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

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 intervention development consistent with the NIMH emphasis on the experimental therapeutic approach in 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 healthy volunteers or in a clinical population. Studies of novel interventions with a rigorous empirical basis for testing are responsive to this FOA and include, but are not limited to: behavioral, biologics-based, cognitive, device-based, interpersonal, pharmacological, physiological, or combined approaches. Studies must include an examination of a defined intervention target based on empirical evidence of disease processes (or for pharmaceuticals, existing information about objective measures that can detect CNS changes during drug exposure), and a clear hypothesis about how an intervention directed at changing the target can lead to functional improvement and/or clinical benefits in persons with mental disorders.

This FOA provides support for testing, refinement, replication, and/or validation for 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 symptoms. 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 contributes to a staged approach to intervention development and testing by requiring a demonstration of the intervention’s effect on a target that lies in the pathway from neurobiology to symptom expression, and the relationship between change in the target and change in symptoms, before moving to a confirmatory efficacy trial.

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 http://www.nimh.nih.gov/research-priorities/strategic-objectives/index.shtml. Applicants are also 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.

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.

Applications to conduct initial tests of feasibility and target engagement for novel interventions should be directed to RFA-MH-16-405, "Exploratory Clinical Trials of Novel Interventions for Mental Disorders (R21/R33).

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-14-107 "First in Human and Early Stage Clinical Trials of Novel Investigational Drugs or Devices for Psychiatric Disorders (U01)". Applications focused on clinical trials to establish the effectiveness of interventions, and to test hypotheses regarding moderators, mediators, and mechanisms of action of these interventions should be directed to RFA-MH-16-420 "Clinical Trials to Test the Effectiveness of Treatment, Preventive, and Services Interventions (R01)", RFA-MH-16-415 "Clinical Trials to Test the Effectiveness of Treatment, Preventive, and Services Interventions (Collaborative R01)" or RFA-MH-16-410 "Pilot Effectiveness Trials for Treatment, Preventive and Services Interventions (R34)".

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 information about target engagement, such trials provide little guidance for further treatment development or refinement. In an effort to glean more information about the mechanisms involved in causing or maintaining mental disorders, and potential mechanisms of intervention effect, 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 intervention target.

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 symptom, behavior, or functional outcomes. A target may be a disease mechanism or related to a disease mechanism, or it may be a hypothesized mechanism of intervention effect. Targets can range from molecular, synaptic- and circuit-level sites proposed for pharmacologic agents, to neural systems and cognitive, behavioral or emotional processes for psychotherapeutic interventions. An appropriate target is an intervening variable that has either been demonstrated to be associated with a clinical symptom or functional deficit, or is hypothesized (based on empirical evidence) to impact the biological pathway through which a clinical or functional benefit would be expected to occur, and thus is hypothesized to contribute to the intervention’s impact.

Target engagement refers to verification that the intervention has had the predicted effect on the target. Once target engagement is demonstrated, measures of target engagement are then related to clinical outcomes to test the hypothesis that the target is relevant to 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 or a novel approach to engaging a known target, and there must be preliminary evidence that the intervention can alter the intervention’s target. A novel approach to altering a known target must be supported by a strong rationale based on an empirically-supported hypothesis that the new approach will significantly improve outcomes.

According to the applicant’s conceptual framework, the intervention’s target might be hypothesized as a mechanism that causes or maintains the disorder of interest, or it might be hypothesized to be a mechanism by which the intervention ameliorates symptoms or dysfunction. In either case, valid and reliable measures of change in the target will be informative whether or not target engagement is achieved. NIMH encourages hypotheses and measures of potential mechanisms across biological and behavioral domains of analysis that might account for change in the target and symptom expression.

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.

Effective prevention and treatment of mental illness 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).

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 or a novel approach to altering a known target. Adaptations of efficacious interventions may be responsive 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 or different approach to the known target.
• Are based on a strong conceptual rationale, including empirical support, for choice of the target and potential for the intervention to have an impact on that target.
• 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.
• 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 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.
• For pharmacological interventions: Evaluation of target engagement must include a functional pharmacodynamic readout. Note that a tool compound (i.e., a promising lead molecule used to validate a target and explore biology) that is impractical as a drug may be sufficiently potent and selective to provide valuable information about the target to stimulate further research and development and thus could be supported under this FOA. Studies to adapt pharmacologic interventions to pediatric populations should be directed to PAR-14-107 "First in Human and Early Stage Clinical Trials of Novel Investigational Drugs or Devices for Psychiatric Disorders (U01) . Studies of multi-target drugs will be considered only if the study design can provide non-ambiguous results about the target of interest.

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), 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 (replicate the prior findings) in a larger clinical population.
• Animal studies are not responsive to this FOA.

Applicants must include all information described in the FOA instructions in Section IV.2 (Instructions for Application Submissions; Other Attachments; PHS 398 Research Plan; Research Stragety ). Incomplete applications will not be reviewed.

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 to discuss how to develop an appropriate project timeline, which is subject to peer review.

For multi-site trials, use of centralized IRBs is encouraged. 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.

Studies under this FOA should replicate preliminary demonstration of target engagement with a larger sample, and conduct a preliminary evaluation of the clinical effect of manipulating the target in a patient population.

Pilot studies supported by this FOA should not be powered as strong tests of clinical efficacy, but rather should test a hypothesis about the intervention’s ability to alter the target, and test the link between target engagement and functional outcomes in a patient population. In addition to the primary aim of linking target engagement and functional outcomes, 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 intervention’s feasibility, safety, and acceptability; 3) preliminary testing of the association between a change in the target, mechanisms of intervention response, and clinical outcomes; 4) evaluating the feasibility of recruitment, randomization (if appropriate), retention, assessments, and reporting of adverse events; and 5) developing functional target engagement and clinical outcome measures feasible for use in larger efficacy and effectiveness trials. The specific activities appropriate for this early stage intervention development study will depend on the type of intervention under study and the stage of the study proposed. The results should 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 change in clinical status. The study should also inform the design of a subsequent confirmatory efficacy trial, if warranted. For pharmacological interventions, unless preliminary data are available, studies must include determination of the optimal dose for a subsequent trial by assessing dose-response with respect to a functional pharmacodynamic readout of target engagement.

Additional information for FDA-regulated interventions

Medical devices. Given the varied nature of the regulatory path, investigators considering applications to evaluate devices are strongly encouraged to contact Scientific/Research Staff as early as possible to discuss these issues and determine the suitability of their project for this funding mechanism.

Pharmacological interventions. This FOA will support development of novel interventions for which there has been a demonstration of adequate functional target engagement. This FOA will support further development, including determining the optimal dose for a subsequent trial by assessing dose-response with respect to a functional pharmacodynamic readout of target engagement.

Applicants should refer to Clinicaltrials.gov for a review of the related FDA-regulated trials already underway or completed to help determine: 1) if the results of ongoing trials can inform the design of the proposed trial and 2) if the proposed trial is innovative.

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.

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.

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).

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

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

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: NIMHClinicalTrials@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. with the following additional instructions:

Other Attachments: Applicants should upload a single attachment including the following information relevant to the proposed clinical trial. This attachment must be no more than 4 pages. Applications that exceed this limit will not be reviewed. Applicants should use the headers below in their description. Applications that lack this attachment will be considered incomplete and will not be reviewed.

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

• Recruitment and Referral sources, including detailed descriptions of the census/rate of new cases and anticipated yield of eligible participants from each source;
• Procedures that will be used to monitor enrollment and track/retain participants for follow-up assessments;
• Strategies that will be used to ensure a diverse, representative sample;
• 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);
• Evidence to support the feasibility of enrollment, including descriptions of prior experiences and yield from research efforts employing similar referral sources and/or strategies.

II. Timeline: Applications must provide a 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) enrollment milestones; (d) completing all subject 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. The proposed timeline should describe projected specific, measureable and achievable progress throughout the project period, which can be used as an indicator of success.

III. Additional Information for FDA-regulated Pharmacological and Device-based Interventions: For studies of pharmacologic compounds and devices, at the time of the application’s submission, there must be either an open Investigational New Drug application (IND), Investigational Device Exemption (IDE), or a documented FDA-submitted application for an IND or IDE. The grant application should describe the status of any such pending regulatory submissions. All necessary agreements for use of the compound or device in the study, including clinical research agreements and licensing agreements, must be executed prior to grant award. For pharmacological compounds there must be documentation of a sufficient compound supply available for testing at the time of award, including expiration date. Documentation should include a letter of agreement from the 3rd party supplying the compound or device, if applicable. A timeline should be included in the application showing activities with 3rd parties, such as: 1) executing necessary agreements, 2) providing compound, and 3) permission to reference an open IND.

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

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 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. Describe 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:

Research Strategy: Applicants must include the following information as part of the Research Strategy. Applications should not duplicate information provided in the attachment described in Section IV.2., SF424 (R&R) Other Project Information , unless needed to provide context.

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

• Describe the unmet therapeutic need that might be addressed by the intervention. Describe the intervention’s potential to significantly reduce the burden of serious mental illness.
• Propose a novel intervention with a strong, well-supported theoretical rationale that is ready for early-phase testing, including preliminary evidence to suggest that the intervention can be administered in a dose that is sufficient to engage the target.
• 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:

• Provide a compelling scientific rationale for the approach chosen. Describe a novel, well-specified intervention target and/or a novel approach to engaging an established target. Present a clear conceptual framework that includes relevant empirical support for the intervention target, as well as hypothesized mechanisms of intervention effect.
• If the project concerns 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:

• Clearly define the target and the rationale for intervening on that target, such as evidence that the target is implicated in causing or maintaining the functional domain or symptom(s) of interest and/or that variability in the expression of the target is associated with variability in symptom severity or presentation.
• Describe a plan that rigorously tests intervention target engagement. Describe hypotheses that are scientifically grounded and theory-driven, about the hypothesized mediators, moderators, or mechanisms of the intervention’s effect.
• Provide the scientific rationale for the measures used to assess the link between the target and functional or clinical effect. Identify objective, quantifiable, and reproducible measures to assess target engagement and validation. 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.
• Describe how the intervention’s dose or protocol will be optimized (e.g., assessment of potency and selectivity) so as to convincingly test the underlying mechanistic hypotheses.
• For pharmacological trials, address the biological rationale for advancing the drug candidate chosen for development as a potential intervention for a mental disorder, functional domain, or symptom(s). The hypothesis should address a pathophysiologic mechanism that is altered by a specific molecular interaction of a compound at least at the level of initiating a series of events that does or does not lead to positive change. A clear description should be included of the approach for determining pharmacological dose/response relationships and target engagement of the drug candidate to determine a dose that adequately engages the target and alters a pharmacodynamics measure. Address whether a tolerable and safe dose range has been proposed that will adequately test the mechanism, so as to avoid revisiting future clinical efficacy trials with additional doses if therapeutic effects are not seen initially. Present a sufficiently robust and reproducible body of evidence to support the study hypothesis and rationale. Include pre-clinical data supporting the intervention approach and sufficient description of the specificity, safety, pharmacokinetics, pharmacodynamics, and brain penetration to support the study. Pharmacological agents must be sufficiently potent and selective for critical evaluation of target engagement and brain exposure.
• Describe how sufficient data will be collected to inform a decision about the therapeutic potential of the intervention (including evidence of safety, acceptability and feasibility; preliminary signal of efficacy; and strength of the association between target engagement and change in clinical status) and its target for further clinical development. Describe how each proposed measure will contribute to assessment of the relationships between intervention, target engagement, mechanism-based functional outcomes, and/or clinical outcomes. Describe the selection of the control condition and how it is likely to address the research question.
• For psychotherapeutic interventions, 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 how the combined expertise of the research team as a whole promotes synergy and covers the critical elements of clinical trials expertise, track record in successfully conducting early clinical trials (e.g., subject recruitment and retention rates, reporting in clinicaltrials.gov, publications, etc.), methodological and statistical expertise, and experience in the measurement of intervention change mechanisms (e.g., handling repeated measures designs, missing methods proposed (e.g., PET, fMRI, MRS).
• Describe the staffing, governance, and organizational structure for conducting the study as proposed and within specified timelines.
• 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.
• For studies that involve the assessment of patient-level outcomes, plans are expected that describe 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 (e.g., services interventions that target provider behavior or systems-level factors), 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.

Protections of Human Subjects: Describe key features of a safety monitoring plan including plans for efficient IRB review and approval including the use of centralized IRB models when multiple clinical sites are planned.

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

• It is strongly recommended that intervention 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. 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.

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 NIMH, 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 NOT-OD-13-030.

Important Update: See NOT-OD-16-006 and NOT-OD-16-011 for updated review language for applications for due dates on or after January 25, 2016.

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.

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, 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 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 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, e.g., PET, fMRI, MRS? 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 application introduce a novel, well-specified target and/or a novel approach to engaging established targets? Is the rationale for the intervention and its target based on empirical evidence about the mechanism involved in triggering or maintaining the disorder, and/or scientifically-grounded hypotheses about the mediators or mechanisms of intervention effect? Is the proposed intervention derived from a recent basic finding or translating an established finding in a novel way (e.g., methods or in 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 or different approach to the known target?

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 proposed study ensure that target engagement will be rigorously tested, and are hypotheses about mechanisms of intervention effect adequately evaluated?

For behavioral interventions, do fidelity measures include an assessment of the quality with which the therapist delivers the intervention so as to produce sufficient target engagement?

Are all the preparations necessary to start the study on time in place (e.g., are all regulatory approvals (IND, IDE) in place if required)?

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

Is there sufficient detail about intervention delivery and monitoring? 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 change in clinical status?

For pharmacologic agents, is there a strong justification for the approach for determining pharmacological effects and target engagement of the drug candidate? Is the rationale for the selection of the compound in terms of potency and selectivity strong? Is the approach feasible? Is there a compelling scientific rationale for the biological measures (mechanistic biomarker) used to assess the link between hypothesized drug mechanism/target and clinical effect?

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? 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? Is there a feasible timeline for establishing necessary agreements with all partners (e.g., compound supplier for drug studies)? Does the environment support timely subject recruitment? Is there evidence that all necessary regulatory clearances and permissions (e.g., IND for compound, permissions for rating scales) have been obtained or will be in place before funding?

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.

Is an appropriate, evaluative timeline clearly defined for the aims? Is the timeline feasible? Are the plans for sample size and timely recruitment of subjects feasible? Is there a clear strategy for tracking recruitment and facilitating retention?

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 Wide Association Studies (GWAS) /Genomic Data Sharing Plan.

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. 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. The proposed milestones may be modified in negotiations with NIMH program officials before an initial award is made, and during the review of annual non-competitive renewal applications. Agreed upon milestones will be included in the Notice of Award, and unmet milestones will be considered in the review and approval of these annual renewals.

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.

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 Research Performance Progress Report (RPPR) annually 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.

Recruitment Reporting and Trial Registration

NIMH requires reporting of recruitment milestones for participants in clinical trials as noted at https://grants.nih.gov/grants/guide/notice-files/NOT-MH-05-013.html. While trials in response to this FOA may not seek 150 subjects or more (the level at which this reporting has been required), we expect reporting for all trials, even those with less than 150 subjects.

The NIMH expects the registration and results reporting for all NIMH-supported clinical trials in ClinicalTrials.gov, regardless of whether or not they are subject to FDAAA (see https://grants.nih.gov/ClinicalTrials_fdaaa/at-a-glance.htm). We plan to include language regarding this expectation 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)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)
Finding Help Online: https://grants.nih.gov/support/index.html
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
Email: support@grants.gov

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-710-0267

For inquiries to the Division of Translational Research (DTR), about all pediatric intervention modalities:

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 Translational Research (DTR), about all adult intervention modalities:

Mi Hillefors, M.D., Ph.D.
National Institute of Mental Health (NIMH)
Telephone: 301-443-1692
Email: hillefom@mail.nih.gov

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

Rita Sisco
National Institute of Mental Health (NIMH)
Telephone: 301-443-2805
Email: siscor@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.