Required Application Instructions

It is critical that applicants follow the 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

Purpose

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 support confirmatory efficacy testing of non-pharmacological interventions for mental disorders in adults and children that address unmet therapeutic needs, and are consistent with the NIMH emphasis on the experimental therapeutics approach. In this approach, clinical trials should be designed to increase knowledge of the relationship between underlying disease processes and the mechanisms of action through which any intervention produces therapeutic change (http://www.nimh.nih.gov/about/director/2012/experimental-medicine.shtml).

Therefore, interventions appropriate for confirmatory efficacy testing must be based on a compelling scientific rationale, previous demonstration that the intervention engages and alters the hypothesized mechanism of action, and a preliminary efficacy signal (for further information, see the NIMH Clinical Trials FAQ webpage at: http://www.nimh.nih.gov/funding/opportunities-announcements/clinical-trials-foas/nimh-clinical-trials-funding-opportunity-announcements-applicant-faqs.shtml). The proposed trial must include plans to replicate these target engagement and validation findings in a fully powered, confirmatory efficacy study that is likely to show superiority of the intervention over an appropriately justified comparison condition.

Interventions appropriate to this FOA may include, but are not limited to: behavioral, cognitive, interpersonal, or combined approaches. Psychopharmacological interventions to establish efficacy are not allowable under this FOA. 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 program staff or view the NIMH Clinical Trial web page.

NIMH Priorities for Confirmatory Efficacy Trials

Traditionally, efficacy testing of interventions for mental disorders involves subjects selected on the basis of heterogeneous clinical indications and outcomes focused on symptom reduction. Such trials, whether positive or not with respect to symptom change, deliver little information about the mechanism of action of the intervention or the underlying cause of the disorder and therefore provide little guidance for further intervention development or refinement. As a result, NIMH is shifting to an experimental therapeutic paradigm in which interventions are evaluated in stages (http://www.nimh.nih.gov/about/director/2012/experimental-medicine.shtml). A preliminary stage in this progressive pipeline is to demonstrate that the intervention exerts some measurable effect on a hypothesized target or mechanism of action, and that measures of change in the target are related to clinical outcomes. Commensurate with the intervention, targets may be behavioral, cognitive, or interpersonal processes (e.g., attention bias, cognitive control, self-regulation, familial criticism).

This FOA supports confirmatory efficacy trials of interventions for which this preliminary evidence of target engagement has already been demonstrated and there is a signal suggesting intervention efficacy. The earlier stages of intervention development, which include preliminary tests of target engagement and target validation, are not appropriate for this FOA and are supported by NIMH through companion FOAs (NIMH Clinical Trials FOA page). Interventions appropriate for confirmatory efficacy testing under this FOA are those for which the following preliminary evidence already exists:

• Evidence of the target’s association with the etiology or maintenance of a critical domain of function;
• Compelling evidence of the intervention’s target engagement (e.g., a significant difference in target change between the experimental and control intervention groups) has been demonstrated;
• Evidence of target validation (e.g., a signal that the clinical outcome is changing in the hypothesized direction as a result of the intervention); and
• An initial efficacy signal that serves as a basis for anticipating at least a moderate effect size (d = 0.5) in the fully-powered confirmatory efficacy trial.

In order to address the lack of uptake of research-based therapies and the alarming fall-off in effect sizes from efficacy to effectiveness studies, NIMH will prioritize studies that incorporate a deployment-focused approach, taking into account typically available resources (e.g., the training and skill level of average providers), usual care service structures (including healthcare financing, reimbursement mechanisms), and typical service use patterns, in order to test more practice-ready interventions.

NIMH is particularly interested in the development of therapeutic and preventive 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 (see http://www.nimh.nih.gov/research-funding/rdoc/nimh-research-domain-criteria-rdoc.shtml for more details). 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.

NIMH will consider the following critical pre-requisite criteria prior to funding a confirmatory efficacy trial:

• The intervention addresses an unmet therapeutic need for serious mental disorders;
• There is compelling evidence from prior studies and/or the extant literature supporting the intervention’s ability to engage the hypothesized target or mechanism of action, preliminary target validation, and a signal of change in clinical or functional status;
• The study design incorporates a plan to develop surrogate endpoints, or early indicators of treatment effect, that would be feasible to use in every day clinical settings;
• The design of the trial would inform the next stage of intervention development, whether that be an effectiveness trial, further investigation in dissemination and or implementation research, or actual dissemination into practice;
• There is evidence of the potential impact of the intervention compared to existing approaches and should address the degree to which the proposed intervention could potentially be brought to scale in an effectiveness study or be disseminated into practice.

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

• Applications that focus on efficacy without having already established compelling evidence of target engagement and at least initial evidence for target validation, in addition to an initial efficacy signal.
• Applications lacking a focus on an experimental therapeutic approach (i.e., not testing a mechanism of action).
• Adaptation of an efficacious intervention in the absence of a compelling justification for such a need, and in the absence of a clear experimental therapeutics approach (see the NAMHC Workgroup Report, From Discovery to Cure: Accelerating the Development of New and Personalized Interventions for Mental Illnesses http://www.nimh.nih.gov/about/advisory-boards-and-groups/namhc/reports/fromdiscoverytocure.pdf , see Recommendation 2.4.1, page 19, for additional guidance regarding the empirical justification for intervention adaptations and augmentations.)

Applicants are strongly encouraged to consult with Scientific/Research Contacts when developing plans for an application. This early contact will provide an opportunity to clarify NIMH policies and guidelines as well as to discuss how to develop an appropriate project timeline, which is subject to peer review.

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. Cost-sharing, including in-kind support, is encouraged.

PD(s)/PI(s)s submitting applications consistent with the experimental therapeutic approach but whose scope does not fall within that of the current R01 FOA are encouraged to contact program staff or view the NIMH Clinical Trial web page. Investigators interested in conducting fully-powered effectiveness trials in community-practice settings are referred to RFAs RFA-MH-15-320 and RFA-MH-15-325.

Please note, per NOT-MH-14-007 NIMH will not accept R01, R21, or R03 applications that include clinical trials of potential therapies for mental disorders, under the NIH parent R01 Funding Opportunity Announcement (FOA) PA-13-302, NIH parent R21 FOA PA-13-303, and NIH Parent R03 FOA PA-13-304, and subsequent reissuances of these FOAs.

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
• 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.

NIH will not accept any application that is essentially the same as one already reviewed within the past thirty-seven months (as described in the NIH Grants Policy Statement), except for submission:

• To an RFA of an application that was submitted previously as an investigator-initiated application but not paid;
• Of an investigator-initiated application that was originally submitted to an RFA but not paid; or
• Of an application with a changed grant activity code.

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.

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: NIMHClinicalTrials@mail.nih.gov

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

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

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. with the following additional instructions:

Other Attachments: Applicants should upload a single attachment that includes the following information relevant to the proposed clinical trial. It is recommended that this attachment include no more than 4 pages. Applicants should use the headers below in their description.

I. Study Participant and Recruitment Descriptors: Applications must provide a clear description of:

• The proposed subject eligibility criteria; address how the criteria are related to a measurable disruption in the mechanism under study; discuss how the symptoms, functional domain, or disorder under which the subjects are eligible will maximize the probability that all subjects share the same perturbation.
• The recruitment and retention strategy and potential issues that could arise when trying to administer and integrate the proposed measures; describe recruitment tracking and follow-up procedures.
• The procedures to minimize bias in allocation of participants to treatment and in assessment of outcomes.
• The proposed sample sizes based on power calculations that include pre-specified effect sizes for the parameters under study.

II. Milestones and Timeline: Applications must provide a clear description of:

• Objective, quantifiable, and scientifically justified milestones; and
• A proposed timeline for reaching important study milestones such as: (a) finalizing the study procedures and training participating clinical site staff; (b) finalizing the intervention manual and assessment protocols, including fidelity measures/procedures, where applicable; (c) enrolling 25%, 50%, 75% and 100% of the sample; (d) completing all subject follow-up assessments and data collection activities, including data quality checks; (e) analyzing and interpreting results;, and (f) preparing de-identified data and relevant documentation to facilitate data sharing, as appropriate.

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

Succinctly document the collective expertise and track record in clinical trials of the Senior/Key Personnel including: recent recruitment and retention rates of trial subjects; methodological and statistical expertise (e.g. handling repeated measures designs, missing data; assessing effect size; and measurement of intervention change mechanisms). Also include recent collaborative clinical research efforts among members of the proposed team, if any.

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:

Research Strategy: Applicants must include the following information as part of the research strategy.

In order to be considered complete, applications must address the transportability/scalability of the proposed intervention and should detail how the treatment manual, therapist training procedures, and fidelity assessment and enhancement methods could be adapted and refined to be applicable to clinical practice. The application should justify the potential impact of the intervention compared to existing approaches and should address the degree to which the proposed intervention could potentially be brought to scale in an effectiveness study or be disseminated into practice.

In order to be considered complete the application must:

• Include plans to replicate previous target engagement findings in a fully-powered confirmatory study.
• Include plans to replicate prior target validation findings in a fully-powered confirmatory study.
• Explicate a power analysis and a rationale for expecting the intervention to yield a medium effect size (d = 0.5) or larger.
• Explicate a rationale for expecting the intervention to yield a clinically-significant effect.
• Addresses how, if the intervention is efficacious, it would be possible to adapt/refine the treatment manual, therapist training packages, and fidelity assessment and enhancement methods to be applicable to community practice.
• Utilizes innovative and efficient research designs and statistical plans that maximize ability to measure intervention effects, promote understanding of mediators/moderators, and minimize patients exposure to ineffective interventions (e.g., SMART adaptive designs (as relevant), stratification of participants on variables related to hypothesized mechanism of action, surrogate endpoints or early indicators of treatment response).
• Includes reliable outcome measures that capture changes in the disorder, functional domain, or symptom(s) within the context of a trial.

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

• Describe the unmet therapeutic need that will be addressed by the intervention. Describe the intervention’s potential to significantly reduce the burden of serious mental illness.
• Describe how the proposed project will advance knowledge of pathophysiologic and/or psychopathologic mechanisms relevant to the functional domain, symptom(s) or diagnosis of interest.
• 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.
• Present a clear rationale for the effect size threshold that would be clinically meaningful and justify additional studies for further clinical development.

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

• If testing the efficacy of a novel intervention, describe a novel, well-specified target (i.e., mechanism of action) and/or a novel approach to engaging an established target. Include how the proposed intervention stems from a basic finding or is translating an established finding in a novel way (e.g. novel methods or in a novel developmental framework).
• If testing the efficacy of an adaptation or extension of an intervention with established efficacy, describe how the study will focus on novel targets and how the design will be able to provide an empirically supported basis for (a) identifying prognostic indicators (subgroups) that predict differential benefit from target engagement (e.g., in comparison to the existing, unadapted intervention), and/or (b) paring the intervention down to its essential elements based on clear evidence of target engagement.

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

• Provide a compelling scientific rationale for the approach chosen. The approach should describe hypotheses that are scientifically grounded and theory-driven, about the mechanisms involved in triggering or maintaining the disorder and the mediators or mechanisms of the intervention’s effect. The applicant should describe how the approach will ensure that the underlying hypothesized target mechanisms will be tested.
• Describe the existing evidence of the intervention's potential, including 1) evidence of the intervention's target engagement (e.g., a significant difference in target change between the experimental and control groups; 2) evidence of target validation (e.g., a signal that the clinical outcome is changing in they hypothesized direction after interventions; and 3) an initial efficacy signal that serves as a basis for anticipating at least a moderate effect size (d=0.5) in the fully-powered confirmatory efficacy trial.
• Describe preliminary evidence of feasibility, including the availability of intervention manuals and fidelity measures.
• Provide the scientific rationale for the measures used to assess the link between the hypothesized target and functional or clinical effect. Information on measurement validity and reliability should be included in the application. Describe measurement schedules that are suitable for detecting relevant changes in the target.
• Explain how the delivery of the intervention will be operationalized, monitored, and quantified, including any modifications to existing treatment manuals and fidelity measures.
• Address the intervention’s potential scalability (e.g., compatibility with typically available resources, reimbursement practices). Address how the treatment manual, therapist training procedures and protocols for monitoring and enhancing fidelity could be adapted for use in community practice if the intervention is found to be efficacious. Is there a plan to develop surrogate endpoints that would be feasible to use in everyday clinical settings?
• Describe the clinical trial methodology, including: a) how the replication and extension of preliminary target engagement findings will be conducted and b) how the trial will evaluate associations between target engagement and subsequent clinical or functional change. Describe how sufficient data will be collected to inform a go/no-go decision about the therapeutic target for further clinical development or effectiveness testing. Describe the selection of the control condition and how it is likely to address the research question. Are subject inclusion/exclusion criteria well-justified and is the selection made on the basis of a measurable disruption in the mechanism under study?
• Describe the approach feasibility in terms of having in place all the necessary elements to carry out data acquisition and analysis in a timely manner.

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 modification:

• All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan. A data sharing plan is expected for all NIMH-supported clinical trials. A plan for sharing data, including the timeline for making data publically available and for providing access to de-identified patient-level data, may be included in the application. The NIMH will support activities to facilitate sharing (e.g., data description and data management, development of a data dictionary, data quality assurance procedures, and language in consent forms). Data sharing strategies that will allow others to reanalyze results with alternative approaches are also encouraged. As available, common data elements (see http://cde.nih.gov/) should be used to facilitate integration and sharing of data across studies.
• Applications should describe plans to ensure that the data and biospecimens are collected in a manner that will promote appropriate data sharing and integration into larger databases (e.g., use of common data elements), consistent with achieving the goals of this program. Applications should address strategies to ensure that data collected in a manner that could allow other researchers to analyze the data, including conducting meta-analyses, and provisions to support rapid sharing of trial data, as appropriate.

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, with the following modifications:

• It is strongly recommended that complete protocols and manuals be included in the appendix.

When conducting clinical research, follow all instructions for completing Planned Enrollment Reports as described in the SF424 (R&R) Application Guide.

When conducting clinical research, follow all instructions for completing Cumulative Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.

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

Part I. Overview Information contains information about Key Dates. 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.

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. If a Changed/Corrected application is submitted after the deadline, the application will be considered late.

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.

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 by the Center for Scientific Review and responsiveness by NIMH, NIH. Applications that are incomplete and/or nonresponsive will not be reviewed.

NIH 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 NOT-OD-13-030.

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.

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.

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?

Could the intervention fill an important unmet therapeutic need for those living with a mental disorder and substantially reduce the burden of serious mental disorders? Will the study advance the knowledge of the pathophysiologic and/or psychopathologic mechanisms relevant to the functional domain, symptoms, or diagnosis of interest?

Does a robust and reproducible body of evidence support the study hypothesis and rationale? Is there compelling evidence of the intervention’s target engagement (e.g., a significant difference in target change between the experimental and control intervention groups)? Is there evidence of target validation (e.g., a signal that the clinical outcome is changing in the hypothesized direction after intervention)? Is there an initial efficacy signal that serves as a basis for anticipating at least a moderate effect size in the fully-powered confirmatory efficacy trial? Is there a rationale for the effect size threshold that would be clinically meaningful?

Are there established intervention manuals, therapist training packages, and a set of fidelity assessment and enhancement methods?

Does the project propose clear hypotheses and have the potential to test and potentially refute any hypotheses around the proposed mechanism(s) of action? Will it advance knowledge of intervention or disease mechanisms, whether the result is positive or negative?

Investigator(s)

Are the PD(s)/PI(s), 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?

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 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? Is there a description of the expertise needed by any potential consultants?

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?

If the intervention being evaluated is a novel approach, does the application introduce a novel, well-specified target and/or a novel approach to engaging established targets (i.e., mechanisms of disorders or mechanisms of change)? Does the proposed intervention stem from a basic finding, or is it translating an established finding in a novel way?

If the proposed project concerns an adaptation or extension of an intervention with established efficacy, will the study focus on novel targets and will the design be able to provide an empirically supported basis for: (a) identifying prognostic indicators (subgroups) that predict differential benefit from target engagement (e.g., in comparison to the existing, unadapted intervention), and/or (b) further paring the intervention down to its essential elements based on clear evidence of target engagement?

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?

Does the application provide a compelling scientific rationale for the approach chosen? Are there scientifically grounded and theory-driven hypotheses about the mechanisms involved in triggering or maintaining the disorder, and the mediators or mechanisms of the intervention's effect? Is the approach for testing these hypotheses adequate?

Does the application describe preliminary evidence of feasibility, including the availability of intervention manuals and fidelity measures?

Does the application present a solid rationale for the intervention, including 1) preliminary evidence of target engagement (e.g., a significant difference in target change between the experimental and control groups), 2) target validation (e.g., a signal that the clinical outcome is changing in the hypothesized direction after intervention), and 3) an initial efficacy signal that serves as a basis for anticipating at least a moderate effect size (d=0.5) in the fully-powered confirmatory efficacy trial?

Does the application include sound methodology for (a) replicating and extending the initial target engagement findings, and (b) evaluating associations between target engagement and subsequent clinical or functional change (target validation) ?

Are subject inclusion/exclusion criteria well-justified and is the selection made on the basis of a measurable disruption in the mechanism under study? Is the selection of the control condition(s) likely to address the research questions rigorously?

Does the application provide sufficient detail regarding how the delivery of the intervention will be operationalized, monitored, and quantified?

Does the application address the intervention’s potential scalability (e.g., compatibility with typically available resources, reimbursement practices)? Does the application address how the treatment manual, therapist training procedures and protocols for monitoring and enhancing fidelity could be adapted for use in community practice if the intervention is found to be efficacious?

Does the application include valid measures of the intervention’s target engagement, or valid proxy measures, and are the procedures to validate appropriate? Are the measurement schedules suitable for detecting reliable changes in the target? Is there a plan to develop surrogate endpoints that would be feasible to use in everyday clinical settings?

Does the application include reliable measures of outcome that capture changes in the disorder, functional domain, or symptoms(s) within the context of the trial?

Is the approach feasible in terms of realistically having in place everything necessary to carry out data acquisition and analysis in a timely manner? Will sufficient and appropriate data be collected to inform a go/no-go decision about further intervention development or moving the intervention to an effectiveness trial?

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?

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?

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? Does the environment support timely subject recruitment and completion?

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.

Milestones and Timeline

Is the study timeline described in detail, taking into account start-up activities, the anticipated rate of enrollment, and planned follow-up assessments? Is the project 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 data bases, or patient registries) to increase the efficiency of participant enrollment and data collection, as appropriate?

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 Guidelines for the Review of Human Subjects.

Inclusion of Women, Minorities, and Children

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.

Vertebrate Animals

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following five points: 1) proposed use of the animals, and species, strains, ages, sex, and numbers to be used; 2) justifications for the use of animals and for the appropriateness of the species and numbers proposed; 3) adequacy of veterinary care; 4) procedures for limiting discomfort, distress, pain and injury to that which is unavoidable in the conduct of scientifically sound research including the use of analgesic, anesthetic, and tranquilizing drugs and/or comfortable restraining devices; and 5) methods of euthanasia and reason for selection if not consistent with the AVMA Guidelines on Euthanasia. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

Biohazards

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

Resubmissions

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

For Renewals, the committee will consider the progress made in the last funding period.

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 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. Assignment to a Scientific Review Group will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

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

Applications will be assigned 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’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 the DUNS, SAM 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

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

A final progress report, 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.

NIMH requires reporting of recruitment milestones for participants in clinical trials as noted at http://grants.nih.gov/grants/guide/notice-files/NOT-MH-05-013.html. While trials 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.

The NIMH expects the registration and results reporting for all NIMH-supported clinical trials, regardless of whether or not they are subject to FDAAA (see http://grants.nih.gov/ClinicalTrials_fdaaa/at-a-glance.htm). 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 Commons Help Desk (Questions regarding eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

Finding Help Online: http://grants.nih.gov/support/index.html

TTY: 301-451-5939
Email: commons@od.nih.gov

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact CenterTelephone: 800-518-4726

Web ticketing system: https://grants-portal.psc.gov/ContactUs.aspx
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

For inquiries to the Division of Developmental Translational Research and Treatment Development (DDTR):

Ann Wagner, Ph.D.
National Institute of Mental Health (NIMH)
Telephone: 301-443-3633
Email: awagner@mail.nih.gov

For inquiries to the Division of Adult Translational Research and Treatment Development (DATR):

Jovier Evans, Ph.D
National Institute of Mental Health (NIMH)
Telephone: 301-443-6328
Email: jevans1@mail.nih.gov

For inquiries to the Division of Services and Intervention Research (DSIR):

Joel Sherrill, Ph.D.
National Institute of Mental Health (NIMH)
Telephone: 301-443-2477
Email: jsherril@mail.nih.gov

David Armstrong, Ph.D.
National Institute of Mental Health (NIMH)
Telephone: 301-443-3534
Email: armstrda@mail.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 Parts 74 and 92.