Department of Health and Human Services


Part 1. Overview Information
Participating Organization(s)

National Institutes of Health (NIH)

Components of Participating Organizations

National Institute of Mental Health (NIMH)

Funding Opportunity Title

Exploratory Clinical Trials of Novel Interventions for Mental Disorders (R21/R33)

Activity Code

R21/R33 Phased Innovation Award

Announcement Type

New

Related Notices

Funding Opportunity Announcement (FOA) Number

RFA-MH-15-300

Companion Funding Opportunity

RFA-MH-15-310, R33 Exploratory/Developmental Grants Phase II
PAR-14-107, U01 Research Project – Cooperative Agreements
RFA-MH-15-320, R01 Research Project
RFA-MH-15-325, Collaborative R01 Research Project
RFA-MH-15-330, R34 Clinical Trial Planning Grant Program 

Number of Applications

See Section III. 3. Additional Information on Eligibility.

Catalog of Federal Domestic Assistance (CFDA) Number(s)

93.242 

Funding Opportunity Purpose

The purpose of this Funding Opportunity Announcement (FOA) is to support the efficient pilot testing of novel interventions for mental disorders in adults and children through an experimental therapeutics approach. Under this FOA, trials must be designed so that results, whether positive or negative, will provide information of high scientific utility and will support “go/no-go” decisions about further development or testing of the intervention. Studies of novel interventions include, but are not limited to behavioral, pharmacological, biologics-based, cognitive, device-based, interpersonal, physiological, or combined approaches. Support will be provided for up to two years (R21 phase) for preliminary milestone-driven testing and validating of the intervention’s mechanism of action, possibly followed by up to 3 years of support (R33 phase) for studies relating the mechanism to functional or clinical effects. Ultimately, this R21/R33 funding mechanism is intended to speed the translation of emerging basic science findings of mechanisms and processes underlying mental disorders into novel interventions that can be efficiently tested for their promise in restoring function and reducing symptoms for those living with mental disorders.

Key Dates
Posted Date

February 24, 2014

Open Date (Earliest Submission Date)

May 17, 2014

Letter of Intent Due Date(s)

30 days before the application due date

Application Due Date(s)

June 17, 2014, October 17, 2014, and February 17, 2015, by 5:00 PM local time of applicant organization.

Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

AIDS Application Due Date(s)

Not Applicable

Scientific Merit Review

October 2014, February 2015, June 2015

Advisory Council Review

January 2015, May 2015, October 2015

Earliest Start Date

February 2015, June 2015, October 2015

Expiration Date

February 18, 2015

Due Dates for E.O. 12372

Not Applicable

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.


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Table of Contents

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

Part 2. Full Text of Announcement


Section I. Funding Opportunity Description
 
Research Objectives

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 Phased Innovation (R21/R33) 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 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). 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 considered 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 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 up to two years (R21 phase) for milestone-driven testing, refinement, replication, and/or validation of the intervention’s engagement with a well-defined, hypothesized target or mechanism of action with the possibility of up to 3 additional years of support (R33 phase) for studies to confirm target engagement in a larger sample and assess the relationship between target engagement and changes in functional outcomes or clinical symptoms. Results from the R33 phase should support a “go/no-go” decision about further development. This FOA encourages highly innovative projects, with the recognition that such projects may entail a greater failure rate. NIMH values this early, efficient, and objective testing of an intervention’s proposed mechanism of action to better define which interventions should and should not be further developed. This FOA uses a phased innovation approach (R21/R33) to manage the risk by requiring a demonstration of the intervention’s direct effects on its target before moving into the R33 phase of the award.

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 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 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-15-320 Clinical Trials to Test the Effectiveness of Treatment, Preventive, and Services Interventions (R01), RFA-MH-15-325 Clinical Trials to Test the Effectiveness of Treatment, Preventive, and Services Interventions (Collaborative R01) or RFA-MH-15-330 Pilot Effectiveness Studies and Services Research Grants (R34).

NIMH Priorities for Developing and Pilot-testing Interventions

Traditionally, exploratory clinical-trials in mental health involve 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 how the intervention might work or the underlying cause of the disorder and therefore provide little guidance for further treatment 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). The first stage is to demonstrate that the intervention exerts some measurable effect on a hypothesized “target” or mechanism of action; the intervention is used as a probe with the immediate goal of determining whether the intervention affects a target rather than attempting to demonstrate a clinical treatment effect. “Target engagement” refers to verification that the intervention has had the predicted effect on the target. Targets may be molecular, cellular, circuit, somatic, behavioral, or interpersonal, commensurate with the intervention. 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 intervention and posit the intervention’s “target” or mechanism of action by which the intervention might ultimately modify the functional domain or symptom(s) of interest. Objective, quantifiable, and reproducible measures of both target engagement and the intervention’s clinical effects should be detailed in any application submitted to this FOA. A successful application should provide a rigorous response to these two questions: Will the result, whether positive or negative, be informative and provide a definitive test of the hypothesis? Will results be informative about the potential role of the target in the clinical disorder?

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.

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

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

Applicants are strongly encouraged to consult with NIMH staff when developing plans for an application (see Agency Contacts, Section VIII).  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. 

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.

The R21 Phase 

The R21 phase focuses on testing whether the proposed intervention actually alters the presumed target mechanism of action and may include preliminary evaluation of the clinical effect of manipulating the target.  The specific activities and milestones appropriate for the R21 phase will depend on the type of intervention under study and its stage of development.  Generally, these activities and milestones include: 1) operational definition and objective measures of the target (i.e., the hypothesized mechanism of action); 2) evidence that the operational measures of mechanism of action can be reliably and validly manipulated; 3) demonstration of adequate target engagement, including established dose selection; 4) feasibility data to indicate that an adequate dose of the intervention (defined by target engagement) can be applied in the select human population with adequate safety and tolerability; 5) initial manual or protocol development along with initial fidelity scales; and 6) adequate recruitment plans. 

The applicant must justify the need for the R21 phase.  Applications using only the R21 mechanism or only the R33 mechanism will not be accepted under this FOA.  Applicants who already have sufficient preliminary data to progress to the R33 phase should apply directly to RFA-MH-15-310 "Exploratory Clinical Trials of Novel Interventions for Mental Disorders (R33)".

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.  The R21 phase will support development of novel interventions, including determining the optimal dose for a subsequent trial by assessing dose-response with respect to a functional pharmacodynamic readout of target engagement.  Adequate functional target engagement must be a key criterion of a “go/no-go” decision to move from the R21 to R33 phase.

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.     

The R33 Phase

Funding for the R33 phase is contingent on successfully meeting the milestones in the R21 phase (see Section VI. Award Administration Information,1. Award Notices for further information).

The R33 phase should test the link between the degree of target engagement and mechanism-based functional outcomes in a patient population. Pilot studies supported by the R33 should not be powered as strong tests of clinical efficacy, but rather should test a hypothesis about the intervention’s mechanism of action and inform a “go/no-go” decision about whether the intervention warrants further study. In addition to prior demonstration of target engagement, preliminary data for proposed studies should include dose finding, safety, and tolerability data, as appropriate, to justify the stage of the study. In addition to the primary aim of linking target engagement and functional outcomes, secondary aims in the R33 phase 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 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 the R33 phase will depend on the type of intervention under study and the stage of the study proposed. 

Other Resources

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. 

Section II. Award Information
Funding Instrument

Grant: A support mechanism providing money, property, or both to an eligible entity to carry out an approved project or activity.

Application Types Allowed

New
Resubmission
Revision

The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.

Funds Available and Anticipated Number of Awards

NIMH intends to commit approximately $2,500,000 across FY 2015 and FY 2016 to fund 5-10 new awards in response to this FOA.  Future year amounts will depend on annual appropriations.

Award Budget

Application budgets are not limited but need to reflect the actual needs of the proposed project.

Award Project Period

The scope of the proposed project should determine the project period.  The maximum period of the combined R21 and R33 phases is 5 years, with up to 2 years for the R21 phase and up to 3 years for the R33 phase.  Applications with a project period less than 5 years are encouraged where feasible. 

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.

Section III. Eligibility Information


1. Eligible Applicants


Eligible Organizations

Higher Education Institutions

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

Nonprofits Other Than Institutions of Higher Education

For-Profit Organizations

Governments

Other

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.

Required Registrations

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.

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

All PD(s)/PI(s) must have an eRA Commons account and should work with their organizational officials to either create a new account or to affiliate an existing account with the applicant organization’s eRA Commons account. 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.

Eligible Individuals (Program Director/Principal Investigator)

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.

2. Cost Sharing

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

3. Additional Information on Eligibility


Number of Applications

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:

Section IV. Application and Submission Information


1. Requesting an Application Package

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.

2. Content and Form of Application Submission

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.

Letter of Intent

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:

The letter of intent should be sent to:

NIMHClinicalTrials@mail.nih.gov

Page Limitations

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

Required and Optional Components

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.

Instructions for Application Submission

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.

SF424(R&R) Cover

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

SF424(R&R) Project/Performance Site Locations

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

SF424(R&R) Other Project Information

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. 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:

II.  Additional information for FDA-regulated pharmacological interventions:

SF424(R&R) Senior/Key Person Profile

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 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.

R&R Budget

All instructions in the SF424 (R&R) Application Guide must be followed. The R21/R33 Phased Innovation Award application must be submitted as a single application with one Research & Related Budget component.

PHS 398 Cover Page Supplement

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

PHS 398 Research Plan

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

Specific Aims:  Include headers titled R21 Specific Aims and R33 Specific Aims and state the specific objectives of the research effort in the two phases of this project.  Provide a concise description of the exploratory clinical trial as well as how the proposed intervention could fill an important unmet need for those living with mental illnesses. 

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

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

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

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

Milestones and Timeline:  Applications must provide:

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:

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.

The following additional documents may be included:

Planned Enrollment Report

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

PHS 398 Cumulative Inclusion Enrollment Report

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

Foreign Institutions

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.

3. Submission Dates and Times

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.

4. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

5. Funding Restrictions

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.  

6. Other Submission Requirements and Information

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.

Use of Common Data Elements in NIH-funded Research

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.

Post Submission Materials

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-13-030.

Section V. Application Review Information


1. Criteria

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

For this particular announcement, note the following:

For this R21/R33 grant activity, peer review will evaluate the specific goals for each phase and the milestones that would justify expansion to the R33 phase.  A single impact score will be assigned to each discussed application.  Peer reviewers should be sure to address the strengths and weaknesses of each phase of the award in their review as both phases may not garner the same degree of enthusiasm.    

Overall Impact

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).

Scored Review Criteria

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 need for those living with a mental disorder? Will the study advance the knowledge of the functional domain, symptoms, or diagnosis of interest? Does a robust and reproducible body of evidence support the study hypothesis and rationale? Does the proposed project 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 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? Is 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? 

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)? Where applicable, 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) paring the intervention down to its essential elements based on clear evidence of target engagement? Where applicable, is the proposed intervention directed to a recent basic finding or translating an established finding in a novel way (e.g., methods or in a developmental framework)?

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 approach present scientifically-grounded, theory-derived hypotheses about the mechanism involved in triggering or maintaining the disorder, and the mediators or mechanisms of treatment effect? Does the proposed study ensure that the underlying hypothesized target mechanism will be rigorously tested? Are subject inclusion/exclusion criteria well-justified and is the selection made on the basis of a measurable disruption in the mechanism under study? Will the inclusion/exclusion criteria maximize the probability that all subjects share the same perturbation?

When appropriate, does the study design take functional domains, e.g., RDoC constructs, into account in defining the subject eligibility, hypothesis, and outcomes?

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)?

Is the need for the R21 phase well justified? Does the application provide sufficient detail regarding how the delivery of the intervention will be operationalized, monitored, and quantified? Does the R21 application include valid measures of the intervention’s target engagement or are the procedures to validate appropriate? Is there a compelling scientific rationale for the measures to assess the link between the hypothesized target mechanism and functional or clinical effect? Are the measurement schedules suitable for detecting relevant changes in the target?

Does the R33 phase include sound methodology for (a) replicating and extending the initial target engagement findings from the R21 phase, and (b) evaluating associations between target engagement and subsequent clinical or functional change (target validation)?  Is the selection of the control condition(s) in the R33 phase likely to address the research questions rigorously? 

Are plans for data analyses, data management, and quality control adequate to allow others to reanalyze results, including with alternate approaches? Is the approach feasible in terms of realistically having in place everything necessary to carry out data acquisition and analysis in a timely manner? Are there clear, actionable study milestones proposed for moving from the R21 to the R33 phase, including feasible subject accrual goals? Are likely problems anticipated? Will sufficient and appropriate data be collected in the R33 phase to inform a “go/no-go” decision about the therapeutic target for further clinical development?

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? 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 and completion of each of the two phases (R21 and R33)? 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?

Additional Review Criteria

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

R21 Milestones: Are quantitative criteria pre-specified and rigorously defined to assess milestone achievement and operational feasibility relevant to advancing from the R21 to the R33 phase? Are success criteria defined in terms of outcomes achieved rather than as tasks completed? Are R21 milestones feasible, well developed and quantifiable with regard to the specific aims of each stage? Is the timeline feasible? Specifically, will the investigators and NIMH Program Officials be able to determine if the project succeeded in (a) demonstrating that the intervention alters the targeted mechanism (thus providing an initial proof of principle), and (b) providing preliminary evidence that the intervention can be applied in a clinical population with adequate acceptability and tolerability to patients? Do the milestones explicitly assess whether the analysis of the proposed measures can be carried out in a sufficiently timely manner to adaptively adjust sample size should starting assumptions prove incorrect? Do the interim milestones include a futility analysis to assess feasibility for continuing the study if a measure of target engagement or activity is not sufficiently robust to inform dose selection for a potential R33 phase? Does the application specify conditions under which they would not proceed to the R33 phase?

R33 Milestones: Are appropriate, evaluative milestones clearly defined for the aims associated with the R33 phase? Are R33 milestones feasible, well developed and quantifiable with regard to the specific 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? 

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

Not Applicable

Biohazards

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

Resubmissions

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

Renewals

Not Applicable

Revisions

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

Additional Review Considerations

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.

2. Review and Selection Process

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:

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:

3. Anticipated Announcement and Award Dates

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.

Section VI. Award Administration Information


1. Award Notices

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.

Prior to funding an application, the NIMH Program Officer will contact the applicant to discuss the proposed milestones and any changes suggested by the review panel as indicated in the Summary Statement.  The Program Officer and the applicant will negotiate and agree on a final set of R21 milestones.  For funded applications, the Project Director/Principal Investigator (PD/PI) will submit a progress report to the Program Officer upon completion of the R21 milestones.  Receipt of this progress report will trigger an administrative program review that will determine whether or not the R33 should be awarded.  The release of R33 funds will be based on successful completion of negotiated scientific milestones, on program priorities, and on the availability of funds. The R21 and R33 cannot be funded in the same fiscal year.

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.

2. Administrative and National Policy Requirements

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

3. Reporting

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. 

Recruitment Reporting and Trial Registration

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.

Section VII. Agency Contacts

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

Application Submission Contacts

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)

Web ticketing system: https://public.era.nih.gov/commonshelp
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: 301-435-0714
TTY: 301-451-5936
Email: GrantsInfo@nih.gov

Scientific/Research Contact(s)

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

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

Peer Review Contact(s)

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

Financial/Grants Management Contact(s)

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

Section VIII. Other Information

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.

Authority and Regulations

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.


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