Participating Organization(s)	National Institutes of Health (NIH)
Components of Participating Organizations	National Institute of Mental Health (NIMH) Office of Dietary Supplements (ODS)
Funding Opportunity Title	Translational Research for the Development of Novel Interventions for Mental Disorders (R21/R33)
Activity Code	R21/R33 Phased Innovation Award
Announcement Type	New
Related Notices	May 30, 2013 (NOT-OD-13-074) - NIH to Require Use of Updated Electronic Application Forms for Due Dates on or after September 25, 2013. Forms-C applications are required for due dates on or after September 25, 2013. April 22, 2011 - See Notice NOT-MH-11-004 The National Institute of Mental Health (NIMH) will hold a pre-application webinar for this FOA.
Funding Opportunity Announcement (FOA) Number	PAR-11-177
Companion FOA	None
Number of Applications	See Section III. 3. Additional Information on Eligibility.
Catalog of Federal Domestic Assistance (CFDA) Number(s)	93.242
FOA Purpose	This funding opportunity announcement (FOA) encourages Exploratory/Developmental Phased Innovation (R21/R33) grant applications to speed the translation of emerging findings on the neuroscience of mental disorders into novel intervention approaches that will ultimately reduce symptoms and/or restore function. This FOA provides support for up to two years (R21 phase) for preliminary, proof-of-principle studies in human participants, followed by up to 3 years of support (R33 phase) for pilot studies to assess the implementation of the intervention, and evaluate the feasibility of conducting a larger trial to assess the efficacy of the intervention. A range of non-pharmacologic treatment approaches will be accepted, including those based on neurophysiological, cognitive, affective, and/or social neuroscience models, basic behavioral science, and neurodevelopmental models. Applications submitted in response to this FOA must involve novel treatment targets, and/or novel and highly innovative approaches to engage and modify known targets.

Posted Date	March 24, 2011
Open Date (Earliest Submission Date)	May 16, 2011
Letter of Intent Due Date	30 days prior to application due date
Application Due Date(s)	Standard dates apply, by 5:00 PM local time of applicant organization.
AIDS Application Due Date(s)	Standard dates apply, by 5:00 PM local time of applicant organization.
Scientific Merit Review	Standard dates
Advisory Council Review	Standard dates
Earliest Start Date(s)	Standard dates
Expiration Date	May 8, 2014
Due Dates for E.O. 12372	Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in the SF 424 (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

The NIMH Strategic Plan calls for the development of new or improved interventions for people with mental disorders. This FOA addresses Strategy 3.1 of the NIMH Strategic Plan: Further develop innovative interventions and designs for intervention studies.

The National Advisory Mental Health Council's (NAMHC) workgroup report, From Discovery to Cure: Accelerating the Development of New and Personalized Interventions for Mental Illnesses, recognizes the gap between advances in understanding the neural circuitry and neurobiological mechanisms underlying mental disorders, and the development of novel interventions, and suggests strategies for facilitating the development of novel interventions in order to meet this need.

This FOA addresses a specific gap in intervention development research at NIMH: the translation of neurobiological and neurobehavioral science findings into novel psychosocial (e.g., cognitive strategies and innovative behavioral approaches) and other non-pharmacologic interventions (e.g., brain stimulation, protocols designed to enhance plasticity). Concurrent with an increasing understanding of neural networks associated with mental disorders, there is an increasing appreciation of the role of experience in neurodevelopment, and in the impact at the neural level of cognitive/behavioral and other non-pharmacologic interventions (see the NAMHC Workgroup report, Transformative Neurodevelopmental Research in Mental Illness). Hence, there is great opportunity for translating this emerging knowledge into intervention strategies.

The goal of this FOA is to speed the translation of emerging findings on the neuroscience of mental disorders into novel intervention approaches that will ultimately reduce symptoms and/or restore function. The FOA encourages novel approaches to intervention based on prior basic research that has identified a neural circuit or other biological mechanism that is clearly associated with a symptom or functional process central to mental disorders. Basing their approach on data from biological measures or laboratory tasks that have been previously validated as reflecting neural functioning, investigators will test novel approaches to achieve changes in relevant pathological behavior (and, where feasible, the relevant mechanisms). Upon completion, successful projects will have developed a new intervention that is rooted in neuroscience research and will have pilot tested the intervention and demonstrated feasibility for testing in larger-scale efficacy studies.

The NIH Office of Dietary Supplements (ODS) may provide co-funding for applications that meet the criteria of this FOA and fall within the mission of the ODS. The ODS supports research on the mechanisms underlying the effects of dietary supplement use on health and reducing risk of disease, including genetic, molecular, biochemical, cellular, metabolic, or physiologic mechanisms. With this FOA, the ODS seeks to support research that tests the effects of biologically active components or constituents of foods and dietary supplements on mental disorders through their effect on novel treatment targets and/or mechanisms.

The focus of this FOA is on the early phases of intervention development, during which basic research is translated into clinical application and novel interventions are first tested in a clinical population. Applications submitted in response to this FOA will propose a biologically-informed, novel approach to engage and alter a functional treatment target at the level of behaviors (e.g., skills training), patterns of thinking (e.g., cognitive reappraisal), cognitive/affective processes (e.g., cognitive control, stress regulation), or clinical elements of psychopathology (e.g., anhedonia, impulsivity). These applications may involve novel treatment targets, or novel and highly innovative approaches to engage and modify known treatment targets.

A range of intervention approaches will be accepted, including those based on cognitive and/or social neuroscience models, basic behavioral science, neurophysiology, and neurodevelopmental models. Brain stimulation protocols that utilize Investigational Device Exemption (IDE)-approved devices (e.g., transcranial magnetic stimulation or transcranial direct current stimulation) will be accepted, alone or in combination with cognitive or behavioral interventions. Interventions utilizing dietary supplements or other bioactive ingredients (biologically active components or constituents of foods) will be accepted if the application aims to demonstrate an effect on a novel treatment target, or if the intervention is a novel approach to altering a known treatment target. For combination treatment approaches, at least one component must be a novel application that requires proof-of-principle and preliminary development compatible with the R21 phase of the R21/R33 mechanism (described in more detail below).

This FOA encourages highly innovative projects with the recognition that such projects may entail a greater level of risk of failing to produce the expected results than is typically supported by NIMH grants. This FOA uses a phased approach (R21/R33), which manages risk by requiring a demonstration of proof-of-principle before moving into a pilot clinical trial. The phased approach also facilitates more rapid translation by moving promising intervention approaches into pilot studies without requiring an additional grant application and peer review. Cross-disciplinary research teams may be necessary for successful translation of basic science to clinical application. Applicants are encouraged to leverage existing resources and infrastructure such as those provided by institutions with Clinical and Translational Science Awards (CTSAs) and/or other existing consortia/networks to promote efficient cross-disciplinary collaborations. NIMH is particularly interested in the development of strategies to pre-empt or arrest disease progression associated with biological risk/vulnerability, prevent relapse, or restore function by targeting intermediate phenotypes or domains of functioning such as those reflected in Research Domain Criteria (RDOC) constructs, as well as interventions that are informed by individual variability in biological or clinical features.

Although the R21/R33 mechanism does not require extensive preliminary data, successful applications will propose a theoretically-justified model of the mechanism involved in triggering or maintaining the disorder, and a scientific rationale for the proposed treatment target(s) and intervention approach. Investigators will be expected to include assessment of the relevant pathway(s) of treatment response, using neurophysiological measures (e.g., neuroimaging) or laboratory tasks that have been previously validated as reflecting underlying pathophysiology (e.g., the anterior network task to reflect effortful control in the anterior cingulate) or intermediate phenotypes previously shown to be associated with a clinical feature or symptom (e.g., eye tracking as a measure of attention). Investigators are encouraged to employ assessments at multiple levels to contribute data towards validation of the theoretical model. For example, a behavioral intervention may have a biological impact at a neurophysiological or circuit level that mediates its treatment response; assessments at the biological and behavioral levels will contribute to a model of the mechanism of treatment effects. Sensitive objective measures of treatment response, as well as potential mediators and moderators, may be piloted during the R21 and/or R33 phases, in preparation for including such measures in a larger efficacy trial.

This FOA provides support for up to two years (R21 phase) for preliminary, proof-of-principle studies in human participants, followed by up to three years of support (R33 phase) for pilot studies to evaluate feasibility and tolerability of the novel intervention. Appropriate activities for the R21 phase may include identification of optimal parameters of the intervention to demonstrate change in the treatment target and/or mechanism; determination of optimal dose (e.g., level of intensity, frequency and duration of session); pilot measures to demonstrate sensitivity to change in the target or hypothesized mechanism; determination of whether novel interventions engage the same biological mechanisms in humans as has been previously demonstrated in model systems. The applicant must justify the need for the R21 phase. Applications using only the R21 mechanism or only the R33 mechanism will not be accepted under this FOA.

Funding for the R33 phase is contingent on successful completion of the R21 phase. See Section IV.6., Specific Instructions for Preparing a Combined R21/R33 Phased Innovation Award Application for information regarding the reporting of progress and completion of R21 milestones.

The R33 phase is expected to be a pilot study, the results of which will inform the design and implementation of a larger scale efficacy study of promising interventions. Activities appropriate for the R33 phase may include evaluation of the feasibility of recruitment, randomization, retention, assessment procedures, reporting of adverse events, further piloting of assessment procedures, and implementation of the intervention. Pilot studies are not expected to be sufficiently powered to test efficacy, and inferential statistical tests are not expected at this phase in intervention development.

In most cases, data sharing is not expected at this stage of intervention development (see Section 4.2, Resource Sharing, for exceptions). However, a future efficacy trial may be subject to NIH data sharing expectations; therefore, data collection, data description and data management procedures should be designed and piloted in the R33 phase with future data sharing in mind (e.g., development of a data dictionary, data quality assurance procedures, language in consent forms).

The goal of this FOA is to facilitate the efficient translation of emerging neuroscience findings into novel intervention approaches for mental disorders across the lifespan. NIMH will accept a higher level of risk to attract high innovation, and anticipates that results from these studies will test and inform knowledge of mechanisms underlying mental disorders and treatment response. To this end, applications are expected to:

• Propose a novel intervention with a rationale grounded in scientific findings that is ready for early-phase testing in patients.
• Provide a rationale for the need for additional preliminary, proof-of-principle studies (R21 phase) prior to pilot testing (R33 phase).
• Focus on objectively-measured impairing functions or symptoms of mental disorders (e.g., attentional bias, interpretive bias, worry) via their underlying neurobiology (e.g., fear circuit activation, hypothalamic-pituitary-adrenal [HPA] axis activity).
• Incorporate and validate sensitive measures with which to assay and monitor neural, behavioral, and/or cognitive changes (target engagement) and their impact on functioning.
• Employ measures of the clinical dimension or construct being targeted and the hypothesized pathway (e.g., a genetic abnormality, circuit activity, neuroplasticity, cognitive deficit), to test the hypothesis that the intervention targets a specific mechanism.
• Consider potential moderators of treatment response, including age, sex, severity, stage of illness, and the potential impact of such moderators on the biological and functional targets.

Highest priority will be given to meritorious applications with the potential to address an unmet therapeutic need. Examples of areas of interest include, but are not limited to:

• Interventions that reduce deficits and/or restore function in clinical dimensions common across disorders, e.g., social cognition and/or impairments in social/interpersonal functioning, poor emotion regulation, deficient cognitive control. Or innovative improvements in strategies that might be accomplished with greater precision in the pathway/circuit being targeted, or augmentation strategies to increase plasticity.
• Novel interventions for mental disorders across the lifespan, or pre-emptive intervention strategies for individuals who are at high risk for serious mental illness. Highest priority will be given to applications that focus on ages or stages of illness for which current interventions are non-existent or inadequate.
• Interventions that improve functional outcomes for children, youth, and adults with chronic, significantly-impairing mental disorders, including autism, schizophrenia, bipolar disorder, and attention deficit hyperactivity disorder.
• Interventions to prevent suicidality in at-risk populations.

This FOA does not support adaptations of existing interventions for the same target in a different patient population, unless a strong scientific rationale is made for the innovation of the adaptation, and the need for extensive preliminary proof-of-principle data necessitating the R21 phase. Other mechanisms are available for pilot studies of interventions for which early conceptual and proof-of-principle work has been completed (PAR-09-173, Pilot Interventions and Services Research Grants; PA-09-075, Collaborative R34s for Pilot Studies of Innovative Treatments in Mental Disorders).

This FOA does not support research aimed at examining the neurobiological mechanisms of existing interventions on established targets. This FOA does not support research aimed at testing novel pharmacological approaches either alone or in combination with other treatment strategies. For these types of studies, applicants should consider the R34 FOAs for pilot studies noted above or the Research Project Grant (Parent R01)

Funding Instrument	Grant
Application Types Allowed	New Resubmission Revisions The OER Glossary and the SF 424 (R&R) Application Guide provide details on these application types.
Funds Available and Anticipated Number of Awards	The NIMH intends to commit approximately $2,000,000 in FY 2012 to fund up to 8 awards in response to this FOA. Future year amounts will depend on annual appropriations..
Award Budget	The R21 phase may not exceed two years or $325,000 in direct costs, with no more than $225,000 in direct costs in any single year of the R21 phase. The R33 phase may not exceed three years or $525,000 in direct costs, with no more than $250,000 in direct costs in any single year of the R33 phase.
Award Project Period	Scope of the proposed project should determine the project period. The maximum period is 5 years.

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:

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

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 Organizations)

Foreign (non-U.S.) components of U.S. Organizations are allowed.

Applicant organizations must complete the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. Applicants must have a valid Dun and Bradstreet Universal Numbering System (DUNS) number in order to begin each of the following registrations.

• Central Contractor Registration (CCR) must maintain an active registration, to be renewed at least annually
• Grants.gov
• eRA Commons

All Program Directors/Principal Investigators (PD/PIs) must also work with their institutional officials to register with the eRA Commons or ensure their existing eRA Commons account is affiliated with the eRA Commons account of the applicant organization.

All registrations must be completed by the application due date. Applicant organizations are strongly encouraged to start the registration process at least four (4) weeks prior to the application due date.

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director/Principal Investigator (PD/PI) 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 SF 424 (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.

NIH will not accept any application in response to this FOA that is essentially the same as one currently pending initial peer review unless the applicant withdraws the pending application. NIH will not accept any application that is essentially the same as one already reviewed. Resubmission applications may be submitted, according to the NIH Policy on Resubmission Applications from the SF 424 (R&R) Application Guide.

Applicants must download the SF424 (R&R) application package associated with this funding opportunity using the Apply for Grant Electronically button in this FOA or following the directions provided at Grants.gov.

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, 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.

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 research
Name, address, and telephone number of the PD(s)/PI(s)
Names of other key personnel
Participating institutions
Number and title of this funding opportunity

The letter of intent should be sent to:

Ann Wagner, Ph.D.
Division of Developmental Translational Research
National Institute of Mental Health
6001 executive boulevard, Room 6184, MSC 9617
Bethesda, MD 20892-9617
Rockville, MD 20852 (for express/courier service)
Email: awagner@mail.nih.gov

The forms package associated with this FOA includes all applicable components, mandatory and optional. Please note that some components marked optional in the application package are required for application submission. Follow all instructions in the SF424 (R&R) Application Guide to ensure you complete all appropriate optional components.

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

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

Resource Sharing Plan

Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS)) as provided in the SF424 (R&R) Application Guide, with the following modifications:

• Sharing Human Data: In order to advance the program goal of widespread data sharing, investigators funded under this FOA are expected to share those data through a broadly accessible database. For example, data from humans for Autism Spectrum Disorders related research are expected to be shared via the National Database for Autism Research (NDAR).

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.

Foreign (non-US) organizations must follow policies described in the NIH Grants Policy Statement, and procedures for foreign organizations described throughout the SF424 (R&R) Application Guide.

Part I. Overview Information contains information about Key Dates. Applicants are encouraged to submit in advance of the deadline to ensure they have time to make any application corrections that might be necessary for successful submission.

Organizations must submit applications via 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.

Applicants are responsible for viewing their application 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 SF 424 (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.

Important reminders:
All PD/PIs must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF 424(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.

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 Central Contractor Registration (CCR). 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 by the Center for Scientific Review, NIH. Applications that are incomplete will not be reviewed.

In order to expedite review, applicants are requested to notify the NIMH Referral Office by email at nimhreferral@mail.nih.gov when the application has been submitted. Please include the FOA number and title, PD/PI name, and title of the application.

• The R21/R33 Phased Innovation Award application must be submitted as a single application with one PHS398 Cover Page Supplement component and one Research & Related Budget component.
• Within the Research Strategy, applicants should describe both the R21 phase and the R33 phase.
• The description of the R21 phase should include milestones that, if met, will justify taking the proposed intervention into a pilot study.
• Description of the R33 phase should include indicators that will be used at the completion of the pilot study to inform whether the intervention is feasible and promising for evaluation of efficacy in a larger clinical trial.
• Indicate in the budget justification whether the budget year is for the R21 phase or the R33 phase.
• The total length of the Research Strategy section cannot exceed 12 pages including milestones, tables, graphs, figures, diagrams, and charts.
• The Introduction (for resubmissions only) is limited to 1 page.

For the R21/R33 Phased Innovation Award application, the initial review group will evaluate the specific goals for each phase and the milestones that would justify expansion to the R33 phase. A single impact/priority score will be assigned to each discussed application. For the R21/R33 application the initial review group may recommend that only the R21 phase be supported, based on concerns related to the application’s specific goals and the feasibility milestones justifying the expansion to the R33 phase. A recommendation to delete the R33 phase by the review panel or presentation of inadequate milestones in the application may affect the merit rating of the application.

The milestones proposed in the application should be well described, quantifiable, and scientifically justified to allow program staff to assess progress in the R21 phase. The milestones should also provide data that will demonstrate sufficient potential for clinical application to justify proceeding to a pilot intervention study (the R33 phase), including demonstration that the intervention engages and alters the target at the level of circuits, behaviors, cognitive/affective processes, or clinical elements of psychopathology. The milestones will be considered in evaluating the approach proposed by the investigator. A discussion of the milestones relative to the progress of the R21 phase and the implications of successful completion of the milestones for a pilot study should be included. Applications lacking this information, as determined by the NIMH staff, will not be reviewed.

The description of the R33 phase should include concrete indicators of feasibility of taking the proposed intervention to a larger clinical trial of efficacy, and how these indicators will be used to inform the next phase of intervention development. Appropriate indicators may include, but are not limited to, a predetermined number of sessions attended, completion of activities outside of the clinic ("homework"), demonstration that assessment instruments are sensitive to change in the treatment target or symptom, measures of patient satisfaction, reports of adverse events. These are examples only; goals and feasibility milestones/indicators must be specific to the proposed intervention.

The clarity and completeness of the R21/R33 application with regard to specific goals and feasibility milestones/indicators are critical.

Prior to funding an application, the Program Officer will contact the applicant to discuss the proposed milestones and any changes suggested by the review panel as indicated in the Summary Statement. The Program Officer and the applicant will negotiate and agree on a final set of R21 milestones. These will be the basis for judging the success of the R21 work. For funded applications, the Project Director/Principal Investigator (PD/PI) will submit a progress report to the Program Officer upon completion of the R21 milestones. Receipt of this progress report will trigger an administrative program review that will determine whether or not the R33 should be awarded. The release of R33 funds will be based on successful completion of negotiated scientific milestones, on program priorities, and on the availability of funds. In addition, the final report for the R33 should include indicators of feasibility of taking the proposed intervention to a larger clinical trial of efficacy.

The R21 and R33 cannot be funded in the same fiscal year..

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-10-115..

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.

The R21/R33 grant supports exploratory/developmental investigation of novel scientific ideas and strategies that have the potential for significant improvements in prevention or treatment of mental disorders. The R21/R33 grant application need not have extensive background material or preliminary information. Accordingly, reviewers will focus their evaluation on the conceptual framework, the level of innovation, and the potential to significantly impact the outcomes and functioning of individuals with mental disorders, or those at high risk for mental disorders. Appropriate justification for the proposed work can be provided through literature citations, data from other sources, or, when available, from investigator-generated data. Preliminary data are not required for R21/R33 applications; however, they may be included if available..

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

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

Significance

Does the project address an important problem or a critical barrier to progress in the field? 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? Does the intervention strategy fill an important need or gap in our armamentarium of interventions for mental disorders? Does the intervention approach hold promise for altering a symptom or domain of function that is commonly disrupted in mental disorders? Does the proposed intervention hold promise for altering illness trajectories? Does the intervention approach hold promise of being utilized in clinical practice?

Investigator(s)

Are the PD/PIs, collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, or 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? Does the research team, as a whole, provide expertise in the areas of neuroscience and interventions research relevant to the proposed line of research? Is there sufficient methodological and statistical involvement to assure that the findings will be interpretable?

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? Does the intervention proposed involve a novel treatment target, or a novel and highly innovative approach to engage and modify a known target? Does the intervention approach offer potential for having high clinical influence, e.g., by stimulating new, even groundbreaking, intervention approaches or dramatically improving patient functioning?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? 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?

If the project involves clinical research, are the plans for 1) protection of human subjects from research risks, and 2) inclusion of minorities and members of both sexes/genders, as well as the inclusion of children, justified in terms of the scientific goals and research strategy proposed? Is the rationale for the proposed targets and intervention approach grounded in scientific findings and based on a well-articulated theoretical model?

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?

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/priority score, but will not give separate scores for these items.

Is there adequate justification for the need for the preliminary work proposed in the R21 phase? Are the R21 and R33 phases clearly described and integrated? Does the work proposed for the R21 phase provide a solid foundation for the R33 phase? Are the milestones well described, quantifiable, and scientifically justified? Do the aims of the R33 phase provide the foundation for conducting a larger (e.g., R01) study of the efficacy of the intervention?

Protections for Human Subjects

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 Human Subjects Protection and Inclusion Guidelines.

Inclusion of Women, Minorities, and Children

When the proposed project involves clinical research, the committee will evaluate the proposed plans for inclusion of minorities and members of both genders, as well as the inclusion of children. For additional information on review of the Inclusion section, please refer to the Human Subjects Protection and Inclusion Guidelines.

Vertebrate Animals

Not Applicable.

Biohazards

Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.

Resubmissions

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

Renewals

Not Applicable.

Revisions

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

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

Applications from Foreign Organizations

Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.

Select Agent Research

Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Resource Sharing Plans

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: 1) Data Sharing Plan; 2) Sharing Model Organisms; and 3) Genome Wide Association Studies (GWAS).

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.

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by the NIMH, in accordance with NIH peer review policy and procedures, using the stated review criteria. Review assignments 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/priority 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 Mental Health Council. The following will be considered in making funding decisions:

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

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.

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 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 the DUNS, CCR Registration, and Transparency Act requirements as noted on the Award Conditions and Information for NIH Grants website.

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.

Cooperative Agreement Terms and Conditions of Award

Not Applicable.

See Section IV.6 - Specific Instructions for Preparing a Combined R21/R33 Phased Innovation Award Application, for additional reporting requirements related to the R21/R33 mechanism.

When multiple years are involved, awardees will be required to submit the Non-Competing Continuation Grant Progress Report (PHS 2590) annually and financial statements as required in the NIH Grants Policy Statement.

A final progress report, invention statement, and Financial Status Report are required when an award is relinquished when a recipient changes institutions or when an award is terminated.

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.

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

Investigators are strongly encouraged to contact the Scientific/Research Contact listed below to discuss the relevance of the proposed study to the Institute's priorities, and its appropriateness for the R21/R33 funding mechanism.

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

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone 301-710-0267
TTY 301-451-5936
Email: GrantsInfo@nih.gov

eRA Commons Help Desk(Questions regarding eRA Commons registration, tracking application status, post submission issues)
Phone: 301-402-7469 or 866-504-9552 (Toll Free)
TTY: 301-451-5939
Email: commons@od.nih.gov

Ann Wagner, Ph.D.
National Institute of Mental Health
Telephone: (301) 443-5944
Email: awagner@mail.nih.gov

Rebecca Costello, Ph.D., F.A.C.N.
Office of Dietary Supplements
Telephone: 301-435-3605
Email: costellb@od.nih.gov

David Armstrong, Ph.D.
National Institute of Mental Health
Telephone: (301) 443-3534
Email: armstrda@mail.nih.gov.

Joy Knipple
National Institute of Mental Health
Telephone: (301)443-8811
Email: knipplej@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 Parts 74 and 92.