announcement are due on this date.
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.
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.
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.
There is growing evidence that there are neurocognitive complications of T1D, with approximately 28% of middle aged adults and 48% of older adults meeting criteria for clinically significant cognitive impairment (defined as performance =1.5 standard deviations below normative data on =2 cognitive tests). Early age of onset, duration of disease and severity of hyperglycemia (including noctural hyperglycemia), frequency and severity of episodes of hypoglycemia, hypoglycemia unawareness, diabetic ketoacidosis (DKA), and clinical severity at the time of diagnosis may increase risk for impaired neurocognitive and psychological function. However, age-related changes and vascular complications associated with T1D in adults and older adults make isolating mechanisms more complex and clinical targets may be less modifiable as individuals advance in age and disease burden increases. Therefore, research earlier in the developmental spectrum, especially prior to the development of complex disease (e.g., severe complications of T1D, CVD, dementia) may help us better understand mechanisms for neuropsychological complications of T1D, critical periods for prevention and intervention, and strategies to mitigate the risk of neurocognitive complications of T1D in later life.
Early childhood development is characterized by marked changes in brain structure and function at a time when the brain may be especially vulnerable to dysglycemia and T1D. There are limited data from adequately powered, longitudinal studies on the brain and neuropsychological function, especially in pediatric T1D, and the existing longitudinal studies with brain and neuropsychological data have shown mixed results, which has limited our knowledge of how specific parameters associated with T1D (e.g., age of onset, disease duration, glycemic variability and control, timecourse of dysglycemia, frequency and severity of hypoglycemic episodes, DKA) may lead to changes in brain structure and function and deficits in neurodevelopment and neuropsychological function, and how this may impact disease management, clinical course of T1D, and other important outcomes (e.g., academic function). Moreover, it can be difficult to distinguish the etiology of cognitive impairment from adult cohorts alone since individuals with T1D are at increased risk for other factors that could impact neurocognition later in life (e.g., micro- and macro-vascular disease), but that should be less prevalent in the pediatric and adolescent population. There has also been increased interest in the role of DKA, especially the potential for neurocognitive impairment at the time of diagnosis and following treatment, but there is little long-term (i.e., > 3 months) longitudinal neurocognitive data post-DKA. Recent advances in neuroimaging, computerized neurocognitive assessment, and continuous glucose monitoring and artificial pancreas technologies could lead to improvements in characterizing brain structure/function, cognition, and clinical aspects of pediatric and adolescent T1D and promote understanding of the critical risk or protective factors (e.g., role of DKA, premorbid neurocognition, key developmental periods, effects of treatment regimen) for neurocognitive complications of T1D. If specific risk or protective factors for adverse or optimal neurocognitive outcomes could be defined, treatment protocols could be developed to limit neurocognitive complications associated with T1D. Artificial pancreas technology may mitigate glycemic excursions and improve glycemic control. Information on neurocognitive risks and benefits of glycemic control approaches and outcomes may inform algorithms for future closed-loop artificial pancreas systems.
If successful, this observational cohort study is expected to inform the timing and approach for future research to decrease adverse neurodevelopmental outcomes and long-term neuropsychological sequelae of T1D.
This FOA will utilize the U34 planning cooperative agreement to determine whether a rigorous, adequately powered national, multisite, observational cohort study to prospectively examine the risk and protective factors for neurocognitive complications of pediatric T1D (onset approximately ages 5-10 years) can be designed and what resources would be required. The U34 is a cooperative agreement award mechanism, with the NIH staff being substantially involved as a partner with the Principal Investigator/Program Director. The U34 FOA is designed to: 1) Permit early peer review of the rationale for the proposed cohort study; 2) Permit assessment of the design and protocol of the proposed study; and 3) Provide support for the development of essential elements required for the design and conduct of the cohort study and the management and analysis of the study data.
The U34 is not designed for the collection of preliminary data or for the conduct of pilot studies to support the rationale for an observational cohort study or to test or develop new interventions. The U34 will include the proposed study design (including primary and secondary outcomes) and protocol, but modifications to the study design and protocol will be permitted after peer review.
Contingent on the outcome of the planning cooperative agreements (U34s) and the availability of funds, NIH may fund a consortium to complete the proposed study. As this may require cooperation across some or all U34 awardees, applicants should clearly state that they are willing to work with other U34 awardees to finalize the study design and protocol should a consortium be formed to complete the proposed study, which would be funded through future FOAs.
The U34 Planning Cooperative Agreement is intended to support all administrative study group activities that are required in order to begin recruitment of participants and execution of the proposed study, including finalizing study design; protocol development, implementation, and standardization; integration of all core data collection, sharing, processing, storage, and analyses; and coordination of all activities across the consortium. These activities include, but are not limited to: establishing the research team; identifying the clinical research sites and service cores; developing training materials and training/certification plans for study staff; satisfying all regulatory elements of the Food and Drug Administration if an IND/IDE is needed for implementation of the research plan; negotiating agreements with industry, academic centers, and other entities, as needed, for implementation of the research plan; testing and implementation of data collection protocols, including quality assurance and quality control for comparison across research sites where data collection would occur; developing tools for data management and stewardship to ensure they meet FAIR (Findable, Accessible, Interoperable, and Reusable) data principles; developing plans for resource and data sharing and study outcome dissemination; defining recruitment strategies, retention and protocol completion strategies, and contingency plans if recruitment, retention, and protocol completion milestones are not met; finalizing the protocol; writing the Manual of Operations; developing a safety oversight plan (NIDDK will appoint an Observational Study Monitoring Board (OSMB) for the full cohort study); initiating the IRB approval process; and developing an oversight plan for all research activities across the project.
Applicants are expected to provide a detailed description of a proposed study that will accomplish the scientific aims described above, as well as detailed information about the target population and comparison sample for recruitment and enrollment and recruitment capacity and capability for studying this target population and comparison sample. The proposed research study will enable reviewers to evaluate the applicant's ability to identify the critical issues to be addressed in the study and rigorously design such a study. In addition, the application should include a description of how the cohort study could inform future research to decrease adverse neurodevelopmental outcomes and long-term neuropsychological sequelae of T1D. Preliminary results and background to support the cohort study should be provided. The application should include important details and considerations for the design of the cohort study, including a description of the study population and the comparison group with inclusion and exclusion criteria; study design (including primary and secondary outcomes); and power calculations. Detailed information on neuroimaging protocols and/or a neuropsychological battery, specifically, should be included. Primary outcomes based on neuroimaging or other surrogate markers of brain function and health will need justification. Applicants should address internalizing (i.e., anxiety, depressive) and externalizing symptoms in children and anxiety and depression in parents, and consider these confounding variables in the context of this study. A plan for how the availability of the requisite participant population will be established should be included. A recruitment and retention plan should be a part of that consideration. Issues and challenges related to completing to the proposed studies, including addressing study burden and other barriers and meeting data goals should be addressed. Finally, the application should describe the activities proposed to be conducted during the funding period.
Multidisciplinary teams will be required for these planning grants, including expertise in pediatric T1D, developmental neuropsychology and neuroscience, neuroimaging, diabetes technology, research methods and study designs, and data science for the type of complex study designs and data types expected for the proposed study. A Multiple Principal Investigator (MPI) application should be strongly considered for the type of proposed study expected.
Consultation with NIDDK program staff as soon as possible prior to the application due date is strongly encouraged.
The overall goal of the U34 funding period is to complete all administrative tasks required before recruitment of participants can begin. In the event of an award, the NIDDK and the PD/PI will agree on a list of milestones to be completed during the U34 project period. Successful completion of the U34 may result in an application to conduct the full cohort study, but this is contingent upon the outcome of the U34 and availability of funds. Completion of the full cohort study may require the formation of a consortium, which may require cooperation across some or all U34 awardees. Therefore, applicants should clearly state that they are willing to work with other U34 awardees to finalize the study design and protocol should a consortium be formed to complete the proposed study. As this consortium and the full cohort study would be supported with new FOA(s) issued shortly after completion of the U34, applicants should also clearly state their willingness to submit applications to these future FOA(s) in a timely manner. During the U34 award, NIDDK will appoint an expert panel to review the study design and make recommendations to NIDDK concerning the proposed study, including the study design. Discussions about whether the study should be conducted will include consideration of the following factors: attainment of pre-specified milestones, the expert panel recommendations, scientific landscape, study costs, opportunity cost, and availability of funds. Award of a U34 does not guarantee submission or funding of an application for the full cohort study.
Applicants must state their willingness to comply with the following performance requirements:
The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.
NIDDK intends to commit $1.25 million in FY 2019 to fund up to 3 awards.
Higher Education Institutions
The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:
Nonprofits Other Than Institutions of Higher Education
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.
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.
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.
The NIH will not accept duplicate or highly overlapping applications under review at the same time. This means that the NIH will not accept:
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.
For information on Application Submission and Receipt, visit Frequently Asked Questions – Application Guide, Electronic Submission of Grant Applications.
The letter of intent should be sent to:
John Connaughton, Ph.D.
Chief, Scientific Review Branch
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Additional information below should also be included. The following items must be included as attachments under Other Attachments.
Protocol: The filename “Protocol.pdf” should be used.
The application must include a detailed description for the proposed design for the full cohort study, addressing the scientific rationale for the design chosen, the population to be studied, including detailed information about the available population (based on the proposed inclusion/exclusion criteria and recruitment plan), and the outcomes being assessed. Sufficient details of the study design must be provided to permit assessment of the scientific importance of the study, the validity of the design and the feasibility of the study. Critical elements include overall design, primary objective, inclusion and exclusion criteria, proposed study population, and sample size. The primary endpoint and key secondary outcomes should be delineated. The proposed timeline for recruitment, follow-up and study close-out should be documented. The statistical methods, including the assumptions made for power calculations for the full study, must be described. The sample size and statistical power calculations must contain enough detail so that a reviewer can readily duplicate the analysis. The power analysis should include a discussion of the anticipated level of adherence to the intervention and rates of follow-up (i.e., drop out/lost to follow up) during key outcome collection contacts and any anticipated issues with data quality and complexity, including technical issues that may compromise the collection, use, sharing, and analysis of the data.
Applications that lack the Protocol are considered incomplete and will not be peer reviewed.
Milestone Plan: The filename "Milestone Plan.pdf" should be used.
Applicants are required to provide detailed performance measures and timelines for completing key objectives and administrative functions for the proposed planning grant, as applicable. Milestones should be easily measurable and realistic.
These milestones will be negotiated at the time of the award, as appropriate. Failure to meet milestones may result in the applicant being unable to move into the U01 application phase.
Applications that lack the Milestone Plan are considered incomplete and will not be peer reviewed.
Organization Plan: The filename "Organization Plan.pdf" should be used.
The application must describe how the study will be organized and managed, both for the planning period and for the full study. This should include information on the leadership of the study, the proposed clinical sites and the ability of the PD/PI to bring together the necessary study network. Describe the process for identification and selection of additional collaborators that will be added during the U34 period, if applicable. The PD/PI should discuss in detail whether he/she, as well as other key members of the team, have experience in the conduct and administration of complex studies, including delineation of the success of those studies in terms of recruitment, retention, and dissemination activities (e.g., publications, resource and data/knowledge sharing, etc.).
Provide a description of the study organization and administration, including, but not limited to: a description of committee structures needed to manage the complexity of the trial, including plans to assure fidelity to the protocol and integrity of the data; the role of any internal or external advisory committees; the oversight, responsibilities, and coordination of any sites or cores proposed. If an advisory committee is planned, applicants should not contact or name potential advisory committee members.
Applications that lack the Organization Plan are considered incomplete and will not be peer reviewed.
All instructions in the SF424 (R&R) Application Guide must be followed.
Specific Aims: This section must delineate the aims for both the U34 planning period and for the full study. The primary and major secondary endpoints for the proposed full study should be specified.
Research Strategy: This section must address both the planning period and the full study.
The investigator must describe how the planning period will be used and what activities will be conducted. The applicant must clearly articulate the significance of the proposed study including why the observational cohort study is needed and what evidence gap the study will address, including a discussion of how the results will inform the timing and approach for future research to decrease adverse neurodevelopmental outcomes and long-term neuropsychological sequelae of T1D. Preliminary data addressing the need for and supporting the feasibility of the study must be discussed. The discussion of supporting data that will provide the basis for the study's design must address the adequacy and quality of previous studies and include a plan to address research gaps, including improved rigor and reproducibility of existing research, where needed.
Letters of Support: A letter of support must be provided from all clinical centers, reading centers, central laboratories of other central cores or required study components. If co-funding or in-kind support is planned from non-NIH sources, letter(s) outlining details of the commitment (e.g., type, amount and source of support), signed by a business official on organization letterhead, must be included in the Letters of Support section.
The following modifications also apply:
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.
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.
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.
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.
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.
Use of Common Data Elements in NIH-funded Research
Many NIH ICs encourage the use of common data elements (CDEs) in basic, clinical, and applied research, patient registries, and other human subject research to facilitate broader and more effective use of data and advance research across studies. CDEs are data elements that have been identified and defined for use in multiple data sets across different studies. Use of CDEs can facilitate data sharing and standardization to improve data quality and enable data integration from multiple studies and sources, including electronic health records. NIH ICs have identified CDEs for many clinical domains (e.g., neurological disease), types of studies (e.g. genome-wide association studies (GWAS)), types of outcomes (e.g., patient-reported outcomes), and patient registries (e.g., the Global Rare Diseases Patient Registry and Data Repository). NIH has established a “Common Data Element (CDE) Resource Portal" (http://cde.nih.gov/) to assist investigators in identifying NIH-supported CDEs when developing protocols, case report forms, and other instruments for data collection. The Portal provides guidance about and access to NIH-supported CDE initiatives and other tools and resources for the appropriate use of CDEs and data standards in NIH-funded research. Investigators are encouraged to consult the Portal and describe in their applications any use they will make of NIH-supported CDEs in their projects.
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.
Only the review criteria described below will be considered in the review process. Applications submitted in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.
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?
Specific to this FOA: For the proposed clinical study, are the scientific rationale and need for a clinical study 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? Do the aims of this application indicate that this project could significantly contribute to the overarching goals to establish a longitudinal cohort study to examine the risk and protective factors for neurocognitive complications of pediatric T1D?
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?
Specific to this FOA: 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 cohort study, including a track record of performing the specialized work required for the project (e.g., sampling, recruitment, retention, comprehensive phenotypic assessments, multi-site and multi-modal neuroimaging, biospecimen collection, etc., of children with T1D), to meet milestones and timelines? Do they have appropriate expertise in study coordination, data management and statistics? For a multicenter study, is the organizational structure appropriate and does the application identify a core of potential center investigators and staffing for a coordinating center?
Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?
Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators 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?
Specific to this FOA: Are the activities proposed for the planning period adequate? Will the activities proposed be sufficient to allow for timely and successful study implementation? Will the proposed planning activities address all major barriers to the future cohort study? Is there an appropriate and feasible timeline for all planning activities and are clear milestones presented? For the proposed full study, does the application adequately address the following, if applicable?
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 a previous body of rigorous and reproducible research? Given the methods proposed, is the study design adequately powered to answer the research question(s), test the proposed hypothesis/hypotheses, and provide interpretable results? Is the study appropriately designed to conduct the research efficiently? Are the study populations (size, gender, age, demographic group), protocols (including measures and measurement frequency and duration), and overall duration of the observational study, 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, poor data quality, and losses to follow-up appropriate to ensure adequate data collection to test the proposed hypotheses? Are the planned recruitment timelines feasible and is the plan to monitor accrual adequate? Are differences addressed, if applicable, in the expected differences in outcomes due to sex/gender, race/ethnicity, and/or socioeconomic status?
Are the plans to standardize, assure quality of, and monitor adherence to, the protocol and data collection or distribution guidelines appropriate? Is there a plan to obtain required study agent(s) or other resources? 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? Are the procedures for data management and quality control of data adequate at clinical sites and/or at laboratories and centers, as applicable? Have the methods for standardization of procedures for data management and quality control been addressed? Is there a plan to complete data analysis within the proposed period of the award?
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?
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?
Specific to this FOA: For the proposed full study, are the administrative, data coordinating, enrollment and laboratory/testing centers, appropriate for the study proposed?
Does the application adequately address the capability and ability to conduct the study at the proposed site(s) or centers?
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?
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.
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.
The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.
Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.
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).
For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.
Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.
Information regarding the disposition of applications is available in the NIH Grants Policy Statement.
A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the grantee’s business official.
Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.
Any application awarded in response to this FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this website.
Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person’s race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency. HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research.
In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 “Federal awarding agency review of risk posed by applicants.” This provision will apply to all NIH grants and cooperative agreements except fellowships.
For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/index.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-individuals/section-1557/index.html; and https://www.hhs.gov/civil-rights/for-providers/laws-regulations-guidance/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see https://www.hhs.gov/civil-rights/for-individuals/disability/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. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.
The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Part 75, and other HHS, PHS, and NIH grant administration policies.
The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.
The PD(s)/PI(s) will have the primary responsibility for:
1. Developing the research design and study protocol, including definition of objectives and approaches, sample size and power calculations, and establishing procedures for participant recruitment and follow-up, data collection, quality control, interim data and safety monitoring, final data analysis and interpretation, and publication of results.
2. Establishing a Steering Committee to implement, coordinate and manage the project(s). Awardee(s) will name investigators to serve as members on a Steering Committee and other subcommittees, as appropriate, meeting periodically. Awardees will be required to accept and implement the common protocol(s) and procedures approved by the Steering Committee.
3. Designating Protocol Chairs. The Program Directors/Principal Investigators (for studies involving multiple protocols) shall designate a single Protocol Chairperson (if the Program Director/Principal Investigator does not assume this role) for each protocol to be carried out by the study group. The Protocol Chairperson shall function as the scientific coordinator for the protocol and shall assume responsibility for obtaining approval to implement the protocol from the Steering Committee and for developing and monitoring the protocol. Significant modifications to approved protocols must be approved by the Steering Committee.
4. Implementing collection of data specified by the study protocol. For a multi-center study, each awardee/site is required to ensure that data will be submitted expeditiously to the Data Coordinating Center. Additionally, individual investigators/sites must demonstrate the ability to implement the strategy specifically designed for their individual study population.
5. Establishing procedures for data quality and completeness. Awardees are responsible for ensuring accurate and timely assessment of the progress of each study, including development of procedures to ensure that data collection and management are: (1) adequate for quality control and analysis; (2) for clinical trials, as simple as appropriate in order to facilitate cooperation/referral of study participants by physicians to avoid unnecessary expense; and (3) sufficiently staffed across the participating institutions. For research involving multiple sites, a plan for analysis of pooled data will be developed by the Steering Committee.
6. Submitting interim progress reports, when requested or agreed upon by both parties, to the NIDDK Program Official including as a minimum, summary data on protocol performance. For coordinated multiple awards or a multi-site single award, the NIDDK Program Official may require additional information from individual awardees/sites. Such reports are in addition to the required annual noncompeting continuation progress report.
7. Reporting of the study findings. Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies. The awardee must also be adherent to Study Publication and Presentation Policy. The NIDDK will have access to and may periodically review all data generated under an award. NIDDK staff may co-author publications of findings with awardees consistent with NIH and study policies.
8. Agree that any third-party (including both industry and academia) collaboration should be governed by a research collaboration agreement (e.g. Clinical Trial Agreement, Research Collaborative Agreement, Memorandum Of Understanding, etc.) with terms that ensure the collaboration is conducted in accordance with the Cooperative Agreement, applicable NIH/NIDDK policies and procedures. The NIDDK Program Official may consult with others at NIH including the NIDDK Technology Advancement Office.
9. Any involvement of a third party in the study (including both industry and academia), including access to any study data; study results; using the name of the study; or the name of the NIH or NIDDK, is permitted only after written concurrence by the NIDDK Program Official who may consult with others at NIH including the NIDDK Technology Advancement Office.
10. Study investigators are required to publish and to release publicly and disseminate results and other products of the study, in accordance with study protocols and steering committee policies on publications.
11. Maintaining confidentiality of information: The awardee(s) will maintain the confidentiality of the information developed by the investigators (i.e., protocols, data analysis, conclusions, etc.) as well as proprietary information of a company collaborating with the study.
12. The NIDDK has established Central Biosample, Genetic, and Data Repositories for the archiving and storage of data and biosamples collected in large, multi-site studies funded by NIDDK. Prior to enrolling participants, the PI or his/her designee will coordinate with the NIDDK Central Repository to develop a Data Sharing Plan and prepare the collected data for eventual archiving and distribution. In addition, if applicable, the PI or his/her designee will work with the NIDDK Biosample Repository to coordinate procedures for coding, shipping, processing, receipt, storage, and sharing of study samples that are to be maintained in the Repository. All samples and data transferred to the Repositories will be under the custodianship of the NIDDK, although the study’s Steering Committee will have proprietary control of and exclusive access to the samples and data for an agreed-upon period of time. Subsequently samples and data will be available to the wider scientific community in accordance with the NIH policy on Data Sharing ( http://grants.nih.gov/grants/policy/data_sharing/ and,
http://grants.nih.gov/grants/policy/data_sharing/data_sharing_guidance.htm#goals , and http://grants.nih.gov/grants/policy/data_sharing/data_sharing_faqs.htm ), as well as the NIDDK policy for data sharing in multi-center and large single-center clinical studies http://www.niddk.nih.gov/research-funding/process/human-subjects-research/Documents/PublicversionNIDDKdatasharingpolicy2013July2013.pdf .
13. The Food and Drug Administration Amendments Act of 2007 (FDAAA or US Public Law 110-85) was passed on September 27, 2007. The law requires mandatory registration and results reporting for certain clinical trials of drugs, biologics, and devices. If trials conducted under this grant are applicable clinical trials subject to FDAAA, the sponsor or his/her designee will perform the mandatory study registration and reporting of study results to ClinicalTrials.gov. For more information about this law and requirements for sponsors and/or investigators, visit the PRS and U.S. Public Law 110-85 Information Page at http://prsinfo.clinicaltrials.gov/fdaaa.html . In addition, grantees should be aware that clinical trials not covered by FDAAA may still require registration in an approved registry in order to be published, according to the guidelines issued by the International Committee of Medical Journal Editors ( http://icmje.org/recommendations/browse/publishing-and-editorial-issues/clinical-trial-registration.html ).
NIH staff have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:
An NIDDK Project Scientist with substantial involvement will:
1. Serve as the contact point for all facets of the scientific interaction with the awardee (s). As required for the coordination of activities and to expedite progress, NIDDK may designate additional NIDDK staff to provide advice to the awardee on specific scientific and/or analytic issues. Such staff may include another Project Scientist or Project Coordinator, who will provide direct technical assistance to the awardees to optimize the conduct and/or analysis of the study; or who may assist in the coordination of activities across multiple sites.
2. For multi-center studies, participate in the Steering Committee that oversees study conduct. The NIDDK Project Scientist or Project Coordinator will be a full participant and voting member of the Steering Committee and, if applicable, subcommittees.
3. Serve as a resource to study investigators with respect to other ongoing NIDDK activities that may be relevant to the study to facilitate compatibility with the NIDDK missions and avoid unnecessary duplication of effort.
4. Have substantial involvement assisting in the design and coordination of research activities for awardees as elaborated below:
a. Assisting by providing advice in the management and technical performance of the investigations, coordinating required regulatory clearances for investigational agents used in the study, which are held by NIDDK. The NIDDK may reserve the right to cross file or independently file an Investigational New Drug Application or an Investigational Device Exemption form with the FDA.
b. The NIDDK Project Scientist or Project Coordinator may coordinate activities among awardees by assisting in the design, development, and coordination of a common research or clinical protocol and statistical evaluations of data; in the preparation of questionnaires and other data recording forms; and in the publication of results.
c. Reviewing procedures for assessing data quality and study performance monitoring.
d. The NIDDK Project Scientist or Project Coordinator may be co-authors on study publications. In general, to warrant co-authorship, NIDDK staff must have contributed to the following areas: (a) design of the concepts or experiments being tested; (b) performance of significant portions of the activity; (c) participation in analysis and interpretation of study results and (d) preparation and authorship of pertinent manuscripts.
The NIDDK Program Official identified in the Notice of Award will:
Interact with the Program Director(s)/Principal Investigator(s) on a regular basis to monitor study progress. Monitoring may include: regular communications with the Program Director/Principal Investigator and staff, periodic site visits, observation of field data collection and management techniques, quality control, fiscal review, and other relevant matters; as well as attendance at Steering Committee, data safety and monitoring board, and related meetings. The NIDDK retains, as an option, periodic review of progress by researchers not involved with the study.
Review and approve protocols prior to implementation to insure they are within the scope of peer review, for safety considerations, as required by Federal regulations.
The NIDDK Program Official will monitor protocol progress, and may request that a protocol study be closed to accrual for reasons including: (a) accrual rate insufficient to complete study in a timely fashion; (b) accrual goals met early; (c) poor protocol performance; (d) patient safety and regulatory concerns; (e) study results that are already conclusive; (f) low likelihood of showing a benefit of the intervention (futility); and (g) emergence of new information that diminishes the scientific importance of the study question. The NIDDK will not permit further expenditures of NIDDK funds for a study after requesting closure except as specifically approved by the NIDDK.
Make recommendations for continued funding based on: a) overall study progress, including sufficient patient and/or data accrual; b) cooperation in carrying out the research (e.g., attendance at Steering Committee meetings, implementation of group decisions, compliance with the terms of award and reporting requirements); and/or c) maintenance of a high quality of research, which will allow pooling of data and comparisons across multiple cooperative agreement awards for common data elements.
Appoint an independent Data and Safety Monitoring Board (DSMB) as appropriate for Phase III clinical trials or other high risk studies, or an Observational Study Monitoring Board (OSMB) for observational/epidemiologic studies; these Boards will review study progress, safety data, and interim results, as appropriate, and provide guidance to the NIDDK. The NIDDK Program Official or their Project Coordinator will serve as the Executive Secretary and/or NIDDK program representative on the DSMB/OSMB.
Areas of Joint Responsibility include:
In addition to the interactions defined above, NIDDK Project Scientist and Awardees shall share responsibility for the following activities:
A Steering Committee organized by the study investigator(s) will be the main governing body of the study.
The Steering Committee has primary responsibility to design research activities, establish priorities, develop common protocols and manuals, questionnaires and other data recording forms, establish and maintain quality control among awardees, review progress, monitor patient accrual, coordinate and standardize data management, and cooperate on the publication of results. Major scientific decisions regarding the core data will be determined by the Steering Committee. The Steering Committee will document progress in written reports to the NIDDK Program Official, and will provide periodic supplementary reports upon request.
The Steering Committee will be composed of all Program Director(s)/Principal Investigator(s), (including those of data coordinating /statistical centers, if any) and co-investigators as deemed necessary, and the NIDDK Project Scientist. The final structure of the Steering Committee and voting procedures will be established at the first meeting. The NIDDK Project Scientist will have voting membership on the Steering Committee, and as appropriate, its subcommittees. The frequency of Steering Committee meetings will be dictated by a vote of the members of the Steering Committee.
A Chairperson of the Steering Committee, other than the NIDDK Project Scientist, will be selected by the NIDDK, in consultation with the Steering Committee. The Chairperson provides leadership to the Committee by conducting the Steering Committee meetings, representing the study group to the External Oversight Committee established by the NIDDK and by interacting closely with the awardees during protocol development and implementation.
Any disagreement that may arise on scientific/programmatic matters (within the scope of the award), between award recipients and the NIDDK may be brought to dispute resolution. A dispute resolution panel will be composed of three members --one selected by the awardee (or the Steering Committee, with the NIDDK member not voting), a second member selected by NIDDK, and the third member elected by the two prior selected members. These special dispute resolution procedures in no way affect the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulations at 42 CFR Part 50, Subpart D, and HHS regulations at 45 CR Part 16.
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.
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Luke Stoeckel, Ph.D.
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Michele Barnard, PhD
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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