Part 1. Overview Information

Key Dates

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

The effects of a variety of dietary interventions on aging-related outcomes have been examined in human and animal studies. Caloric restriction (CR) has long been known to extend life span and delay onset of a variety of age-related conditions in many, but not all, animal models. A randomized controlled clinical trial, Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE), in non-obese adults age 51 and under, showed favorable effects of two years of CR on risk factors for aging-related conditions and effects on mechanisms that may influence health span and longevity. However, there remains significant uncertainty about the feasibility of sustaining a longer-term CR intervention (e.g., five years or longer) and about whether the effects of CR, including rates of physiologic aging changes and pre-morbid disease progression, would be amplified or attenuated with the increased duration of CR. The findings of such a longer-term CR trial would be valuable whether or not CR is found to be feasible for a large segment of the population, since they would provide data on the relationship of CR effects on longer-term outcomes to mechanisms that could potentially be targeted by pharmacologic or other strategies.

Model organism studies and short-term human studies of interventions that modify timing of food intake indicate that they may also have favorable effects on aging-related outcomes and may influence mechanisms affected by CR. These interventions include intermittent fasting and time-restricted feeding, the latter referring to eating only within a limited time interval (e.g., 8 hours) each day. Interventions that modify macronutrient proportions (e.g., lower protein/carbohydrate ratio) or source (e.g., plant-based versus omnivorous diet) have also been reported to have favorable effects on aging-related factors in model organism and/or human studies.

Given that a number of dietary interventions may have long-term benefits for delaying or treating multiple age-related conditions, there is a need for trials long enough to provide insights into their potential long-term benefits and risks if maintained by individuals over years. Trials allowing comparisons between CR and other dietary interventions would be especially valuable for understanding possible similarities and differences in their effects, underlying mechanisms, and factors influencing adherence to the interventions.

The benefits and risks of CR and other nutritional interventions could differ over the life span. Younger and older persons differ considerably in physiology, health status, and risk for clinical and functional outcomes. Trials need to be designed to address the most pertinent issues regarding the effects of the interventions in older and younger age groups with regard to selection of outcome measures, eligibility criteria, and other design elements.

Experience with CALERIE and other dietary intervention trials indicates that extensive preliminary planning is needed to design and implement trials that will adequately test the above dietary hypotheses. Such planning requires comprehensive preliminary activities, including data analyses; pilot studies; and consideration of options regarding intervention selection, recruitment, inclusion and exclusion criteria, behavioral intervention design and implementation, adherence assessment and maintenance, outcome selection and evaluation, and data quality control.

Objectives and Scope

This FOA invites applications for three-year planning and protocol development projects for trials of five-year nutritional interventions in either of two age ranges: 25 to <50 or ≥ 50 years of age. Applicants may propose narrower age spans within these boundaries.

Prospective applicants may propose planning projects for trials in both the younger and older age groups. In such cases, separate applications for planning projects should be submitted for trials in each of the age groups and will be peer reviewed independently.

The trials to be planned are required to have a minimum of three arms: a CR arm, at least one other dietary intervention, and a control group.

The types of interventions, besides CR, that may be planned for inclusion in the trial design are:

• Intermittent fasting
• Time-restricted feeding
• Amino acid restriction
• Modified macronutrient proportions (e.g., low protein/high carbohydrate)
• Specified nutrient sources (e.g., whole-food plant-based)

Planning for inclusion of either an intermittent fasting or time-restricted feeding arm is strongly encouraged but not required. If neither of these arms is chosen, applicants must select at least one non-CR arm in addition to CR.

For each age group, trials should be designed to address key health and biological aging issues regarding the effects of the interventions in that age range:

Younger age range. In this age group, there is a need for greater understanding of longer-term effects of CR and other nutritional interventions relatively early in life in healthy, non-obese persons. The eligible BMI range for planned trials in this age group should be 22 to <30. Exclusion criteria based on presence of chronic diseases should be considered. Important types of study outcomes include effects on rates of changes with age in physiologic functions, disease risk factors, pre-clinical disease progression, predictors of future life span, aging-related mechanisms, and long-term sustainability of adherence.

Older age range. In this age group, aging-related changes have progressed to the extent that elevations in disease risk factors, pre-clinical disease progression, overt morbidity, and incident clinical events are common. There is a need to understand the effects of nutritional interventions in the presence of these aging-related changes, morbidities, and concomitant medical treatments. Outcomes of interest include clinical and functional outcomes, potential reversal of physiologic aging changes, and outcomes also of interest in the younger group, such as effects on disease risk factors and predictors of future life span. Planning for trials to address the above questions should consider their implications for design elements such as inclusion/exclusion criteria, selection of pre-specified outcomes, and age range. Although applicants may propose an upper age limit for trials in this age range, the target population should include enough older persons (e.g.,≥ 70 years old) to provide information on effects at these ages. Given limited information about effects of these nutritional intervention in obese older persons, applicants may (but are not required to) select a BMI as high as <35 as the upper limit for study eligibility.

Considerations regarding both age ranges. As noted above, many physiologic, mechanistic, and disease risk factors will be of interest in both age ranges. Since both age ranges include perimenopausal women, trial planning for both age groups should consider measures and analyses to assess interactions of menopausal status with treatment effects. In addition, potential adverse effects (e.g., on bone or muscle) should be considered in both age ranges, regarding both outcome assessment and intervention design, to minimize or mitigate risks.

Communication and coordination among planning projects. It is likely that many outcome measures will be planned in both age ranges. It is also possible that, in addition to CR, one or more interventions will be planned in both age ranges. Communication and coordination among awardees while trials are planned in order to harmonize data collection would enhance the value of the set of trials by improving comparability across age ranges and allowing pooled analyses of outcomes and effects of covariates on treatment responses. Applicants should request funding for such communication and harmonization activities in their applications.

Planning project organization and activities. It is expected that applications for the planning projects would be submitted by multidisciplinary research teams with expertise in clinical trials design and implementation, biostatistics, nutrition, behavioral interventions, biology of aging, clinical physiology and pathology, and other topics such as exercise physiology, depending on the selection of interventions. During the three-year planning projects, awardees may simultaneously conduct activities such as:

• Analyses of databases (e.g., from nutrition intervention trials, longitudinal cohort studies, and populations with specific dietary practices and exposures) to inform considerations about elements such as sample size and selection of outcome measures.
• Pilot studies to inform decisions on trial design, e.g., surveys of willingness to be randomized to differing interventions; assessment of adherence to various interventions; assays of range, variability, and correlation of possible biological outcomes for use in power calculations; characterization of potential recruitment populations to estimate yield rates; etc.
• In-person meetings and teleconferences to consider these analyses, consider design options, and discuss draft protocol components.
• Development of infrastructure for collaborative planning and data analyses within the study team.
• Harmonization of data collection and definitions with other planning projects supported through this initiative.

During the three-year planning projects, each multidisciplinary team would assess options for design and implementation of a trial, addressing the elements described below, and develop a protocol or protocols for a proposed trial(s). A number of specific issues and choices should be considered in the planning projects. In their application, investigators should discuss approaches for addressing elements such as the following:

1. Interventions:
   • Criteria and process for selecting which interventions, in addition to CR, would be included for the trial protocols to be developed.
   • Measures of dose-response relationships between adherence to the possible interventions and the chosen outcomes. Evidence should be collected to determine whether the measure of adherence is equally collectable across interventions and whether it is more appropriate for interventions of short or long duration.
   • Approaches to adherence monitoring, including possible use of biomarkers, wearable devices or smartphones, and/or novel self-report instruments.
   • Process and staff expertise for developing structured behavioral intervention programs for proposed interventions, including intervention delivery, tracking, and quality control system.
   • Selection of a control group regimen, including the extent and nature of guidance on diet or other health-related issues during the course of the trial.
   • Extent to which the level of physical activity in intervention arms is to be specified.
   • Content and focus of surveys to assess individuals willingness to be randomized to differing interventions and pilot tests to assess the feasibility of implementing the interventions and of achieving and monitoring adherence.
2. Outcome measures and hypothesis testing:
   • Process for selection of primary outcome(s) and statistical approaches for dealing with limitations of the selected measures.
   • Use of composite outcomes or combined measures to assess the effects of interventions on multiple aging-related clinical or physiologic phenotypes, including use of measures of biological age or scores constructed of components used in clinical practice.
   • Analyses of relationships between possible individual or composite study outcomes and longevity and/or health span, using data and/or specimens from long-term observational studies and clinical trials to evaluate their possible value in the proposed trials.
   • Distribution within the study populations of values of the components of composite or combined measures and the reliability of measures of their change within individuals to determine power of the proposed trials to assess treatment effects.
   • Ability to ensure adequate follow up on all components of composite or combined outcomes and obtain evidence that an intervention will impact components in a similar direction.
   • Criteria and process for the selection of secondary and exploratory outcomes, including but not limited to predictive markers of future aging events; biologic mechanisms influencing aging changes; endocrine, inflammatory, and other physiologic factors; cardiometabolic and other disease risk factors; progression of pre-morbid or overt pathology; clinical events; psychological factors, including mood and cognition; quality-of life-measures; and physical function.
   • Feasibility of using resilience-based measures, such as response to influenza vaccination or exercise endurance, and a process for selecting measures that may emerge as candidates during the planning phase.
3. Adaptive designs and other design issues. Applicants are encouraged to consider adaptive designs, but may also propose alternative designs that will:
   • Consider the possibility of using interventions of different length (e.g., a longer CR and a shorter TRF intervention).
   • Have established criteria and algorithms for deciding on continuation vs. cessation of interventions, including such factors as the dose-response relationship between adherence and treatment effects, potential differential effects of early vs. late adherence, and the availability of short-term surrogate markers that predict effects on key longer-term outcomes.
4. Target populations and subgroup hypotheses:
   • Analyses of interactions between baseline dietary factors and treatment effects to address the heterogeneity of dietary features, such as proportion of calories from different macronutrient categories or vegan vs. nonvegan.
   • Prespecified subgroup hypotheses to account for population covariates that could plausibly influence treatment effects and their implications for sample size and composition of the study population (e.g., stratifying enrollment to enhance power for subgroups).
   • Potential interactions of menopausal status with treatment effects and selection of outcomes particularly important to this group, such as sleep, mood, and libido.
5. Sample size calculations should provide for a sample size large enough to ensure pairwise hypothesis testing on a primary outcome among intervention groups and suffice for an adaptive design, if such design is used.
6. Recruitment strategies should discuss approaches for pre-testing of targeting strategies to reach groups likely to respond and evaluating willingness to be randomized to identify correctable impediments.
7. Participant safety:
   • Prespecified safety outcomes for interventions with known safety risks (e.g., diminution of bone mass, muscle mass, and strength by CR) and development of monitoring plans to minimize the risk of serious adverse events.
   • Approaches for developing a set of measures of safety and adverse effects to identify unanticipated problems early in the intervention to reduce these risks later in the trials.
   • Plans for close monitoring for adverse effects of restricting dietary amino acids or protein on muscle mass or strength.
   • Plans for protecting participants privacy, if social media will be used in the trials.
8. Study organization and implementation:
   • Criteria for assessing potential sites, including their expertise and capabilities for participation.
   • Process for making study-wide decisions.
   • Given the multiple types of expertise needed, the planning projects will likely include numerous researchers at multiple institutions. Each trial will probably need a clinical coordinating center and a bioinformatics center.
   • Operational plan for integration of study activities to provide for efficient sharing of data and documents between the study components and working groups during all stages of the trials, from protocol, manual of procedure, and data collection elements development, through study implementation, to data analysis and publication of the study results.

Interactive and collaborative activities among the planning projects. Awardees will be expected to interact through regular teleconferences/videoconferences and annual in-person meetings to exchange information and explore opportunities for shared resources and collaborations that could enhance the contributions of differing awardees' strengths to the progress of each other’s planning project.

NIA expects that, following the completion of planning and protocol development supported by these awards, awardees will submit applications to support the conduct of trials. NIA will support at least one trial in each age range, depending on the receipt of sufficiently meritorious applications. Any resulting award will be a Cooperative Agreement with appropriate terms and conditions of the award.

Pre-Application Webinar

A webinar is planned to provide prospective applicants the opportunity to receive information and ask questions about the scientific scope of this announcement and technical details for applying. Please refer to www.nia.nih.gov/NutritionalInterventions for details on the webinar (such as time and date) and registration. Potential applicants are also strongly encouraged to review the FAQ section.

Section II. Award Information

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)

Governments

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

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

Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.

Non-domestic (non-U.S.) components of U.S. Organizations are 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.

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

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)

Prospective applicants may choose to propose planning projects for trials in both the younger and older age groups. Under these circumstances, separate applications for planning projects should be submitted for trials in each of the age groups and will be peer reviewed independently.

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:

Giovanna Zappal , Ph.D., MPH
National Institute on Aging (NIA)
Telephone: 301-827-6240
Email:[email protected]?

Describe in the planning activities proposed uses of existing research resources (e.g., relevant cohorts, data sets, and/or biorepositories) provided by both the sponsoring institution and other research entities, and include letters of support from the governing body/oversight committees for the research resources to document that necessary approvals for access have been obtained. Provide evidence that these resources are sufficient to plan and conduct the intended research activities.

Describe the structure of the proposed interdisciplinary research team, and explain how the specific expertise of each member of the research team will contribute to achieving the objectives of the proposed planning project(s), without duplicating information in the biosketches. Areas of recommended expertise include, but are not limited to, clinical trial design and implementation, biostatistics, nutrition, behavioral interventions, the biology of aging, clinical physiology and pathology, and other topics, depending on the selection of interventions. Applicants are encouraged to present information about team members' previous collaborations in interdisciplinary projects, including collaborations with each other.

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

Applicants should include travel funds for key investigators to participate in annual meetings in Bethesda, MD.

Applicants should provide a project management plan which outlines a tentative timeline for conducting the proposed planning activities and pilot studies, with brief descriptions of how the proposed specific aims will be achieved on a year-by-year basis.

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.

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.

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

4. Submission Dates and Times

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.

6. Funding Restrictions

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.

7. Other Submission Requirements and Information

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.

In order to expedite review, applicants are requested to notify the NIA Referral Office by email at [email protected] when the application has been submitted. Please include the FOA number and title, PD/PI name, and title of the application.

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.

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?

Is there adequate representation of the necessary areas of expertise in the composition of the proposed research team? Recommended areas of expertise include, but are not limited to, clinical trial design and implementation, biostatistics, nutrition, behavioral interventions, the biology of aging, clinical physiology and pathology, and other topics, depending on the selection of interventions.

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?

Are the proposed organizational structure and project management plan (e.g., study committees, decision-making process, day-to-day communications) reasonable and likely to support the proposed research activities? Are the proposed plans for interactions and collaborations with another planning grant adequately described and feasible?

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?

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?

Has the applicantprovided evidence that both the sponsoring institution as well as other research entities identified through letters of support will provide resources sufficient to plan and conduct the intended research activities (e.g., access to relevant cohorts and/or data sets)?

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?

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 thecategories 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

Not Applicable

Renewals

Not Applicable

Revisions

Not Applicable

Applications from Foreign Organizations

Not Applicable

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: Data Sharing Plan.

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 NIA, 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.

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

Applications will be assigned to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the National Advisory Council on Aging.

. 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

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.htmlhttps://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.htmlor 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:

• Defining the scientific objectives and approaches for the project, including research design and study protocol development, data collection, quality control, and interim data and safety monitoring, as well as analysis and publication of results.
• Accountability to the applicant organization officials and to NIA for the performance and proper conduct of the research supported by the U01 mechanism in accordance with the terms and conditions that are stated in this FOA.
• Developing practices for data sharing and collaborative arrangements with other awardees supported through this FOA.

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.

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

A designated NIA Program staff member serving as Project Scientist will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards in coordinating and facilitating interactive and collaborative activities of the awardees, including developing agendas for annual meetings, exploring possibilities for developing common data formats, and establishing shared data resources and public data resources, including awardees' results.

Additionally, an NIA Program Director acting as Program Official will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.

Areas of Joint Responsibility include:

Research Governing Body:

A Steering Committee (SC) will serve as the main governing body for the planning projects and will be chaired by the PD(s)/PI(s). The leadership of the planning project and a designated NIA Project Scientist will comprise the voting members of the SC, with each having one vote. The SC will meet regularly to review and monitor progress, plan research activities, and establish priorities. Meetings may occur as regularly scheduled teleconferences/videoconferences and must include at least one in-person meeting each year in the Bethesda, MD area. The PD(s)/PI(s) will be responsible for scheduling the meetings, as well as preparing and archiving concise meeting minutes from teleconferences/videoconferences and in-person meetings. The meeting minutes will be distributed to the NIA Program Office and to research team members within one week of the meeting.

External Advisory Board:

Awardees may elect to have an External Advisory Board that can provide guidance to the project as needed, with subject matter expertise to supplement or complement the areas of expertise of the research team members. This information should be included in the Approach section of the Research Strategy. The application should identify the expertise appropriate for the Advisory Board and the number of members

Applications should NOT recommend individuals or provide biographical sketches of proposed Advisory Board members.

Dispute Resolution:

3. Reporting

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 agreementsare 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

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]

Giovanna Zappal , Ph.D., MPH
National Institute on Aging (NIA)
Telephone: 301-827-6240
Email: [email protected]

Ramesh Vemuri, Ph.D.
National Institute on Aging (NIA)
Telephone: 301-402-7700
Email: [email protected]

Megan Hancock
National Institute on Aging (NIA)
Telephone: 301-827-6335
Email:[email protected]

Section VIII. Other Information