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

The mission of NIMH is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery and cure. The purpose of this Funding Opportunity Announcement (FOA) is to encourage exploratory (R33) clinical trial grant applications that focus on psychosocial intervention development consistent with the NIMH emphasis on the experimental therapeutic approach for the treatment and prevention of mental disorders in adults and children. In this approach, clinical trials should be designed so that even negative results will provide information to guide further intervention development efforts (http://www.nimh.nih.gov/about/director/2012/experimental-medicine.shtml). The focus of this FOA is on the early phases of intervention development, during which basic research is translated into clinical hypotheses and novel interventions are tested in a clinical population or population at-risk.

This FOA supports the development and testing of innovative psychosocial intervention approaches where the target and/or the intervention strategy is novel. Targets might include, but are not limited to, potentially modifiable behavioral, cognitive, affective and/or interpersonal factors or processes, neural circuits or neural activity subserving specific behaviors or cognitive processes, and/or other neurobiological mechanisms associated with risk for, causation or maintenance of a mental disorder. Eligible psychosocial intervention strategies might include in-person or technology-assisted delivery, provided the target and/or the intervention strategy is novel. This FOA supports the development and testing of novel psychosocial interventions, as defined above, as monotherapies or as augmentations to a standard treatment (which may be psychosocial, pharmacological, neuromodulation, biologic, or other somatic modality).

This FOA provides support for replication, and/or validation of an intervention's engagement with an empirically-supported, measurable intervention target and to assess the relationship between target engagement and changes in functional outcomes or clinical status. Studies must include justification for the target/mechanism based on empirical evidence of disease processes or mechanisms that confer risk, causation, or maintenance of a disorder, and a clear hypothesis about how an intervention directed at changing the target/mechanism can lead to clinical benefit in persons with or at risk for mental disorders.

The intended clinical endpoint will vary with the type of intervention. In the case of preventive interventions, the proximal target might involve a risk factor that has been associated with the etiology or onset of a MH disorder. Accordingly, the intervention's efficacy might be evaluated in terms of whether or not the intervention, mediated by changes in the target, resulted in decreased onset of the MH disorder/condition (i.e., the clinical endpoint). Alternative conceptualizations might propose proximal targets/mechanisms that are intervening variables purported to be instrumental in reducing the risk state itself (i.e., with the clinical endpoint defined in terms of a reduction of risk). Examples might include studies of strategies for modifying an intervening factor hypothesized to be critical for achieving reduction of expressed emotion in families of patients who have experienced psychotic episodes, where high expressed emotion is considered an established risk factor for recurrence of psychosis.

This FOA provides up to 3 years of support for studies to replicate target engagement findings from prior studies, assess the relationship between target engagement and changes in measures of clinical benefit, and examine preliminary signal of efficacy. Results should provide evidence to determine whether further development of the intervention is warranted, and if it is, to inform the design of a subsequent confirmatory efficacy trial. This FOA encourages highly innovative projects, with the recognition that such projects may entail a greater failure rate. NIMH values this early, efficient, and objective testing of an intervention's ability to alter a well-defined and objectively measured target/mechanism to help inform decisions about which interventions should be further developed.

Information about the mission, strategic plan and research interests of the NIMH can be found at the NIMH website (http://www.nimh.nih.gov/) including https://www.nimh.nih.gov/about/strategic-planning-reports/strategic-research-priorities/index.shtml Applicants are also strongly encouraged to review the information on the NIMH website focused on clinical trials https://www.nimh.nih.gov/funding/opportunities-announcements/clinical-trials-foas/index.shtml.

Applications to conduct initial tests of feasibility and target engagement for novel interventions should be directed to RFA-MH-18-704, "Development of Psychosocial Therapeutic and Preventive Interventions for Mental Disorders (R61/R33)".

This FOA is not intended to support research on novel pharmacological interventions or devices administering direct brain stimulation, alone or in combination. Applications to conduct Phase Ia First in Human testing of new chemical entities or trials of novel first-in-children pharmacological agents in pediatric populations (i.e., first exposure in children or first in pediatric indication) should be directed to PAR-17-327 "First in Human and Early Stage Clinical Trials of Novel Investigational Drugs or Devices for Psychiatric Disorders (U01)". Applications to test other novel pharmacological agents or biologics, or devices administering direct brain stimulation, should be directed to RFA-MH-18-703, " Early Stage Testing of Pharmacologic or Device-based Interventions for the Treatment of Mental Disorders (R33)" and RFA-MH-18-702, " Early Stage Testing of Pharmacologic or Device-based Interventions for the Treatment of Mental Disorders (R61/R33)". Applications focused on clinical trials to establish the effectiveness of interventions with known clinical efficacy, and to test hypotheses regarding moderators, mediators, and mechanisms of action of these interventions should be directed to RFA-MH-18-701 "Clinical Trials to Test the Effectiveness of Treatment, Preventive, and Services Interventions (R01)", RFA-MH-18-700 "Clinical Trials to Test the Effectiveness of Treatment, Preventive, and Services Interventions (Collaborative R01)" or RFA-MH-18-706 "Pilot Effectiveness Trails for Treatment, Preventive and Services Interventions (R34)". The Effectiveness FOAs (RFA-MH-18-701, RFA-MH-18-700, and RFA-MH-18-706) may also support investigations of the use of technology applications to enhance therapeutics or extend the reach of existing intervention strategies.

Traditionally, exploratory clinical trials in mental health involve subjects selected on the basis of heterogeneous clinical indications and outcomes focused on symptom reduction. In the absence of testable hypotheses about target engagement, such trials provide little guidance for further intervention development or refinement. In an effort to glean more information about the mechanisms underlying mental disorders, and potential mechanisms of intervention effects, NIMH is requiring an experimental therapeutic approach for NIMH-supported research to develop and test interventions (http://www.nimh.nih.gov/about/director/2012/experimental-medicine.shtml). With this approach, as an initial proof of concept, a study is designed to demonstrate that the intervention exerts some measurable effect on a well-defined and measurable proximal intervention target/mechanism that is associated with risk for, causation, or maintenance of a clinical condition, and modification of which it is hypothesized will result in clinical benefit for the condition.

The term "target" refers to a factor that an intervention intends to modify, based on a hypothesis that modification of that factor will result in improvement of symptoms, behavior, or functional outcomes, or lower risk for the onset of mental disorders. A target may be a disease mechanism, a factor related to a disease mechanism, or a factor that confers significant risk. Targets can range from molecular, neural or neurophysiological systems to cognitive, behavioral or emotional processes, to interpersonal/social group processes or contextual factors. An appropriate target is an intervening variable that has either been demonstrated to be associated with risk for a mental disorder, with a clinical symptom or functional deficit, or is hypothesized (based on empirical evidence) to impact the biological or psychological pathway through which a clinical or functional benefit would be expected to occur. Thus it is hypothesized that change in the target will mediate the intervention's clinical or functional impact. For preventive interventions, appropriate intervention targets are individual (e.g., neural, behavioral, psychological, cognitive) or interpersonal mechanisms that mediate the risk for mental disorders from an exposure of some kind. While exposure to broad, societal/environmental circumstances might be used to identify at-risk populations, NIMH will not accept applications that propose to directly target or intervene on broad, societal adverse exposures, such as strategies to reduce poverty or violence.

"Target engagement" refers to verification that the intervention has had the predicted effect on the target/mechanism. In the experimental therapeutic approach, once target engagement is demonstrated, measures of target engagement are then related to clinical outcomes to begin to test the hypothesis that modification of the target/mechanism is sufficient to alter the clinical problem under study. Applicants are strongly encouraged to review the information on the NIMH website focused on clinical trials http://www.nimh.nih.gov/funding/clinical-trials-for-researchers/index.shtml.

A study under this FOA must include a novel target/mechanism or a novel approach to engaging a known target/mechanism, and there must be preliminary evidence that the intervention can alter the intervention target/mechanism. A novel approach to altering a known target/mechanism must be supported by an empirically supported rationale and testable hypothesis about why the new approach will substantially improve outcome, based on the predicted effect of engaging/modifying the target/mechanism. More than one target/mechanism may be proposed if each target/mechanism is supported by an empirically supported rationale, there are testable hypotheses proposed for each, and there are valid and reliable measures of change available for each.

Adaptations of efficacious interventions may be supported if they are based on empirical evidence suggesting that efficacy or specificity of the intervention could be substantially improved for a defined subpopulation of patients (e.g., non-responders) by engaging a different intervention target/mechanism or utilizing a different approach to the known target/mechanism. Adaptations of efficacious interventions may also be supported it they are based on evidence that the intervention may improve outcomes in a new subpopulation (e.g., children) or disorder by engaging a target that has not previously been known to be critical or considered feasible to address in that subpopulation or disorder. While this FOA will support pilot testing of novel technology-assisted intervention approaches, it is not intended to support the translation of existing treatments into technology-based applications (e.g., mHealth).

Valid and reliable measures of change in the target/mechanism will provide useful information about the potential for further development of the intervention. In the assessment of target engagement, NIMH encourages the use of measures that are as direct and objective as is feasible in the clinical research setting. NIMH encourages hypotheses and measures of potential mechanisms across molecular, biological, cognitive, psychological, social, and/or behavioral domains of analysis that might account for change in the target and symptom expression. The type of measures will depend on the conceptual model, the nature of the targeted construct, and the availability of valid, reliable measures of change in the target/mechanism. Measures might include self-reports, lab-based neurocognitive tasks or other behavioral measures, psychophysiological measures, neuroimaging or other brain-based measures, sensor-based or other observational measures of interpersonal processes or contextual/environmental factors, or valid proxy measures as alternatives. Specifically encouraged are empirically validated measures of the construct that extend beyond self-reports and other subjective measures, where possible, and inclusion of measures that span more than one level of assessment if possible and appropriate.

NIMH is particularly interested in the development of novel interventions that focus on operationally-defined, empirically-supported functional domains or symptom(s) of mental disorders as opposed to broad diagnostic categories in which not all subjects may share the same underlying disease process. For example, NIMH Research Domain Criteria (RDoC) constructs may inform mechanism-based hypotheses and the selection of interventions, outcome measures and clinical subjects. Intervention targets related to RDoC constructs are of interest for this FOA, but other, non-RDoC constructs may be suitable as well, especially if they maximize the probability that subjects share the same mechanism of disorder.

Pilot studies supported by this FOA should not be powered as strong tests of clinical efficacy, but rather should test the link between the degree of the intervention's target engagement and functional outcomes in a clinical or at-risk population. In addition to the primary aim of linking target engagement and clinical benefit, secondary aims may include: 1) intervention refinement and standardization (e.g., further manual or protocol development along with fidelity scales); 2) further testing of the feasibility, safety, and acceptability of the intervention; 3) preliminary testing of the association between a change in the target/mechanism and clinical benefit; 4) evaluating the feasibility of recruitment, randomization (if appropriate), retention, assessments, and reporting of adverse events; and 5) developing measures of functional target engagement and of clinical benefit feasible for use in larger efficacy and effectiveness trials. The specific activities appropriate for the study will depend on the type of intervention under study and the stage of the study proposed. The results of the study should inform a decision about whether the intervention shows the potential for improving clinical outcomes, including evidence of safety, acceptability and feasibility and a preliminary signal of efficacy, and regarding the strength of the association between target engagement and clinical benefit. The study should also inform the design of a subsequent confirmatory efficacy trial, if indicated.

Examples of high priority studies under this FOA include those that:

• Are highly innovative and address an unmet therapeutic need, or otherwise have the potential for substantially improving outcomes for people with mental disorders. Innovation is reflected in the choice of a novel target/mechanism or a novel approach to altering a known target/mechanism. Adaptations of efficacious interventions may be considered high priority if they are based on empirical evidence that efficacy or specificity could be substantially improved for a defined subpopulation of patients (e.g., non-responders, children) with a different intervention target/mechanism or different approach to the known target/mechanism.
• Are based on a strong conceptual rationale, including empirical support, for choice of the target/mechanism and potential for the intervention to have an impact on that target/mechanism.
• Are supported by preliminary evidence of target engagement, and propose a rigorous test of target engagement to replicate the preliminary findings. The research strategy should utilize reliable, valid measures of target engagement, including dose and/or protocol optimization to definitively test the ability of the intervention to engage the target/mechanism.
• Evaluate whether the intervention has therapeutic potential (feasibility, acceptability and preliminary signal of efficacy), as well as other information needed to conduct a confirmatory efficacy (e.g., variability and sensitivity of measures, randomization methods) in a patient population.
• Refine and pilot test the experimental protocol, methods, and measures. The study should utilize measures of treatment fidelity and reliable outcome measures that capture changes in the disorder, functional domain, or symptom(s) within the context of a trial.
• Examine whether intervention-induced changes in the target/mechanism are associated with changes in clinical symptoms or function, as predicted by the conceptual framework. Include other variables as appropriate that may inform an understanding of mediators and moderators of intervention effect.

Examples of studies that are not responsive to this FOA and will not be reviewed include the following:

• Applications whose scope of work does not include the measurement of intervention target(s)/mechanism(s), the choice of which is supported by empirical evidence of its potential role in the disorder or symptoms in question, and of its potential to address an unmet therapeutic need.
• Applications whose scope of work includes an initial test of target engagement.
• Applications whose scope of work does not address the intervention's ability to alter the target/mechanism (replicate the prior findings) in a larger clinical population.
• Applications that develop or evaluate pharmacological agents or biologics, or devices administering direct brain stimulation.
• Applications whose scope of work includes animal studies.

Applicants are strongly encouraged to consult with NIMH staff when developing plans for an application (see Agency Contacts, Section VII). This early contact will provide an opportunity to clarify NIMH policies and guidelines, identify whether the proposed project is consistent with NIMH program priorities, and discuss how to develop an appropriate project timeline, which is subject to peer review.

For multi-site trials, use of single IRBs is expected. The number of trial sites should be limited to minimize variability of the data.

PD(s)/PI(s)s submitting applications consistent with the experimental therapeutic approach but whose scope does not fall within that of the current FOA are encouraged to contact Scientific/Research staff or go to http://www.nimh.nih.gov/funding/clinical-trials-for-researchers/index.shtml for further information.

Effective prevention and treatment of mental disorders have the potential to reduce morbidity and mortality associated with intentional injury (i.e., suicide attempts and deaths, see: www.suicide-research-agenda.org). Lack of attention to the assessment of these outcomes has limited our understanding regarding the degree to which effective mental health interventions might offer prophylaxis. Accordingly, where feasible and appropriate, applicants are strongly encouraged to include assessment of suicidal behavior in clinical trials in response to this FOA using strategies that can facilitate integration and sharing of data (e.g., see NOT-MH-15-009 and https://www.phenxtoolkit.org/ for constructs and corresponding assessment strategies).

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.

Applications with data collection plans that involve multiple respondent groups (e.g., clients/patients, therapists/providers, supervisors, administrators) should address provisions for human subject protections and consenting procedures for all participant groups, accordingly.

The NIMH has published updated policies and guidance for investigators regarding human research protection and clinical research data and safety monitoring (NOT-MH-15-025). The application's Protection of Human Subjects section and data and safety monitoring plans should reflect the policies and guidance in this notice. Plans for the protection of research subjects and data and safety monitoring will be reviewed by the NIMH for consistency with NIMH and NIH policies and federal regulations.

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 from 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)

Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Applicant Organizations

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

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• System for Award Management (SAM) (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).

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, 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.

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.

By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:

• Descriptive title of proposed activity
• Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
• Names of other key personnel
• Participating institution(s)
• Number and title of this funding opportunity

The letter of intent should be sent to:

Email: nimhpeerreview@mail.nih.gov

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.

Facilities and Other Resources: Describe the governance and organizational structure for conducting the study as proposed and within specified timelines.

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

As appropriate, Senior/Key Personnel should demonstrate their expertise and track record in clinical trials, including expertise in the recruitment and retention of trial subjects and methodological and statistical expertise. Also highlight recent collaborative clinical research efforts among members of the proposed team, if any. Describe the expertise in the measurement methods proposed (e.g., EEG, fMRI, lab-based cognitive measures).

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

Budget Justification: Justify the staffing for conducting the study as proposed and within specified timelines.

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: Provide a concise description of the exploratory clinical trial as well as how the proposed intervention could fill an important unmet need for those living with mental illnesses.

Research Strategy: Applicants should include the following sections as part of the Research Strategy. Applications should not duplicate information provided in the attachment described in PHS Human Subjects Clinical Trial Information form, but may reference it to provide context as needed.

Significance: In this section of the Research Strategy, the application should:

• Describe the unmet mental health need that will be addressed by the intervention. Describe the intervention's potential to significantly reduce the burden of mental disorders.
• Propose a novel intervention with a strong, well-supported theoretical rationale that is ready for early-phase testing, including preliminary evidence of target engagement.
• Propose clear hypotheses that are refutable. Describe how the project will advance knowledge of intervention and/or disease mechanisms, whether the trial results are positive or negative.
• Address the potential impact of the intervention approach in terms of the clinical meaningfulness of the anticipated effect on clinical benefit and the clinical meaningfulness of the expected increment in clinical benefit compared to existing approaches.

Innovation: In this section of the Research Strategy, the application should:

• Provide a compelling scientific rationale for the approach chosen. Describe a novel, well-specified intervention target/mechanism and/or a novel approach to engaging an established target/mechanism.
• If the project concerns an adaptation or extension of an intervention with established efficacy, describe how the study will focus on novel targets/mechanisms. Describe how the approach would address an unmet mental health need (e.g., among a subgroup of individuals who are refractory to the standard intervention and/or in whom the efficacy of the intervention has not been established but who may share a common mechanism of disorder that it may usefully target).

Approach: In this section of the Research Strategy, the application should describe the elements of the experimental therapeutics approach to be used in the investigation. The elements critical to this approach are described in the specific requirements below.

• Clearly define each target/mechanism and the rationale for intervening on that target/mechanism, such as evidence that the target/mechanism is implicated in conferring risk, causing or maintaining the functional domain or symptom(s) of interest and/or that variability in the expression of the target is associated with variation in symptom severity or presentation. Specify the objective, quantifiable, and reproducible measures of both target engagement and the intervention's clinical benefit that will be used.
• Describe how the study will rigorously test intervention target engagement. Describe hypotheses that are scientifically grounded and theory-driven, about the hypothesized mediators, moderators, or mechanisms of the intervention's effect.
• Describe the measure(s) to be used and measurement schedules that are suitable for detecting relevant changes in each target/mechanism. Information on measurement validity and reliability should be included in the application.
• Describe the protocol parameters that are relevant to configuring the intervention (such as intensity, duration, and/or frequency of sessions in some types of therapies; number, difficulty level and/or intervals between trials in computer-administered intervention applications; various other potential ways of specifying the intervention "dose") and how those parameters of the protocol will be optimized in order to convincingly test the intervention's capacity to engage the specified target.
• Describe how associations between target engagement and clinical benefit will be evaluated. Describe how sufficient data will be collected in order to inform a decision about the therapeutic potential of the intervention for further clinical development. Provide the scientific rationale for the measures to be used and describe how each proposed measure will contribute to assessment of the relationships between intervention, target engagement, mechanism-based functional outcomes, and/or clinical benefit. Describe the selection of the control condition and how it is likely to contribute to addressing the research questions relevant to this phase.
• Explain how the delivery of the intervention will be operationalized, monitored, and quantified. If manuals for delivering the intervention and procedures for assessing fidelity (i.e., adherence to the manual and competent delivery) do not already exist, provide detailed plans to develop protocols and fidelity measures.
• Describe the feasibility of the approach in terms of having in place all the necessary elements to carry out data acquisition and analysis in a timely manner.
• Describe plans for the assessment of suicidal behavior and related outcomes using strategies that can facilitate integration and sharing of data, as appropriate, or provide a rationale for excluding such measures if they are not included. The application should provide the rationale for the selection of suicide-related constructs and corresponding assessment instruments (e.g., measures of ideation, attempts), the time periods assessed (e.g., lifetime history, current), and the assessment schedule for administration (e.g., baseline, during intervention, post-intervention, follow up), taking into account the nature of the target population, participant burden, etc. The application should also address provisions for clinical management when suicidal behavior is reported. In situations where it is not appropriate or feasible to include assessment of suicide outcomes due to the nature of the intervention or the target population (e.g., very young children), or unique issues related to participant burden or safety/monitoring concerns, the application should provide an appropriate justification for excluding these assessments.

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:

In order to advance the goal of advancing research through widespread data sharing among researchers, investigators funded under this FOA are expected to share those data via the National Database for Clinical Trials related to Mental Illness (NDCT; http://ndct.nimh.nih.gov/; see NOT-MH-14-015 and NOT-MH-15-012). Established by the NIH, NDCT is a secure informatics platform for scientific collaboration and data-sharing that enables the effective communication of detailed research data, tools, and supporting documentation. NDCT links data across research projects through its Global Unique Identifier (GUID) and Data Dictionary technology. Investigators funded under this FOA are expected to use these technologies to submit data to NDCT.

To accomplish this objective, it will be important to formulate a) an enrollment strategy that will obtain the information necessary to generate a GUID for each participant, and b) a budget strategy that will cover the costs of data submission. The NDCT web site provides two tools to help investigators develop appropriate strategies: 1) the NDCT Budgeting Spreadsheet http://ndct.nimh.nih.gov/preplanning/budget - a customizable Excel worksheet that includes tasks and hours for the Program Director/Principal Investigator and Data Manager to budget for data sharing; and 2) plain language text to be considered in your informed consent http://ndct.nimh.nih.gov/preplanning/informed-consent. Investigators are expected to certify the quality of all data generated by grants funded under this FOA prior to submission to NDCT and review their data for accuracy after submission. Submission of descriptive/raw data is expected semi-annually (every January 15 and July 15); submission of all other data is expected at the time of publication, or prior to the end of the grant, whichever occurs first (see Data Sharing Expectation http://ndct.nimh.nih.gov/preplanning/#tab-1 for more information); Investigators are expected to share results, positive and negative, specific to the cohorts and outcome measures studied by using the Study functionality(see http://ndct.nimh.nih.gov/results). The NDCT Data Sharing Plan is available for review on the NDCT web site (http://ndct.nimh.nih.gov/wp-content/uploads/NDCT_Data_Sharing_Policy_20141002.pdf ). NDCT staff will work with investigators to help them submit data types not yet defined in the NDCT Data Dictionary http://ndct.nimh.nih.gov/submit/data-dictionary.

Appendix:

Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

Use only for applications with due dates on or after January 25, 2018. When involving NIH-defined human subjects research, clinical research, and/or clinical trials (and when applicable, clinical trials research experience) 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 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 with the following additional instructions:

Section 2 - Study Population Characteristics

2.5 Recruitment and Retention Plan

Recruitment and Retention Plan: Applications must provide a clear description of:

1. Recruitment and Referral sources, including detailed descriptions of the census/rate of new cases and anticipated yield of eligible participants from each source;

2. Procedures that will be used to monitor enrollment and track/retain participants for follow-up assessments;

3. Strategies that will be used to ensure a diverse, representative sample;

4. Potential recruitment/enrollment challenges and strategies that can be implemented in the event of enrollment shortfalls (e.g., additional outreach procedures, alternate/back-up referral sources);

5. Evidence to support the feasibility of enrollment, including descriptions of prior experiences and yield from research efforts employing similar referral sources and/or strategies.

2.7 Study Timeline

Study Timeline: Applications must provide a timeline for reaching important study benchmarks such as: (1) finalizing the study procedures and training participating clinical site staff; (2) finalizing the intervention manual and assessment protocols, including fidelity measures/procedures, where applicable; (3) enrollment benchmarks; (4) completing all subject assessments and data collection activities, including data quality checks; (5) analyzing and interpreting results; and (6) preparing de-identified data and relevant documentation to facilitate data sharing, as appropriate.

5.1 Other Clinical Trial-related Attachments

Other Clinical Trial-related Attachments: Applicants must upload the attachments for Intervention Manual/Materials as separate files, as applicable. Applicants must use the "Intervention Manual/Materials" to name these other attachments files. As appropriate, this may include screenshots of mobile interventions, technological specifications, training manuals or treatment algorithms.

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.

Foreign (non-U.S.) institutions must follow policies described in the NIH Grants Policy Statement, and procedures for foreign institutions.

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 and responsiveness by components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

In order to expedite review, applicants are requested to notify the 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.

NIMH encourages the use of common data elements (CDEs) in basic, clinical, and applied research, patient registries, and other human subject research to facilitate broader and more effective use of data and advance research across studies. CDEs are data elements that have been identified and defined for use in multiple data sets across different studies. Use of CDEs can facilitate data sharing and standardization to improve data quality and enable data integration from multiple studies and sources, including electronic health records. NIH ICs have identified CDEs for many clinical domains (e.g., neurological disease), types of studies (e.g., genome-wide association studies (GWAS)), types of outcomes (e.g., patient-reported outcomes), and patient registries (e.g., the Global Rare Diseases Patient Registry and Data Repository). NIH has established a "Common Data Element (CDE) Resource Portal" (http://cde.nih.gov/) to assist investigators in identifying NIH-supported CDEs when developing protocols, case report forms, and other instruments for data collection. The Portal provides guidance about and access to NIH-supported CDE initiatives and other tools and resources for the appropriate use of CDEs and data standards in NIH-funded research. Investigators are encouraged to consult the Portal and describe in their applications any use they will make of NIH-supported CDEs in their projects.

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

A proposed Clinical Trial application may include study design, methods, and intervention that are not by themselves innovative but address important questions or unmet needs. Additionally, the results of the clinical trial may indicate that further clinical development of the intervention is unwarranted or lead to new avenues of scientific investigation.

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?

Are the scientific rationale and need for a clinical trial to test the proposed hypothesis or intervention well supported by preliminary data, clinical and/or preclinical studies, or information in the literature or knowledge of biological mechanisms? For trials focusing on clinical or public health endpoints, is this clinical trial necessary for testing the safety, efficacy or effectiveness of an intervention that could lead to a change in clinical practice, community behaviors or health care policy? For trials focusing on mechanistic, behavioral, physiological, biochemical, or other biomedical endpoints, is this trial needed to advance scientific understanding?

Could the intervention fill an important unmet mental health need for those living with a mental disorder, or substantially (not incrementally) improve clinical care? Does the proposed project have the potential to test and potentially refute any hypotheses around the proposed mechanism(s) of action?

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?

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?

What evidence indicates that the researchers can function as a team? Does the research team have demonstrated clinical trials expertise and a track record in successfully conducting early clinical trials (e.g., subject recruitment and retention rates, reporting in clinicaltrials.gov, publications, etc.)? Does the investigative team have sufficient methodological and statistical expertise in the study and measurement of intervention change mechanisms (e.g., handling repeated measures designs, missing data, effect size)? Does the investigative team include sufficient expertise in the measurement methods proposed? Are the staffing, governance, and organizational structure appropriate for conducting the study as proposed and within specified timelines?

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 design/research plan include innovative elements, as appropriate, that enhance its sensitivity, potential for information or potential to advance scientific knowledge or clinical practice?

Does the application introduce a novel, well-specified target/mechanism and/or a novel approach to engaging an established target/mechanism? Is the proposed intervention derived from a recent basic finding or translating an established finding in a novel way (e.g., innovative methods or translation to a developmental framework)? Where applicable, if the proposed project concerns an adaptation or extension of an intervention with established efficacy, is the rationale based on empirical evidence that efficacy or specificity could be substantially improved for a defined subpopulation of patients with a different intervention target/mechanism or different approach to the known target/mechanism?

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?

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?

Does the proposed study ensure that the impact of the intervention on the target/mechanism (i.e., target engagement) will be rigorously tested? If more than one target/mechanism is proposed, is there a strong justification for each, and is the impact on each target/mechanism rigorously tested?

Are there adequate plans to optimize the intervention protocol or parameters (such as intensity, duration, frequency, i.e., "dose")?

Does the research plan include sound methodology for (a) replicating and extending preliminary evidence of target engagement, and (b) evaluating associations between target engagement and clinical benefit? Are the plans for sample size and timely recruitment of subjects feasible? Is there a clear strategy for tracking recruitment and facilitating retention?

Does the application provide sufficient detail about procedures for monitoring intervention delivery and for quantifying fidelity and competence of intervention delivery?

Will results from the study inform a decision about whether the intervention has the potential to substantially improve clinical outcomes, including evidence of safety, acceptability and feasibility; preliminary signal of efficacy; and strength of the association between target engagement and clinical benefit?

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?

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?

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?

Is there documented evidence that the PD(s)/PI(s) successfully carried out studies of similar structure and complexity as in the current application in the specified setting? If needed, is there a realistic timeline for establishing necessary agreements with all partners (e.g., single IRB)? Does the environment support timely subject recruitment and completion of the study?

As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.

Study Timeline

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.

Not Applicable

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.

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.

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 NIMH, 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.

Appeals of initial peer review will not be accepted for applications submitted in response to this FOA.

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. 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.

Recruitment Reporting and Trial Registration

NIMH requires reporting of recruitment milestones for participants in all NIMH extramural-funded clinical research studies proposing to enroll 150 or more subjects per study, and all clinical trials, regardless of size (see http://grants.nih.gov/grants/guide/notice-files/NOT-MH-16-013.html ). While research in response to this FOA might not seek 150 subjects or more (the level at which this reporting has been required), all trials funded under this FOA must report recruitment milestones, including those with fewer than 150 subjects. This expectation will be stated in the notice of grant award.

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

Alexander M. Talkovsky, Ph.D.
National Institute of Mental Health (NIMH
Telephone: 301-827-7614
Email: alexander.talkovsky@nih.gov

Nick Gaiano, Ph.D.
National Institute of Mental Health (NIMH)
Telephone: 301-827-3420
Email: nick.gaiano@nih.gov

Tamara Kees
National Institute of Mental Health (NIMH)
Telephone: 301-443-8811
Email: tkees@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.