Confirmatory Efficacy Clinical Trials of Non-Pharmacological and Pharmacological Interventions for Mental Disorders (R01 Clinical Trial Required)

Confirmatory Efficacy Clinical Trials of Non-Pharmacological and Pharmacological Interventions for Mental Disorders (R01 Clinical Trial Required) is sponsored by NIH. Supports confirmatory efficacy trials of interventions for mental disorders, including those targeting emotional regulation.

PAR-25-179: Confirmatory Efficacy Clinical Trials of Non-Pharmacological and Pharmacological Interventions for Mental Disorders (R01 Clinical Trial Required) This funding opportunity was updated to align with agency priorities. Carefully reread the full funding opportunity and make any needed adjustments to your application prior to submission. 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 Confirmatory Efficacy Clinical Trials of Non-Pharmacological and Pharmacological Interventions for Mental Disorders (R01 Clinical Trial Required) R01 Research Project Grant Notices of Special Interest associated with this funding opportunity March 31, 2025 - This funding opportunity was updated to align with agency priorities.

Carefully reread the full funding opportunity and make any needed adjustments to your application prior to submission. April 4, 2024 - Overview of Grant Application and Review Changes for Due Dates on or after January 25, 2025. See Notice NOT-OD-24-084 .

August 31, 2022 - Implementation Changes for Genomic Data Sharing Plans Included with Applications Due on or after January 25, 2023. See Notice NOT-OD-22-198 . August 5, 2022 - Implementation Details for the NIH Data Management and Sharing Policy.

See Notice NOT-OD-22-189 .

Funding Opportunity Number (FON) Companion Funding Opportunity Research Project (Cooperative Agreements) Exploratory/Developmental Grants Phase II Phase 1 Exploratory/Developmental Grant/ Exploratory/Developmental Grants Phase II Exploratory/Developmental Grants Phase II Phase 1 Exploratory/Developmental Grant/ Exploratory/Developmental Grants Phase II Phase 1 Exploratory/Developmental Grant/ Exploratory/Developmental Grants Phase II See Section III.

3. Additional Information on Eligibility . Assistance Listing Number(s) Funding Opportunity Purpose The purpose of this NOFO is to support confirmatory efficacy testing of non-pharmacological preventive and therapeutic interventions, and under certain conditions, selected pharmacological interventions for mental disorders in adults and children through an experimental therapeutics approach.

Under this NOFO, 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, effectiveness testing, or dissemination of the intervention.

Interventions to be studied include, but are not limited to, behavioral, cognitive, interpersonal, and device-based (both invasive/surgically implanted as well as noninvasive/transcranial) approaches, or a combination thereof. Pharmacological interventions to be studied under this grant mechanism are expected to primarily focus on drugs approved for marketing by the FDA (for any indication).

These will include medications off-patent which are undergoing development for a new mental health indication. Confirmatory efficacy trials studying monotherapy, combination treatments, and stepped approaches, including multiple treatment modalities, may be supported.

Interventions appropriate for efficacy testing must be based on a compelling scientific rationale, previous demonstration that the intervention engages and alters the hypothesized mechanism of action (target), a preliminary efficacy signal, and must address an unmet therapeutic need.

Support will be provided for a trial of the intervention's efficacy that includes measurement of the hypothesized mechanism of action and the relationship between change in the target mechanism and change in functional or clinical effects. Ultimately, this NOFO is intended to support a sufficiently-powered efficacy trial to determine the intervention's potential for significant clinical benefit.

Applicants pursuing other stages of the clinical trial pipeline should consider one of the companion NOFOs listed above. Funding Opportunity Goal(s) The mission of the National Institute of Mental Health (NIMH) is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery, and cure.

Open Date (Earliest Submission Date) Renewal / Resubmission / Revision (as allowed) AIDS - New/Renewal/Resubmission/Revision, as allowed All applications are due 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.

Required Application Instructions It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide , except where instructed to do otherwise (in this NOFO or in a Notice from NIH Guide for Grants and Contracts ). Conformance to all requirements (both in the Application Guide and the NOFO) 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.

There are several options available to submit your application through Grants. gov to NIH and Department of Health and Human Services partners. You must use one of these submission options to access the application forms for this opportunity.

Use the NIH ASSIST system to prepare, submit and track your application online. Use an institutional system-to-system (S2S) solution to prepare and submit your application to Grants. gov and eRA Commons to track your application.

Check with your institutional officials regarding availability. Workspace to prepare and submit your application and eRA Commons to track your application. Part 1.

Overview Information Part 2. Full Text of Announcement Section I. Notice of 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.

Notice of Funding Opportunity Description The purpose of this notice of funding opportunity (NOFO) is to support confirmatory efficacy testing of non-pharmacological and, under certain conditions, pharmacological, therapeutic and preventive interventions for mental disorders in adults and children that address unmet therapeutic needs, and are consistent with the NIMH emphasis on the experimental therapeutics approach .

In this approach, clinical trials should be designed to increase knowledge of the relationship between underlying disease processes and the targets/mechanisms of action through which any intervention produces therapeutic change.

Therefore, interventions appropriate for confirmatory efficacy testing must be based on a compelling scientific rationale, previous demonstration that the intervention engages and alters the hypothesized mechanism of action, and a preliminary efficacy signal (for further information, see the NIMH webpage on Clinical Trials ).

The proposed trial must include plans to replicate these target engagement and validation findings in a fully powered, confirmatory efficacy study that is likely to show superiority of the intervention over an appropriately justified comparison condition.

Interventions appropriate to this NOFO may include in-person or technology-assisted psychosocial intervention approaches, device-based approaches (both invasive and non-invasive), or combinations of these approaches as monotherapies, stepped approaches, or as augmentations to standard interventions.

While this NOFO will support efficacy testing of novel technology-assisted intervention approaches, it is not intended to support the translation of existing treatments into technology-based applications (e.g., mHealth). FDA-indicated drugs may be included as part of a combination treatment when the intent is to test the efficacy of the other (novel) non-pharmacological treatment component or the novel combination.

However, applications to establish the efficacy of pharmacological interventions will be considered responsive to this NOFO primarily for drugs lacking a commercial sponsor and otherwise meeting the criteria for confirmatory efficacy testing as described in this announcement.

While in the usual case of drug development leading to regulatory approval for marketing, confirmatory efficacy and subsequent effectiveness clinical trials would be supported by the industry sponsor, the presence of an industry sponsor will not preclude support of pharmacotherapy confirmatory efficacy clinical trials that are designed to address important scientific questions of public health significance during drug development; such applications should indicate whether the sponsor is supplying the drug without costs.

Scale and Scope of Research Under the required experimental therapeutics approach (see " An Experimental Therapeutic Approach to Psychosocial Interventions "), intervention targets, or mediators, might include, but are not limited to, potentially modifiable specific psychological, behavioral, or interpersonal processes (e.g., cognitive-affective processes such as attention bias, cognitive control, stress regulation) or neurobiological processes or entities (e.g., brain circuits).

Circuit-based targets can include networks of brain regions defined anatomically as well as temporal dynamics of network function defined physiologically as neural oscillatory patterns. The intended target(s)/mechanism(s) and clinical endpoints will vary with the type of intervention.

In the case of preventive interventions, the proximal target might involve a risk factor that has been associated with the etiology or onset of a mental health disorder. Accordingly, the intervention's efficacy might be evaluated in terms of whether or not the intervention, mediated by changes in the target, resulted in decreased onset of the mental health disorder/condition (i.e., the clinical endpoint).

More than one target/mechanism may be proposed if each target/mechanism is supported by an empirical rationale, there are testable hypotheses proposed for each, and there are valid and reliable measures of change available for each. In the assessment of target engagement, NIMH encourages the use of measures that are as direct and objective as is feasible in the clinical research setting.

Specifically encouraged are empirically validated measures of the construct that extend beyond self-reports and other subjective measures, where possible, and inclusion of measures that span more than one level of assessment if possible and appropriate. The detailed data analysis plan for examining changes in targets and related changes in outcomes should be included in the Research Strategy of the application.

This NOFO supports confirmatory efficacy trials of non-pharmacological and pharmacological therapeutic and preventive interventions that are powered to provide a definitive answer regarding the study intervention's efficacy.

PD(s)/PI(s)s submitting applications consistent with the NIMH experimental therapeutic approach but whose application does not fall within the scope of this NOFO are encouraged to contact Scientific/Research staff or view the NIMH Clinical Trial web page and Frequently Asked Questions section: http://www. nimh. nih.

gov/funding/clinical-trials-for-researchers/index. shtml . This NOFO is focused on trials that establish the efficacy of interventions.

Applications that involve adding a new level of analysis to assess or better understand mechanisms of an established intervention (e.g., a study that adds brain-based assessments such as neuroimaging or psychophysiological measures to evaluate neurobiological underpinnings/correlates that are associated with changes in cognitive/affective processes commonly targeted by CBT) are encouraged to consult NIMH Program Staff and consider NOFOs that NIMH uses to support mechanistic trials (see Support for Clinical Trials at NIMH ).

Applicants interested in initial intervention development and pilot testing of novel non-pharmacological interventions are directed to PAR-25-182 Development of Psychosocial Therapeutic and Preventive Interventions for Mental Disorders (R61/R33)" and PAR-25-181 "Development of Psychosocial Therapeutic and Preventive Interventions for Mental Disorders (R33)" for psychosocial interventions and to PAR-25-184 , "Early Stage Testing of Pharmacologic or Device-based Interventions for the Treatment of Mental Disorders (R61/R33)" and PAR-25-183 "Early Stage Testing of Pharmacologic or Device-based Interventions for the Treatment of Mental Disorders (R33)" for pharmacological and device-based intervention development and pilot testing.

Investigators interested in conducting fully-powered effectiveness trials in community-practice settings are referred to PAR-25-177 "Full-Scale Hybrid Effectiveness-Implementation Trials for Mental Health Interventions (R01 Clinical Trial Required). A review of the NIMH role in several aspects of medication development can be found in the report of the 2020 NAMHC Workgroup on Drug Development.

Potential applicants are strongly encouraged to contact the Scientific/Research contacts far in advance as possible to discuss the potential clinical practice/public health impact of the proposed confirmatory efficacy investigation, as well as concordance with current NIMH priorities. NIMH Priorities for Confirmatory Efficacy Trials NIMH is interested in pivotal studies to enable device-based interventions to receive FDA approval.

Studied interventions should be compared against established treatments in superiority or non-inferiority trials, based on the clinical context. It is advised that research groups consider utilizing a project manager with industry experience in managing clinical trials to oversee their pivotal study.

Contract Research Organizations (CROs) or institutions with Clinical and Translational Science Awards (CTSAs) may be appropriate to conduct device trials. FDA involvement may not be necessary for those trials where device-based measures are employed as a component of an intervention that is centered on a psychosocial or software-based treatment that is the focus of establishing confirmatory efficacy.

This NOFO supports confirmatory efficacy trials of interventions for which preliminary evidence of target engagement has already been demonstrated and there is a signal suggesting clinical efficacy that serves as a basis for anticipating at least a moderate clinically meaningful effect size (d = 0. 5) in the fully-powered confirmatory efficacy trial.

The earlier stages of intervention development, which include optimization of intervention delivery parameters, preliminary tests of target engagement, and target validation, are not appropriate for this NOFO and are supported by NIMH through companion NOFOs ( NIMH Clinical Trials NOFO page ).

It is expected that the design of the trial would inform the next stage of intervention development, whether that be an effectiveness trial, further investigation in dissemination and/or implementation research, or actual dissemination into practice.

NIMH is particularly interested in the development of therapeutic and preventive interventions that focus on operationally defined, empirically supported functional domains or symptom(s) of mental disorders as opposed to broad diagnostic categories in which not all subjects may share the same underlying disease process.

NIMH Research Domain Criteria (RDoC ) principles and constructs should, as appropriate, inform subject eligibility or stratification, identification of intervention targets, and/or selection of outcome measures, and in many cases can serve to complement traditional DSM diagnostic categories. Studies that incorporate a deployment-focused approach are encouraged.

Deployment-focused research considers the perspective of key stakeholders (e.g., service users, providers, administrators, payers) and the characteristics of the settings (e.g., resources, including workforce capacity; existing clinical workflows) where optimized mental health interventions and services are intended to be implemented, and are likely to be feasible and scalable.

Applications Not Responsive to this NOFO Studies that are not responsive to this NOFO and will not be reviewed include the following: Applications that test efficacy of a new intervention that is undergoing initial development with the ultimate aim of seeking FDA approval that fail to meet NIMH Clinical Trial experimental therapeutics requirements.

Applications that are not focused on a functional domain, symptoms, or mental health disorder. Applications that focus on efficacy without having already established compelling evidence of target engagement and at least initial evidence for target validation, in addition to an initial efficacy signal.

Applications that do not propose an experimental therapeutics approach (i.e., do not test a mechanism of action), including the following components of the application: (1) specified target(s)/mechanism(s) of action; (2) measurement plans designed to assess the target(s)/mechanism(s) of action and clinical outcomes; and (3) a description of the analytic plan for evaluating whether intervention-induced target(s)/mechanism(s) of action are associated with outcomes.

Applications that involve adding a new level of analysis to assess or better understand mechanisms of an established intervention (e.g., a study that adds brain-based assessments such as neuroimaging or psychophysiological measures to evaluate neurobiological underpinnings/correlates that are associated with changes in cognitive/affective processes commonly targeted by CBT (see Support for Clinical Trials at NIMH ).

Adaptation of an efficacious intervention in the absence of a compelling justification for such a need, and in the absence of a clear experimental therapeutics approach (in the NAMHC Workgroup Report, “ From Discovery to Cure: Accelerating the Development of New and Personalized Interventions for Mental Illnesses ,” see Recommendation 2. 4.

1, page 19, for additional guidance regarding the empirical justification for intervention adaptations and augmentations.) Studies involving vertebrate animals.

For applications that plan to test the efficacy of devices that require federal regulatory approval processes, NIMH expects FDA guidance meetings to be performed prior to submission of the application, so that information from the guidance meeting is incorporated into the protocol design. Documentation of discussions and meetings with FDA staff should be included in the application.

While digital mental health interventions that meet the above criteria are acceptable for confirmatory efficacy testing, given the inherent necessity of scalability and implementation in the community for such approaches, most mobile-application-based treatment studies are supported using an Effectiveness Clinical Trial mechanism ( PAR-25-177 ; PAR-25-178 ) or the Laboratories to Optimize Digital Health mechanism ( PAR-25-136 ).

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. Applicants are also expected to use common data collection instruments (see: NOT-MH-20-067 ).

Data and Safety Monitoring: The NIMH has published updated policies and guidance for investigators regarding human research protection and clinical research data and safety monitoring ( NOT-MH-19-027 ) and Conducting Research with Participants at Elevated Risk for Suicide: Considerations for Researchers) .

The application's PHS Human Subjects and Clinical Trials Information, including the Data and Safety Monitoring Plan, should reflect the policies and guidance in this notice. Applications with data collection plans that involve multiple respondent groups should include human subject protections, consenting procedures, and planned enrollment tables for each participant group.

Plans for the protection of research participants and data and safety monitoring will be reviewed by the NIMH for consistency with NIMH and NIH policies and federal regulations. Investigators proposing NIH-defined clinical trials may refer to the Research Methods Resources website for information about developing statistical methods and study designs. See Section VIII.

Other Information for award authorities and regulations. Section II. Award Information Grant: A financial assistance mechanism providing money, property, or both to an eligible entity to carry out an approved project or activity.

Application Types Allowed The OER Glossary and the How to Apply Application Guide provide details on these application types. Only those application types listed here are allowed for this NOFO. Required: Only accepting applications that propose clinical trial(s).

Need help determining whether you are doing a clinical trial? Funds Available and Anticipated Number of Awards NIMH intends to commit a total of $27,000,000 million for FY 2026 to fund this NOFO and the companion NOFOs listed in Part 1. Overview Information.

Future year amounts will depend on annual appropriations Application budgets are not limited but need to reflect the actual needs of the proposed project. The maximum project period is 5 years; however, applicants are strongly encouraged to consider efficiencies and projects of shorter duration, as feasible.

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from this NOFO. Section III.

Eligibility Information Higher Education Institutions Public/State Controlled Institutions of Higher Education Private Institutions of Higher Education 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 (Other than Small Businesses) 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 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 Non-domestic (non-U.S.) Entities (Foreign Organizations) Non-domestic (non-U.S.) Entities (Foreign Organizations) 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 must complete and maintain the following registrations as described in the How to Apply- 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. Failure to complete registrations in advance of a due date is not a valid reason for a late submission, please reference the NIH Grants Policy Statement Section 2.

3. 9. 2 Electronically Submitted Applications for additional information.

System for Award Management (SAM) – 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. Unique Entity Identifier (UEI) - A UEI is issued as part of the SAM. gov registration process.

The same UEI must be used for all registrations, as well as on the grant application. eRA Commons - Once the unique organization identifier is established, organizations can register with eRA Commons in tandem with completing their Grants. gov registrations; all registrations must be in place by time of submission.

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 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.

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 their organization to develop an application for 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 How to Apply-Application Guide. This NOFO does not require cost sharing as defined in the NIH Grants Policy Statement Section 1. 2 Definition of Terms .

3. Additional Information on Eligibility 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, per NIH Grants Policy Statement Section 2.

3. 7. 4 Submission of Resubmission Application .

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 NIH Grants Policy Statement 2. 3. 9.

4 Similar, Essentially Identical, or Identical Applications ). Section IV. Application and Submission Information 1.

Requesting an Application Package The application forms package specific to this opportunity must be accessed through ASSIST, Grants. gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.

gov Workspace are available in Part 1 of this NOFO. See your administrative office for instructions if you plan to use an institutional system-to-system solution. 2.

Content and Form of Application Submission It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide except where instructed in this notice of funding opportunity 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. All page limitations described in the How to Apply- Application Guide and the Table of Page Limits must be followed. Instructions for Application Submission The following section supplements the instructions found in the How to Apply- Application Guide and should be used for preparing an application to this NOFO.

All instructions in the How to Apply - Application Guide must be followed. SF424(R&R) Project/Performance Site Locations All instructions in the How to Apply- Application Guide must be followed. SF424(R&R) Other Project Information All instructions in the How to Apply- Application Guide must be followed.

Facilities and Other Resources: Provide the description of the resources available which include an overview of the institutional environment and expected commitment, as reflected in physical resources, staffing – including any expertise contributed by individuals not listed as “key personnel” – governance, and organizational structure as appropriate to conduct the study as proposed and within efficacy clinical trial principles and specified timelines.

Address how the proposed study utilizes relevant existing infrastructure (e.g., electronic medical records, administrative databases, patient registries) or utilizes other available resources to increase the efficiency of participant recruitment and data collection. Discuss ways that the proposed confirmatory efficacy clinical trial will benefit from unique features of the scientific environment or from unique subject populations.

If multiple performance sites are planned, describe intended collaborative arrangements and the resources available at each site. SF424(R&R) Senior/Key Person Profile All instructions in the How to Apply- Application Guide must be followed.

As appropriate, biographical sketches and the Research Strategy section are required to detail the expertise and track record of the Senior/Key Personnel in clinical trials of similar structure and complexity, including: recent subject recruitment and retention rates of trial subjects; reporting in ClinicalTrials.

gov; publications; methodological and statistical expertise (e.g., handling repeated measures designs, missing data; assessing effect size; and measurement of intervention change mechanisms). Also include recent collaborative clinical research efforts among members of the proposed team, if any. All instructions in the How to Apply- Application Guide must be followed.

All instructions in the How to Apply-Application Guide must be followed. PHS 398 Cover Page Supplement All instructions in the How to Apply- Application Guide must be followed. All instructions in the How to Apply- 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 Other Attachment included on the PHS Human Subjects and Clinical Trial Information form, but can refer to it as needed in order to provide context.

Applications must address the transportability/scalability of the proposed intervention and should detail how the treatment manual, therapist training procedures, and fidelity assessment and enhancement methods could be adapted and refined to be applicable to clinical practice.

Justify the potential impact of the intervention compared to existing approaches and should address the degree to which the proposed intervention could potentially be brought to scale in an effectiveness study or be disseminated into practice. Factor 1. Importance of the Research Describe the unmet therapeutic need that will be addressed by the intervention.

Describe the intervention's potential to significantly reduce the burden of serious mental disorders. Describe how the proposed project will advance knowledge of pathophysiologic and/or psychopathologic mechanisms relevant to the functional domain, symptom(s) or diagnosis of interest, or mechanisms that underlie intervention response, whether the trial results are positive or negative.

Describe the rationale for the anticipated effect size and explain how it is clinically meaningful. Describe the scientific advances to be gained in the research study. Describe how technology or other innovative approaches will be leveraged, as appropriate, to facilitate the delivery, efficacy, and future scalability of the approach that is being evaluated.

Factor 2.

Rigor and Feasibility Approach: In this section of the Research Strategy: Provide a compelling scientific rationale for the approach chosen, including: 1) theory-driven, scientifically grounded, and refutable hypotheses about the mechanisms involved in triggering or maintaining the disorder and the mechanisms/mediators of the intervention's effect; 2) a description of how the approach will ensure that the underlying hypothesized target(s)/mechanism(s) will be tested; and 3) a detailed data analysis plan for examining changes in target(s)/mechanism(s) and related changes in outcomes.

For multi-component interventions, hypothesized targets/mechanisms are expected for each intervention component.

If testing an adaptation or extension of an intervention with established efficacy, describe how the study will focus on providing clear evidence of target engagement 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.

Describe the existing evidence of the intervention's potential, including 1) evidence of the intervention's target/mechanism engagement (e.g., a significant difference in target/mechanism change between the experimental and control groups); 2) preliminary evidence of target/mechanism validation (e.g., a signal that changes in the presumed target/mechanism are associated with changes in the clinical outcome in the hypothesized direction); and 3) an initial efficacy signal that serves as a basis for anticipating at least a moderate clinically meaningful effect size (d=0.

5) in the fully-powered confirmatory efficacy trial. Describe the empirical foundation for the intervention dosage and delivery parameters. For psychosocial interventions, these parameters may include duration, frequency, and number of sessions.

For computer-administered interventions, parameters may include the stimulus characteristics, number of trials, difficulty level and intervals between trials. For pharmacological interventions, these parameters include dose, formulation, mode and frequency of administration, and duration of treatment course.

For neuromodulatory interventions, these parameters include all aspects of the administered electric field or alternative form of energy, including the spatial distribution (including specification of the electric field distribution in the brain as quantified via realistic head modeling), the temporal characteristics (including all aspects of pulse shape, pulse directionality, frequency, inter-train interval, burst paradigms, etc.), and the contextual aspects of when and how the dose is administered (e.g., time-locking to underlying neural oscillations, brain state at time of administration, engagement in on-line or off-line cognitive/behavioral therapies, concomitant pharmacological intervention, etc.).

Describe preliminary evidence of feasibility, including the availability of intervention manuals and fidelity measures. Provide the scientific rationale for the measures used to assess the link between the hypothesized target(s)/mechanism(s) and clinical/functional outcomes, including measurement reliability and validity, and measurement schedules suitable for detecting relevant changes in target(s)/mechanism(s).

Explain how the delivery of the intervention will be operationalized, monitored, and quantified, including any modifications to existing treatment manuals and fidelity measures. For neuromodulatory interventions, this should include information on device operator performance and accuracy in site identification and dosage individualization.

Describe features that will be incorporated to help ensure that the approach can be feasibly implemented in practice, and