PAR-25-207: Effectiveness Trials for Post-Acute Interventions and Services to Optimize Longer-term Outcomes (R01 Clinical Trial Required)

PAR-25-207: Effectiveness Trials for Post-Acute Interventions and Services to Optimize Longer-term Outcomes (R01 Clinical Trial Required) is sponsored by National Institutes of Health (NIH). Encourages clinical trials to evaluate the effectiveness of therapeutic and service delivery interventions for post-acute management of mental health conditions.

PAR-25-207: Effectiveness Trials for Post-Acute Interventions and Services to Optimize Longer-term Outcomes (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 Effectiveness Trials for Post-Acute Interventions and Services to Optimize Longer-term Outcomes (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 See Section III. 3.

Additional Information on Eligibility . Assistance Listing Number(s) Funding Opportunity Purpose NIMH seeks applications for research projects to evaluate the effectiveness of therapeutic and service delivery interventions for the post-acute management of mental health conditions affecting youth, adults, and older adults.

This notice of funding opportunity (NOFO) encourages clinical trials to establish the effectiveness and test hypotheses regarding mechanisms of action, mediators, and predictors and moderators of post-acute phase therapeutic and services interventions that are matched to the stage of illness in terms of both their focus (e.g., consolidating and maintaining gains from initial treatment, managing residual symptoms/impairment, preventing relapse, promoting adherence and appropriate service use) and intensity/burden for promoting optimal longer-term outcomes.

This NOFO is intended to support trials that are statistically powered to provide a definitive answer regarding the effectiveness of the post-acute phase intervention.

Support for pilot effectiveness trials designed to evaluate the initial feasibility, tolerability, acceptability, safety and preliminary indications of post-acute phase intervention approaches is provided via the R01 NOFO, PAR-25-206 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) The following table includes NIH standard due dates marked with an asterisk. 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 While there has been progress at developing therapeutic and services interventions for the acute management of many mental health disorders, far less attention has been paid to developing and testing mental health interventions and services to improve longer-term outcomes and recovery of function.

More research on post-acute phase interventions and services is warranted given that mental health conditions are often chronic or relapsing (e.g., anxiety disorders, mood disorders, ADHD, psychotic disorders) and are often better conceptualized and managed as chronic conditions. The clinical response to currently available pharmacological, device-based and psychosocial interventions is often incomplete.

Therapeutic gains can dissipate with time, and residual symptoms and impairment pose risk for relapse and ongoing dysfunction. Even when acute treatment is successful, the risk for associated downstream comorbidities (e.g., substance abuse disorders) remains high.

Management of many mental disorders requires not only ongoing treatment to prevent symptom recurrence, but interventions to promote long-term adherence to treatment plans and engagement with providers and health systems.

Research Scope and Objectives The purpose of this NOFO is to encourage research projects to assess the effectiveness of therapeutic and services interventions for the post-acute phase management of mental health conditions affecting youth and adults, including older adults. The clinical trial should be designed and sufficiently powered to definitively test effectiveness.

The study should also be designed to examine whether the intervention engages the target(s)/mechanism(s) presumed to underlie intervention effects; to address questions regarding the role of such target(s)/mechanism(s) in producing clinical benefit; and to address hypotheses regarding predictors and moderators of effectiveness.

For purposes of this NOFO, acute treatment refers to the management of an episode, crisis, or worsening of mental illness that requires intense treatment in order to contain symptoms, prevent harm, and stabilize functioning, in either outpatient or hospital settings.

While the goal of acute treatment is typically symptomatic improvement, management of immediate risks for harm, and behavioral stabilization, continuation and maintenance treatment aims to achieve symptom recovery and return the patient to an optimal baseline of functioning, while preventing relapse and recurrence.

Likewise, following acute-phase treatment, additional interventions and/or services might be necessary to facilitate care transitions (e.g., from inpatient services to outpatient care) or promote appropriate adherence and continuity of services.

Across conditions, post-acute phase interventions/service strategies are needed that are matched to the stage of illness in terms of both their focus (e.g., consolidating and maintaining gains from initial treatment, managing residual symptoms/impairment, preventing relapse, promoting adherence and appropriate service use) and intensity/burden, in order to ensure that the interventions are not only relevant and effective, but also acceptable and sustainable for promoting optimal longer-term outcomes.

Technology-assisted approaches might be especially useful for facilitating post-acute phase monitoring, for delivering interventions (e.g., maintenance therapy, relapse prevention), and for promoting treatment engagement/adherence and appropriate service use. NIMH is committed to supporting research that reduces disparities in mental health interventions, services, and outcomes.

Accordingly, this NOFO encourages clinical trials that seek to reduce disparities in post-acute care outcomes for underserved groups, for example, racial and ethnic minority groups, individuals limited by language or cultural barriers, and individuals living in rural areas.

Examples of relevant research topics include but are not limited to: Continuation treatments (psychosocial, pharmacological, and/or neuromodulation strategies) that strengthen and extend gains achieved during initial treatment, or specifically target residual symptoms/impairments associated with relapse/ongoing dysfunction; Strategies for negotiating and assisting with transitions from initial intensive treatment to a less intensive follow-up care (e.g., digital mental health applications, care management, crisis care centers); Maintenance therapies that promote ongoing monitoring and continued use of pharmacological, neuromodulation, and/or psychosocial approaches tailored to the stage of illness; Targeted strategies to optimize longer-term pharmacotherapy/neuromodulation, prevent long-term adverse effects of treatment (e.g., metabolic syndrome with antipsychotics, memory loss with electroconvulsive therapy), and reduce unnecessary polypharmacy; Strategies for initiating preventive interventions among youth treated for “gateway conditions” (e.g., ADHD, anxiety, first episode psychosis) in order to reduce risk for common downstream comorbidities (e.g., substance use disorders, suicidality); Novel adherence interventions that combine monitoring with engagement strategies to promote positive mental health habits, adherence, and appropriate service use (e.g., minimize ED visits and re-hospitalization); Novel approaches to stepping or sequencing interventions for the post-acute management of mental health conditions; Strategies for post-acute management that integrate mental health treatment into settings that do not traditionally offer mental health services (e.g., schools, senior housing, medical settings); Technology-assisted self-monitoring or passive monitoring to detect clinical deteriorations or problematic adherence combined with prompts for self-management strategies or more intense services (e.g., via a patient-clinician interface or portal); Empirically informed transition planning strategies to facilitate community reintegration, promote continuity of care, and prevent re-hospitalization following inpatient or residential treatment; Population-level strategies that use routinely collected data within healthcare networks/EHRs for surveilling, monitoring, prompting engagement (e.g., care manager check-ins) and promoting appropriate service use.

Clinical trials that test innovative approaches for reducing disparities in post-acute care outcomes for underserved groups.

Consistent with the NIMH experimental therapeutics approach , this NOFO is intended to support effectiveness trials that not only test the intervention effects on outcomes of interest but also explicitly inform understanding regarding whether the intervention engages associated change mechanisms that were previously identified under more controlled efficacy conditions, thereby reconfirming the intervention targets and testing whether previously identified change mechanisms are operative in the effectiveness context (see NIMH web page on Clinical Trials ).

In this manner, the results of the effectiveness trial will advance knowledge regarding therapeutic change mechanisms and have utility regardless of trial outcomes (e.g., in the event of negative results, information about whether the intervention was successful at engaging its targets can facilitate interpretation).

Depending on the nature of the intervention, the "target" or mechanism of action might involve specific psychological or behavioral processes (e.g., cognitive control, stress regulation) or neurobiological entities (e.g., brain circuits).

For studies that involve preventive or therapeutic interventions, NIMH encourages research that takes into account RDoC or RDoC-like constructs when defining the subject eligibility (inclusion), intervention targets or mechanisms, and outcomes, as appropriate and feasible in the effectiveness setting.

In the case of services interventions, targets/mechanisms might involve mutable consumer or provider behaviors, or organizational-/system-level factors that are intervened upon in order to improve access, continuity, quality, effectiveness, and/or value of services.

Valid and reliable measures of change in the hypothesized target(s)/mechanism(s) will provide useful information about key change mechanisms that account for intervention effects. In the assessment of target engagement, NIMH encourages the use of measures that are as direct and objective as is feasible in the effectiveness 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.

NIMH encourages a deployment-focused model of intervention and services design and testing that 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.

This attention to end-user perspectives and characteristics of intended clinical and/or community practice settings is intended to ensure that the resultant interventions and service delivery strategies are feasible and scalable, and to ensure that the research results will have utility for end users.

NIMH encourages projects testing the effectiveness of preventive, therapeutic, or services interventions that are designed as hybrid effectiveness-implementation trials, as appropriate.

Thus, in addition to testing the effectiveness of a preventive or therapeutic intervention, NIMH encourages effectiveness trials that are designed to assess and examine consumer-, provider- and setting- level factors that might be associated with implementation fidelity (i.e., as Hybrid Type I trials) or to simultaneously test strategies to promote successful implementation (i.e., as Hybrid Type II trials).

Likewise, studies that are primarily aimed at testing an implementation or dissemination strategy should be designed to also assess the outcomes and effectiveness of the intervention/approach that is being implemented, as appropriate and feasible (i.e., as Hybrid Type III trials).

NIMH encourages effectiveness research on potentially scalable preventive, therapeutic, and services interventions that focuses on practice-relevant questions. Accordingly, collaborations between academic researchers and clinical or community practice partners or networks are encouraged.

When possible, studies should capitalize on existing infrastructure (e.g., practice-based research networks such as the NIMH-sponsored Mental Health Research Network (MHRN) and Early Psychosis Intervention Network (EPINET), electronic medical records, administrative databases, patient registries, institutions with Clinical and Translational Science Awards) to increase the efficiency of participant recruitment (i.e., more rapid identification and enrollment) and to facilitate the collection of moderator data (e.g., clinical characteristics, biomarkers), longer-term follow-up data, and broader, stakeholder-relevant outcomes (e.g., mental health and general health care utilization, value and efficiency of intervention approaches).

NIMH encourages studies that test intervention and service delivery strategies that incorporate features that are specifically designed to prevent threats to implementation fidelity, as appropriate.

Strategies that might be used to enhance scalability and sustained implementation include but are not limited to: consumer-facing technology (e.g., self-administered content) and provider-facing technology (e.g., technology to support provider training and sustained implementation fidelity); expert consultation via existing resources or other sustainable means (e.g., telehealth, collaborative care approaches); or other robust design features that promote provider competence and sustained implementation fidelity.

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: https://www. hhs. gov/programs/prevention-and-wellness/mental-health-substance-abuse/national-strategy-suicide-prevention/index.

html ). 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. Where feasible and appropriate, NIMH encourages intervention research that includes assessment of suicidal behavior in order to advance understanding of how effective prevention and treatment of mental disorders might impact suicide relevant outcomes.

Potential applicants are also strongly encouraged to consult with NIMH staff as early as possible when developing plans for an application (see Scientific/Research Contacts, Section VII ). This early contact will provide an opportunity to clarify NIH policies and guidelines and help to identify whether the proposed project is consistent with NIMH program priorities and the goals of this NOFO.

Applications Not Responsive to this NOFO The following will be considered nonresponsive to this NOFO and will not be reviewed: Studies examining the effectiveness of acute phase interventions. Studies that do not involve trials with prospective data collection in which patients are assigned to specific intervention conditions.

While random allocation to intervention conditions is expected in most cases, depending on the study question, practical constraints, and ethical considerations, quasi-experimental designs with non-randomized comparison groups might be appropriate, with strong justification.

Applications whose scope of work involves examining intervention effectiveness without studying whether the intervention engages the target(s)/mechanism(s) presumed to underlie benefits and without examining whether intervention-induced changes in target(s)/mechanism(s) are associated with clinical benefit.

Adaptations of existing interventions in the absence of a compelling justification and in the absence of a clear experimental therapeutics approach to examining how the intervention engages the adaptation target (see 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.) Applications focused on the development and initial efficacy testing of novel intervention strategies and/or novel intervention targets for the post-acute phase or on interventions for the acute phase of treatment will not be supported under this NOFO.

Studies conducted in academic research laboratories as opposed to effectiveness studies in community practice clinics/settings (e.g., studies in research clinics that involve research therapists or other features that are not representative of typical practice settings and substantially impact generalizability).

Trials using patented medications that lack superior efficacy or safety relative to currently available off-patent medications. Studies of stigma or health literacy interventions that do not explicitly study the impact on mental health service access, engagement, quality and/or outcomes of care. Studies that address questions regarding the impact of interventions using only archival or observational/naturalistically collected data.

Scale and Scope of Studies Covered Under this Announcement This NOFO is intended to support effectiveness trials testing post-acute phase interventions that are statistically powered to provide a definitive answer regarding the study intervention's effectiveness in comparison to usual care practices or alternative intervention/services approaches.

The study should also be designed to examine whether the intervention engages the target(s)/mechanism(s) presumed to underlie the intervention effects; to address questions regarding the action of such target(s)/mechanism(s) in producing clinical benefit; and to address hypotheses regarding predictors and moderators of effectiveness.

Support for pilot effectiveness trials to inform the design of definitive effectiveness trials and to evaluate the initial feasibility, tolerability, acceptability, safety and preliminary indications of effectiveness of post-acute phase intervention approaches is provided via PAR-25-206 "Pilot Effectiveness Trials for Post-Acute Interventions and Services to Optimize Longer-term Outcomes (R01)".

This NOFO is intended to support research focused on the effectiveness of therapeutic and service-delivery interventions: (1) that are intended specifically for the post-acute management of mental health conditions, and (2) that principally involve the use of research-supported strategies (e.g., in sequence or in combination), matched to the stage of illness.

Applicants are encouraged to visit the NIMH Clinical Trials webpage for a list of alternative NOFOs, including NOFOs that are intended to support the translation of emerging basic science findings of mechanisms and processes underlying mental disorders into novel psychosocial interventions ("Development of Psychosocial Therapeutic and Preventive Interventions for Mental Disorders," PAR-21-135 (R61/R33) and PAR-21-134 (R33)) and novel pharmacological or device-based interventions (“Early Stage Testing of Pharmacologic or Device-based Interventions for the Treatment of Mental Disorders," PAR-21-137 (R61/R33) and PAR-21-136 (R33)).

Effectiveness research for acute-phase interventions is supported through additional NOFOs, including "Pilot Effectiveness Trials for Treatment, Prevention and Services Interventions" ( PAR-21-131 (R34)) and "Clinical Trials to Test the Effectiveness of Treatment, Preventive, and Services Interventions" ( PAR-21-130 (R01)).

All PD(s)/PI(s)s submitting clinical trials applications consistent with NIMH priorities are encouraged to visit the NIMH Clinical Trials webpage and consult with Scientific/Research Staff regarding NOFOs that are appropriately matched to the study scope and stage of intervention development and testing.

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

The NIMH has published updated policies and guidance for investigators regarding human research protection and clinical research data and safety monitoring ( NOT-MH-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. 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 Resubmission from PAR-21-210 and PAR-25-207 Revision from PAR-17-272 , PAR-18-430 , PAR-21-210 , and PAR-25-207 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 The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications. Application budgets are not limited but need to reflect the actual needs of the proposed project. Scope of the proposed project should determine the project period.

The maximum period is 5 years; however, most awards will be for 3-4 years. 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: The description of the resources and environment should address how the study utilizes existing infrastructure (e.g., CTSAs, practice-based research networks, electronic medical records, administrative databases, patient registries) or utilizes other available resources to increase the efficiency of participant recruitment and data collection or provide a justification in the event that such efficiencies cannot be incorporated.

SF424(R&R) Senior/Key Person Profile All instructions in the How to Apply- Application Guide must be followed. As appropriate, Senior/Key Personnel must describe in the biosketch their experience and expertise collaborating with community practice partners/providers, consumers, and relevant policy makers to conduct effectiveness studies 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 should include the following sections as part of the Research Strategy.

Applications should not duplicate information provided in the attachment described in the PHS Human Subjects Clinical Trial Information form but may reference it to provide context as needed. Factor 1.

Importance of the Research Justify the practical effect of the intervention or service approach in terms of the estimated hypothesized effect size (e.g., with respect to remediation of residual symptoms/functional impairment, reduced likelihood of relapse or re-hospitalization, improved adherence), compared with already available approaches.

Address the potential impact of the intervention/service delivery approach in terms of both: (1) the empirical basis for the anticipated effect size (e.g., citing data regarding the magnitude of the association between the target and the clinical endpoint of interest and/or effect sizes obtained in prior efficacy studies); and (2) the clinical meaningfulness of the anticipated increment in effects compared to existing approaches.

Address the degree to which the proposed intervention/service delivery approach is scalable and could be disseminated into practice, given typically available resources, clinical workflows, and service structures (e.g., trained and skilled providers, mental health financing).

Highlight how innovative research strategies and design/analytic elements (e.g., adaptive sequential randomization, equipoise stratification) are incorporated, as appropriate, in order to enhance the study's potential for yielding practice-relevant information.

As relevant, highlight how applications of information technology are leveraged to increase the reach, efficiency, or effectiveness of interventions to improve the post-acute outcomes. Factor 2.

Rigor and Feasibility Detail the rationale and empirical basis for the intervention approach in terms of: (1) the intended target population (e.g., with respect to their prior acute-phase intervention exposure and current status, pre-defined level of residual symptoms/functional impairment, risk for relapse); (2) the stage of illness targeted (e.g., continuation therapy, maintenance therapy, illness management, transition to outpatient care); (3) the corresponding goals and focus of the intervention (e.g., remediating residual symptoms or functional impairment; preventing relapse or re-hospitalization; promoting adherence, appropriate service use, and/or health-maintaining behaviors); (4) the key window or timeframe for administering the intervention; (5) the match between the stage of illness/goals and the intensity of the intervention (e.g., in terms of patient/consumer burden, provider/system demands, and cost).

Consistent with NIMH's experimental therapeutics approach , detail plans to explicitly address whether the preventive, therapeutic, or services intervention engages the target(s)/mechanism(s) presumed to underlie the intervention effects (the target(s)/mechanism(s) that accounts for changes in clinical/ functional outcomes, changes in patient or provider behavior, etc.).

Include the following: (1) a conceptual framework that clearly identifies the target(s)/mechanism(s) and the empirical evidence linking the target(s)/mechanism(s) to the clinical symptoms, functional deficits, or patient-, provider- or system-level behaviors/processes that the intervention seeks to improve; (2) plans for assessing the engagement of the target(s)/mechanism(s) using valid measures that are as direct and objective as is feasible in the