It is critical that applicants follow the Research (R) Instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

Part 1. Overview Information
Part 2. Full Text of the Announcement

Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

Current evidence indicates that interventions provided simultaneously at several levels across the Socio-Ecological Model are most likely to be successful in achieving increases in physical activity. The socioecological model of behavior change provides a framework for understanding the interactive effects of factors that determine behaviors, including physical activity. There are five nested levels of the socioecological model: individual, interpersonal, organizational, community, and policy. The individual level encompasses characteristics of an individual that influence behavior change; the interpersonal level includes formal and informal social networks; the organizational level includes organizations and social institutions; the community level refers to relationships among organizations and the built environment; and the policy level includes local, state, and national laws and policies that can impact individual behavior.

Therefore, this Funding Opportunity Announcement (FOA) encourages innovative research to improve our understanding of how to increase and maintain health-enhancing physical activity using multi-level interventions. Applicants should use the Socio-Ecological Model as a framework and should test multi-level interventions targeting at least two levels of the model. Interventions to be tested should seek to increase participants' progression toward achieving the physical activity recommendation appropriate to the participants' health, abilities, and conditions. This FOA also seeks studies that address a wide range of population groups across the lifespan (e.g., racial and ethnic minorities, children, older adults, persons with medical conditions or addictive disorders, and persons with disabilities). Investigators are encouraged to build on prior research to refine evidence-based physical activity interventions and to make use of innovative partnerships within and across sectors as needed to study the implementation and outcomes of the proposed intervention.

This FOA is meant to support developmental work in preparation for a full-scale efficacy study. The R21 phase will support formative assessments and preliminary feasibility studies of the multi-level intervention or intervention components. If the R21 phase milestones are met, the R33 phase will support expanded feasibility work and optimization of the multi-level intervention in preparation for a fully-powered efficacy study. For studies that are ready to implement, test, and evaluate scalable multi-level interventions, please see the companion Research Project Grant (R01) PAR-18-324.

Physical activity is an important health behavior that is associated with numerous health conditions and outcomes. The Physical Activity Guidelines for Americans show that moderate-vigorous physical activity in adults is associated with many health benefits. Despite the well-recognized benefits of physical activity and the myriad of health conditions that physical activity affects, the proportion of people in the United States that engages in a level of physical activity that can promote their health is far less than desired, with only one in five U.S. adults meeting the overall 2008 Physical Activity Guidelines for Americans.

A key conclusion from a 2012 trans-NIH workshop on research priorities for physical activity and disease prevention and other subsequent reports is the need for research that moves beyond individual and single-level interventions to incorporate action at a higher level, such as environments, organizations and communities. Since that time, the Surgeon General released a report "Step it Up: The Surgeon General's Call to Action to Promote Walking and Walkable Communities," which included a call for evaluating community intervention to promote walking and walkability. In addition, the Center for Disease Control's Community Preventive Services Task Force has also issued a number of insufficient evidence statements and positive recommendations that highlight future research needs for physical activity programs that target schools, families, workplaces, and built environments.

This FOA seeks applications to develop multi-level interventions that are designed to increase physical activity or reduce sedentary behavior among specific populations, and are based well-established theory and existing data. Given the strong evidence that physical activity and limited sedentary time are associated with many health benefits, the proposed intervention must include physical activity change as a primary outcome.

Applicants are encouraged to use the Socio-Ecological Model as a framework for conceptualizing ways to develop a multilevel intervention (i.e. incorporating intervention targets at the intrapersonal, interpersonal, organizational, community, and/or public policy levels). For example, an intervention might include pedometer-based challenges at the interpersonal level, as well as the initiation/strengthening of joint-use agreements for community members to use school recreation facilities at the public policy level. A different intervention might focus on methods for enhancing motivation at the intrapersonal level and creating online social support groups for physical activity at the interpersonal level. Policy or built environmental intervention across worksites at an organizational level may be paired with individually targeted intervention components to promote physical activity. There are many ways for an intervention to qualify as multilevel.

Settings for the interventions can include but are not limited to healthcare settings, worksites, households, schools, green space, parks and recreation centers, other community organizations and settings, or entire communities.

Specific interventions incorporated into their application should be justified by the population group of interest and the suitability and tailoring of the intervention, physical activity goals, and measures for the target population. Investigators should pay close attention to the quality of measurement of physical activity and/ or factors influencing physical activity at the individual and other levels, ensuring that the measures are reliable and sensitive to change. Using intervention components with previously developed tools is encouraged.

Investigators are encouraged to address how specific intervention(s) selected at each level will reinforce each other to potentiate a large effect for the overall intervention(s). To clarify how interventions are related, investigators are encouraged to develop a graphic representation of the overall logic model for the proposed study. To facilitate more complete understanding of the logistics of the intervention(s), investigators are also encouraged to develop a graphic representation of the timeline for the intervention and associated measurements.

Investigators may consider collecting qualitative data (e.g., focus group discussions, semi-structured interviews) to better assess fit and capture adaptation within the context in which the intervention is being tested and implemented. Investigators should also consider collecting data on intervention processes and outcomes as well as implementation processes and outcomes.

Physical activity must be one of the outcome measures for an application to be appropriate for these FOAs. While R21/R33 applications must address physical activity change, they are not required to have sample sizes sufficient to measure statistically significant changes in physical activity or related health outcomes. In these developmental or pilot interventions, physical activity should be measured, but with the goal of assessing feasibility and acceptability of the physical activity measurement tool and its administration, such as timing, frequency of measurement, response rate or other issues.

For all applications, the intervention and any comparison/control group should use appropriate and well-justified physical activity measures to enable proper comparisons that are also feasible in real world settings. Measurement of intervention processes and impacts is also encouraged to enable assessment of intervention fidelity and whether hypothesized mediators were affected. For R21/R33 applications, tests of the effects of the intervention on behavioral mediators and/or intermediate outcomes of physical activity change can be used to enable the identification of components of the intervention that appear most promising to investigate in an efficacy study, provided the study is appropriately powered to analyze these indicator variables.

Studies in any age group and special population, including populations at high risk for sedentary behavior, are appropriate for this announcement. Populations of interest include, but are not limited to:

• Healthy but sedentary or inactive individuals
• Persons or groups at high risk for a particular disease or condition (e.g. substance use disorder or nicotine dependence) that can be improved by physical activity
• Persons with an existing disease or condition (e.g., cardiovascular disease, obesity, cancer, or diabetes or Alzheimer's or related dementias) whose outcomes could be improved by physical activity
• Where the population of interest is those with obesity or overweight, the intervention should principally aim to improve physical activity and/or reduce sedentary behavior rather than weight loss as the primary aim.
• Persons of diverse socioeconomic, ethnic, and racial groups with low activity levels
• Persons with physical, developmental, or intellectual disabilities who may need special approaches for activity promotion
• Inactive or sedentary elderly individuals or groups
• Alzheimer's and related dementias
• Minority and underserved populations at higher risk for conditions associated with inactivity
• Other groups, if justified by the investigator
• Comparison of male and female populations or subjects on the desired outcome is highly desired

It is anticipated that each award will support multidisciplinary project teams composed of scientists with expertise to enable all the specific aims to be addressed.

Due to the phased nature of this R21/R33 award, applications should propose to conduct formative assessments and feasibility studies in the R21 phase with possible transition to expanded research support in the R33 phase in order to optimize the multi-level intervention and/or conduct larger-scale feasibility studies in preparation for a powered efficacy study. Planning activities and feasibility studies can include studies utilizing systems science to develop new intervention models based on analyzing key upstream influences, fractional factorial designs that identify promising intervention components, studies testing adaptive interventions that change during the course of the study, or other innovative and state-of-the art approaches to developmental work. Novel approaches based on clinical experience that are well-justified will also be considered. Multiple research designs are appropriate for this FOA, and the choice will depend on the stage of development of the research, the research question, and whether randomization is possible. Investigators should propose the strongest study design that can evaluate the effects of the intervention program with high internal validity, taking into account external validity and generalizability. Interventions that are ready for efficacy testing should apply to the companion Research Project Grant (R01) PAR-17-315.

Examples of research projects that may be appropriate for the R21 phase include but are not limited to the following:

• Qualitative or mixed-methods approaches to determine acceptability and refine intervention components
• Assessment of adherence to dose, frequency and/or duration of intervention components
• Feasibility study of a single-level intervention with measurement of contextual factors operating at another level of the socioecological model to inform the design of a multi-level intervention in the R33 phase
• Separate feasibility studies for each level or component of the proposed multi-level intervention
• Single site feasibility study for the combined multi-level intervention

Examples of research projects that may be appropriate for the R33 phase include but are not limited to the following:

• Larger scale feasibility study of the combined multi-level intervention
• Multi-site feasibility study of the multi-level intervention to assess fidelity of implementation
• Assessment of the effect of the multi-level intervention on hypothesized mediators of physical activity change
• Optimization of the multi-level intervention

ODP: The Office of Disease Prevention is interested in co-funding applications for multi-level physical activity interventions that have strong implications for disease prevention, promise for wider uptake, and that showcase innovative and appropriate design, measurement, and analysis methods.

NCI: The National Cancer Institute is interested in applications of multi-level physical activity interventions that have implications for outcomes across the cancer continuum and that have the potential for adoption, implementation, and sustainability in real-world settings.

NIA: A strategic research goal of NIA is to develop effective interventions to maintain health, well-being, and function and prevent or reduce the burden of age-related diseases, disorders, and disabilities. Sub-categories include developing efficacious and cost-effective strategies for promoting and ensuring adherence to healthy and safe behaviors among older adults and developing interventions for treating, preventing, or delaying the onset of age-related diseases and conditions.

NIAAA: The National Institute on Alcohol Abuse and Alcoholism is particularly interested in research activities which increase the understanding of the role physical activity plays in alcohol use behaviors. More specifically the possible co-benefits of physical activity on alcohol use behaviors.

NIDA: NIDA's strategic priorities are devoted to research that advance science on the causes and consequences of drug use and addiction, and to apply that knowledge to improve more efficacious and effective prevention and treatment interventions that can ultimately reduce the negative impact of drug use (ranging from problem use to addiction). NIDA Strategic Plan is available at https://www.drugabuse.gov/about-nida/2016-2020-nida-strategic-plan

NCCIH: The National Center for Complementary and Integrative Health has a strategic research goal to study complementary health approaches to promote health and wellness across the lifespan in diverse populations. NCCIH's strategic plan is available at: https://nccih.nih.gov/about/strategic-plans/2016. For this FOA, NCCIH is particularly interested in applications that propose to incorporate a mind-body intervention as part of the multi-level intervention for promoting physical activity. NCCIH will not support research proposing efficacy or effectiveness clinical trials with this mechanism. Investigators are strongly encouraged to discuss their research plans with NCCIH program staff prior to submitting their application.

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

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

Higher Education Institutions

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

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

o Hispanic-serving Institutions

o Historically Black Colleges and Universities (HBCUs)

o Tribally Controlled Colleges and Universities (TCCUs)

o Alaska Native and Native Hawaiian Serving Institutions

o Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Governments

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

Other

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

Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are not allowed.

Applicant Organizations

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

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

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

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

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

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

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

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

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

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

Individuals involved in NIH-funded clinical trials must meet the requirements for documented ICH-Good Clinical Practice (GCP) training. Documented means GCP training that provides a certification/documentation of completion indicating that the training requirement has been successfully completed.

Appropriate personnel are those individuals responsible for the design or conduct of the study, including all personnel of participating consortia and performance sites participating in the clinical trial. The description of GCP training for new key personnel or GCP refresher training for other personnel should be part of the progress report submitted as a prerequisite to award. GCP refresher training should occur every 3 years for the length of the trial.

Buttons to access the online ASSIST system or to download application forms 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.

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

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

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

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

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

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

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

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

All instructions in the SF424 (R&R) Application Guide must be followed. Application budgets must include funds for two investigators from each grant to attend one meeting of grantees, to be held in the Washington, DC area.

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

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

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

Specific Aims: Applicants must provide a single attachment of Specific Aims to include both the R21 and R33 phases.

In preparing the R21/R33 application, investigators should consider that the application will be assigned a single overall impact score. Thus, clarity and completeness of the application with regard to specific goals and the feasibility of each phase and the Milestones are critical. The Research Strategy should include:

Separate sections that describe both the R21 and R33 phases, as appropriate. Information or details that are described in the R21 section should not be repeated in the R33 section.

Transition Milestones for the R21 Phase: Transition Milestones should be placed at the end of the R21 Research Strategy section and are included in the page limit. The Transition Milestone section must propose milestones for completion of the R21 part of the project, a discussion of the suitability of the proposed milestones for assessing success in the R21 phase, and a discussion of the implications of successful completion of these milestones for the proposed R33 study. Transition Milestones should be well-defined, specific, quantifiable and scientifically justified; they should not be simply a restatement of the R21 specific aims. Milestones may be provided for the R33 phase at the discretion of the applicant. Transition Milestones should be sufficiently rigorous scientifically to be valid for assessing progress in the R21 phase. Any available preliminary data that will support or justify the proposed hypothesis, rationale or development plan may be included. However, preliminary data are not required for an R21/R33 application.

Investigators should describe the strongest study design that can evaluate the effects of the intervention program with high internal validity, taking into account external validity and generalizability. In general, this would be a randomized controlled trial (RCT) or a hybrid trial design. Most studies proposed for this announcement may require randomization at the group level (Group Randomized Trial, or GRT) to match the level of intervention and to minimize or prevent contamination of the comparison group. In GRTs, groups of participants are randomized to study conditions and interventions are delivered to members of those groups, often defined by their workplace, school, primary care provider, or other organization entity. Interactions occur among participants in the same group or cluster both pre- and post-randomization. The statistical analysis and power calculations should reflect the design and the implications of the study design choice on the methods required for data analysis and sample size estimation. Standard methods are appropriate for RCTs, but adaptations are required for GRTs to reflect the positive intraclass correlation expected in data obtained from participants in the same groups or clusters. The methods proposed for data analysis and the methods used for sample size calculation should reflect both the extra variation expected in the data and the degrees of freedom available to estimate that extra variation. For more guidance, please visit this resource developed by NIH on GRTs. GRTs are often used for pragmatic trials. R21/R33 applications do not need to be powered to assess differences in physical activity since the goal of this FOA is on developing the multi-level intervention, and not on testing efficacy. If proposing a GRT, applications should be testing the feasibility of group randomization.

In some cases, a randomized design may not be possible or feasible, or would raise ethical concerns that are difficult to address. In such instances, investigators could propose and justify alternative, high-quality study designs. Such designs include, but are not limited to, quasi-experimental designs such as multiple baseline or interrupted time series, regression discontinuity, pre-to-post intervention with external comparison, natural experiments, or others).

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

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

Appendix:

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

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

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

Delayed Onset Study

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

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.

This initiative is not subject to intergovernmental review.

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

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

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

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

For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Guidelines for Applicants Experiencing System Issues. 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, NIH. Applications that are incomplete or non-compliant will not be reviewed.

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

Important Update: See NOT-OD-18-228 for updated review language for due dates on or after January 25, 2019.

Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

For this particular announcement, note the following:

The 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.

The R21/R33 phased innovation grant supports investigation of novel scientific ideas or new interventions, model systems, tools, or technologies that have the potential for significant impact on biomedical or behavioral and social sciences research. An R21/R33 grant application need not have preliminary data, extensive background material or preliminary information; however, they may be included if available. Appropriate justification for the proposed work can be provided through literature citations, data from other sources, or, when available, from investigator-generated data. Accordingly, reviewers will focus their evaluation on the conceptual framework, the level of innovation, and the potential to significantly advance our knowledge or understanding. Reviewers will assign a single impact score for the entire application, which includes both the R21 and R33 phases.

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).

Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

Does the project address an important problem or a critical barrier to progress in the field? Is there a strong scientific premise for the project? 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 proposing 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 heatlh 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?

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 proposing 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?

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 proposing 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?

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the 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 children, justified in terms of the scientific goals and research strategy proposed?

In addition, for applications proposing 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?

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 proposing 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?

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 Design

The committee should evaluate whether or not the study design can evaluate the effects of the intervention program with high internal validity, taking into account external validity and generalizability. If a randomized design is not possible or feasible, or would raise ethical concerns that are difficult to address, reviewers should evaluate whether alternative, high-quality study designs are proposed.

Given that the focus of the R21/R33 is on intervention development and feasibility testing, these applications are not required to have sufficient sample sizes to test effects on physical activity. However, any inferential statistics that are proposed (e.g. to examine changes in intermediate outcomes) should be appropriately powered.

Transition Milestones

Given the critical nature of the milestones for the potential R21 to R33 transition, are the proposed Transition Milestones well-defined with quantifiable measures that are appropriate for assessing the success of the R21 phase of the application? Do the Transition Milestones have specific quantifiable criteria that will enable clear decisions about their attainment? Is it clear how the R33 phase of the study will develop and expand once the R21 Transition Milestones are achieved? Given the potential benefits of the proposed research, do the Transition Milestones support the transition and will the overall project advance the intervention, method, or strategy?

Study Timeline

In addition, for applications proposing 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)?

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

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

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

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.

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

Not Applicable.

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

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

Not Applicable

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).

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).

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.

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

As part of the scientific peer review, all applications:

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

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

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

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

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

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

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

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

Any application awarded in response to this FOA will be subject to 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.

Additionally, ICs may specify any special reporting requirements for the proposed clinical trial to be included under IC-specific terms and conditions in the NoA.

For example: If the proposed clinical trial has elevated risks, ICs may require closer programmatic monitoring and it may be necessary to require the awardee to provide more frequent information and data as a term of the award (e.g., to clarify issues, address and evaluate concerns, provide documentation). All additional communications and information related to programmatic monitoring must be documented and incorporated into the official project file.

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 of all trials

whether required under the law or not. For more information, see http://grants.nih.gov/ClinicalTrials_fdaaa/

Institutional Review Board or Independent Ethics Committee Approval: Grantee institutions must ensure that the application as well as 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).

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

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights 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.

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 http://www.hhs.gov/ocr/civilrights/understanding/section1557/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 http://www.hhs.gov/ocr/civilrights/understanding/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.

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.

Cooperative Agreement Terms and Conditions of Award

Not Applicable

When multiple years are involved, awardees will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

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

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

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

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

eRA Service Desk (Questions regarding ASSIST, eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact Center Telephone: 800-518-4726
Email: support@grants.gov

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-945-7573

Melissa C. Green Parker, Ph.D.
Office of Disease Prevention (ODP)
Telephone: 301-480-1161
Email: melissa.greenparker@nih.gov

Frank Perna, Ed.D., Ph.D.
National Cancer Institute (NCI)
Telephone: 240-276-6782
Email: pernafm@mail.nih.gov

Lyndon Joseph, Ph.D.
National Institute on Aging (NIA)
Telephone: 301-496-6761
Email: josephlj@mail.nih.gov

Beverly A. Ruffin, Ph.D.
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Telephone: 301-443-0281
Email: beverly.ruffin@nih.gov

Will M. Aklin, Ph.D.
National Institute on Drug Abuse (NIDA)
Telephone: 301-827-5909
Email: aklinwm@nida.nih.gov

Lanay Mudd, Ph.D., FACSM
National Center for Complementary and Integrative Health (NCCIH)
Telephone: 301-594-9346
Email: lanay.mudd@nih.gov

Weijia Ni, Ph.D.
Center for Scientific Review (CSR)
Telephone: 301-594-3292
Email: niw@csr.nih.gov

Carol Perry
National Cancer Institute (NCI)
Telephone: 240-276-6282
Email: perryc@mail.nih.gov

Mahasin Ingram
National Institute on Aging (NIA)
Telephone: 310-402-7736
Email: mahasin.ingram@nih.gov

Judy Fox
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Telephone: 301-443-4704
Email: jfox@mail.nih.gov

Diana Haikalis
National Institute on Drug Abuse (NIDA)
Telephone: 301-435-1373
Email: diana.haikalis@nih.gov

Shelley Carow
National Center for Complementary and Integrative Health (NCCIH)
Telephone: 301-594-3788
Email: carows@mail.nih.gov

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

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75.