This Notice of Special Interest invites competitive revision applications to support the expansion of existing NIDDK-funded R01, U01, U24, U54, and P30 awards to address the increasing burden of chronic diseases and to reduce health disparities in the development, diagnosis, and treatment of diseases of high priority to the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).

Background

NIDDK’s research interests include chronic diseases and conditions such as diabetes and other endocrine and metabolic diseases; digestive diseases, nutritional disorders, and obesity; and kidney, urologic, and hematologic diseases. Many of these diseases and disorders disproportionately affect the health of under-served populations in the United States. It is recognized that both biologic and non-biologic factors may contribute to the development or progression of diseases of interest to NIDDK for these under-served populations. For the purposes of this FOA, health disparities is defined according to Healthy People 2020 as a particular type of health difference that is closely linked with social, economic, and/or environmental disadvantage. Health disparities adversely affect groups of people who have systematically experienced greater obstacles to health based on their racial or ethnic group; religion; socioeconomic status; gender; age; mental health; cognitive, sensory, or physical disability; sexual orientation or gender identity; geographic location; or other characteristics historically linked to discrimination or exclusion.

Research Objectives

Research approaches relevant for this opportunity may include, but are not limited to metabolic, genetic, genomic, proteomic, behavioral, clinical and/or epidemiologic research in representative populations, including differences across the lifespan. NIDDK particularly encourages projects which create multidisciplinary regional collaborations across areas with high prevalence of health disparities and chronic diseases, such as the southeastern United States.

Collaboration among investigators of extant cohort studies that have been established for investigation of diseases or conditions within NIDDK’s mission would be desirable, so that these studies might jointly develop protocols and evaluate findings. Clinical trials seeking to prevent, mitigate, or treat diseases or conditions within NIDDK’s mission would be appropriate.

Applicants for competitive revision awards are encouraged to form new collaborations between scientists working at different centers and scientists with expertise in varying disciplines. Applications from institutions with a strong existing track record of NIH funding in related areas, such as an NIH-funded Nutrition Obesity Research Center, Center for Diabetes Translation Research, Diabetes Research Center, Nutrition Obesity Research Center, and O'Brien Kidney Center are encouraged.

Potential Research Areas

Appropriate topics for investigation in NIDDK diseases and conditions include, but are not limited to:

• Strategies to improve the identification of NIDDK-specific diseases or disorders that may facilitate or accelerate early intervention, particularly in populations which bear a disproportionate burden of disease;
• Strategies to address social needs and stressors (lack of access to quality food or housing, transportation needs) in healthcare contexts that may include partnerships with community resource organizations/entities with expertise to address social determinants of risk;
• Strategies to slow progression of diseases and disorders in NIDDK’s mission and reduce risk factors for the development of complications, such as but not limited to kidney diseases, liver diseases, gastrointestinal diseases, retinopathy, genitourinary diseases and disorders, neuropathy, cardiometabolic disease, malnutrition, frailty and/or sarcopenia, metabolic bone disease, and depression, especially in populations with increased risk for disease progression and complications;
• Innovative approaches to promote the adoption and maintenance of individual-level behaviors shown to improve outcomes, including, but not limited to dietary intake, physical activity and sedentary behavior, risk factor management, mental health management, and medication and/or treatment adherence;
• Strategies to improve utilization of kidney transplantation and home dialysis in populations with decreased utilization of these modalities;
• Studies designed to better understand racial and ethnic differences in screening, diagnosis, incidence, and prevalence of NIDDK diseases and whether there are differences among sub-groups in the rates of progression; with an emphasis on identifying factors that help inform treatment development, practice, or policy designed to reduce or eliminate disparities;
• Strategies to overcome health care system barriers that reduce the efficiency or effectiveness of patient/provider interactions, reduce barriers to access and improve patient health literacy, education, and treatment adherence, and/or improve implementation of care, which then lead to better health outcomes;
• Rigorous mixed-method approaches to understand facilitators and barriers to research participant engagement (e.g., initializing and sustaining engagement, recruitment/retention);
• Strategies to increase recruitment of participants from high-burden communities above/beyond targeted enrollment in research studies and strategies to improve retention;
• Strategies to improve the science of or activities that promote stakeholder-driven research to include guidance to existing projects or the development of future research activities (e.g., grant proposals), including stakeholder-informed research questions and proposed activities to address the questions and improve uptake of recommendations from research discoveries;
• State-of-the-art, hypothesis-driven mechanistic studies to determine whether there are biological differences that might influence disease development, progression and/or outcomes across populations;
• Basic science studies for health disparities, where scientifically appropriate.

Research with animal models would not be appropriate for the purposes of this funding opportunity. Clinical trials are allowed, but this NOSI will not support new multi-center clinical studies. A study is considered to be "multi-center" if three or more sites are involved in the actual conduct of the study. A clinical study will not be considered to involve multiple centers if participant recruitment occurs at three or more locations, but all interventions and/or outcomes assessments are performed by a single study team.

Application and Submission Information

Revision applications can support a significant expansion of the scope and research protocol approved and funded for the parent award on which the revision application is based. Prospective investigators can consult the Scientific/Research Contact listed below to ensure that projects will considerably contribute to achieving the goal of this Notice.

Applications must be submitted to PA-20-163 using the application forms package with the Competition ID of NOT-DK-20-012-FORMS-E .

Budgets for R01 applications are limited to less than $500,000 direct costs exclusive of consortium F&A costs. P30 and U54 applications may request up to a maximum of $750,000 direct costs exclusive of consortium F&A costs. Applicants may request a maximum of 1 year of support. All budget requests need to reflect the actual needs of the proposed project.

For U01 or U24 applications, applicants requesting equal to or more than $500,000 in direct costs (excluding consortium F&A costs) must contact the Scientific/Research Contact at least two weeks before submission and follow the Policy on the Acceptance for Review of Unsolicited Applications that Request $500,000 or More in Direct Costs as described in the SF424 (R&R) Application Guide and the NIH Grants Policy Statement 2.3.7.2 Acceptance for Review of Unsolicited Applications Requesting $500,000 or More in Direct Costs. Applicants may request a maximum of 1 year of support. All budget requests need to reflect the actual needs of the proposed project.

For applicants with an active NIDDK-funded U01 or U24, applications must include a letter of approval for the ancillary study application from the consortium at the time of submission. Ancillary study approval letters must be submitted as an attachment in Section 12 Other Attachments of the SF424 R&R Other Project Information form. Applications lacking this letter will be considered incomplete and will not proceed to review.

For funding consideration, applicants must include NOT-DK-20-012 (without quotation marks) in the Agency Routing Identifier field (Box 4B) of the SF424 R&R form. Applications without this identifier in Box 4B will not be considered for this special initiative. In addition, applicants should include a cover letter indicating that competitive revision applications are responsive to the requirements of NOT-DK-20-012.. Applications that are non-responsive to the terms of this NOSI will be withdrawn from consideration for this initiative. Note that this Notice announces funds for revisions that address this particular initiative on chronic diseases and health disparities only.

Applications for revisions in response to this Notice must follow the aforementioned application instructions and be submitted by May 14, 2020, by 5pm at the local time of the applicant organization. No late competitive revision applications will be accepted.

Section IV. PHS Human Subjects and Clinical Trials Information

Section 5 Other Clinical Trial-related Attachments

Section 5.1 - Other Clinical Trial-related Attachments

For applications including clinical trials, the following information must be uploaded into Section 5.1 - Other Clinical Trial-related Attachments

The filename "Milestone Plan.pdf" must be used for this attachment. Please amend the file name when more than one attachment with the same file name would be possible (e.g. Milestone Plan.1 for Study Record 1, Milestone Plan.2 for Study Record 2, etc.).

Applicants are required to provide detailed interim performance measures and timelines for completing key objectives and administrative functions for the proposed clinical trial(s), as applicable. Milestones should be easily measurable and realistic. Milestones may include, as applicable, but are not limited to:

• Finalization of the clinical trial protocol(s) and informed consent/assent forms (with NIDDK program official agreement, if applicable) and IRB approval
• Registration of the clinical trial(s) in ClinicalTrials.gov
• Completion of all required regulatory approvals (e.g., Investigational New Drug Application from the Food and Drug Administration)
• Contracts/third party agreements, including intervention product supply
• Training of study staff
• Anticipated date of enrollment of the first participant
• Randomization of 25%, 50%, 75% and 100% of the target sample size
• Follow-up visit completion, if applicable, of 25%, 50%, 75% and 100% of the enrolled or randomized study population, including women, minorities and children
• Expected drop-out or lost-to-follow-up rate overall, or by treatment arm
• Anticipated rate of adherence to the intervention(s)
• Completion of data collection
• Completion of primary endpoint and secondary endpoint data analyses
• Completion of final study report and manuscript submission
• Closeout plans/communication of results to participants
• Reporting of results in ClinicalTrials.gov.

These milestones will be negotiated at the time of the award, as appropriate. The Milestone Plan is not the same as the Study Timeline and must be uploaded as an attachment. Applications that lack the Milestone Plan will be considered incomplete and will not be peer reviewed.

Application Review Information

Review Criteria

The following review criteria will apply to all applications submitted in response to this NOSI. 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.

Overall Impact

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).

Scored Review Criteria

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?

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?

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

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?

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?

Additional Review Criteria

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)? Are the proposed milestones appropriate for the study? Will they allow meaningful tracking of study performance, and are they feasible for the work proposed?
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.

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.

Additional Review Considerations

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.

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.