Part 1. Overview Information

Key Dates

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.

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 How to Apply - Application Guide and the NOFO) is required and strictly enforced. Applicants must read and follow all application instructions in the How to Apply - Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the How to Apply - 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.

1. Use the NIH ASSIST system to prepare, submit and track your application online.
2. 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.
   
   
3. Use Grants.gov Workspace to prepare and submit your application and eRA Commons to track your application.



Table of Contents
Part 1. Overview Information
Key Dates
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

Background

Depressed mood is a common symptom observed in multiple psychiatric disorders and associated with impairment in multiple domains of function (e.g., affective, cognitive, social, sensory, motor) that are fundamental for achieving a good quality of life. Depression is exhibited in many forms (e.g., anxious distress, melancholic, catatonic, premenstrual, postpartum, seasonal) and frequently co-occurs with other symptoms, such as mania and psychosis. There are several treatment options for depression, including medications, psychosocial interventions, digital therapeutics, and various brain stimulation methods, however, treatment selection still relies largely on trial and error. Each treatment may require three months or more to determine its effectiveness for a specific individual, and about 40% of patients treated are not fully recovered, even after one year of treatment with one or more of the available antidepressant therapeutic options.

There is an urgent need for tools that integrate pre-treatment measures to predict whether a depressed individual will have a differential therapeutic response to a specific treatment and aid clinicians in selecting among multiple available treatments.

Therefore, the goal of this NOFO is to create a pipeline to support initial tests of validation and feasibility of objective, easy-to-use, and widely accessible tools for predicting response to depression treatments at the level of the individual.  Investigators will receive consultation, access to resources, and support from teams of experts with clinical, scientific, technical, regulatory, and commercialization expertise. The NOFO will enable projects to enter and exit the program through staged, milestone-driven steps to assess the performance of the measures. The pipeline structure will enable best practices in biomarker and tool development, including consideration of sensitivity, specificity, analytic validity, and clinical validity, through two phases: (1) Preliminary studies to develop prototype tools using nimble, efficient pilot feasibility studies and/or secondary analyses of data from completed clinical trials and/or data from the clinical record; and (2) Efficacy studies to prospectively test tools in larger scale, highly controlled clinical trials.

NIMH supports ongoing research efforts to identify biomarkers and explore biological mechanisms that could inform approaches to treating depression, but there currently are no validated tests that can inform treatment selection at an individual level across two or more treatments for depression. Several challenges and knowledge gaps hinder the development of novel tools for individualized treatment selection for depression. This NOFO encourages studies that propose integrative approaches (combining multidimensional measures such as physiology, behavior, pharmacology, psychosocial, and/or environment) directed toward the development of tools to predict treatment selection utilizing rigorous data collection and innovative computational and analytical approaches. Investigators are encouraged, but not required, to investigate composite, multi-modal signatures to understand and utilize commonalities and differences across related depressive conditions for guiding therapy.

This NOFO aims to support the identification, development, and validation (with a future goal of clinical adoption) of objective tools to be used as treatment selection assays that can withstand rigorous analytic and clinical validation to guide decision-making in clinical practice. The long-term goal is the development of individualized libraries of multi-modal signatures for depression therapeutic selection. These clinical solutions will be developed using empirical clinical research methods that utilize standardized methodologies within and/or across different depressive conditions, illuminating both common mechanisms and those that distinguish one depressive condition from another to guide treatment selection.

Definitions of Terms within This NOFO

Predictive Tools for Treatment Selection ("Tools"): Broadly defined as biomarkers and/or signatures that are assayed at baseline to help a clinician determine whether treatment(s) may be efficacious in that individual or not. They can combine clinician/patient/caregiver assessments with digital health sensors or wearables, deep phenotyping, central nervous system measures (e.g., EEG, fMRI), and/or blood-based assays using computational models and algorithms. These tools will be intended for clinical decision support or companion diagnostics.

Biomarker: Defined as a single characteristic measure to yield a patient-specific predictor of differential treatment response between two or more depression therapeutics. 

Signature: Combination of multiple variables (e.g., quantitative neuro-behavioral assays, brain imaging, omics, actigraphy, ecologically momentary assessment, digital measures, questionnaires) to yield a patient-specific predictor of differential treatment response between two or more depression therapeutics.

Proof of Concept: Establishing, in a prospective clinical trial (UH3 phase), that the tool displays quantitative characteristics that demonstrate it can accurately perform as a predictive biomarker.

Specific Use: A statement that fully and clearly describes the way the tool is expected to be used in clinical practice. This NOFO focuses on predictive tool biomarkers/signatures for therapeutic selection.

Validations: Analytic Validation of the Detection Method is a process to establish that the performance characteristics of a test, tool, or instrument are acceptable in terms of its sensitivity, specificity, accuracy, precision, and other relevant performance characteristics using a specified technical protocol (which may include specimen collection, handling, and storage procedures). The analytical validation establishes the technical performance of a test/tool/instrument/measurement, but does not validate the clinical usefulness of the measurement. On the other hand, Clinical Validation is a process to establish that the performance of a test, tool, or instrument is acceptable for its intended clinical purpose.

Criteria

Rationale: Proposed projects should be supported by a comprehensive rationale for the candidate tool, as well as, by evidence of unmet need and feasibility for its intended use in the development of treatment decision strategies for depression. The rationale should include rigorously obtained evidence that the proposed biomarker or signature can accurately predict treatment selection between two or more therapeutic agents. The applicant should state specific, precise, and empirically testable/falsifiable research hypotheses, and specify how the associations between the input variables of phenotypic/clinical measures and biomarkers at baseline will align with treatment efficacy and how that alignment will establish a prediction tool.

Relevance and unmet need for clinical practice: Proposed projects should be based on a strong argument that the candidate tool will fill an unmet need for decision-making in clinical practice addressing how, if successful, the tool could be implemented into current medical practice (types of practices, institutions, etc.). Projects will be required to include clinicians (e.g., treating psychiatrists, psychologists, physicians) and/or end-users as consultants to provide input on practical limitations of using the tool in clinical settings and potential corrective approaches to increase the chance that the tool can be successfully implemented into clinical workflow and eventually adopted into practice.

Study design: The UG3 phase should be designed to establish/confirm the candidate biomarker’s and/or signature’s performance in assessing whether a subject with depression will positively respond to a well-established treatment for depression. UH3 phase would support conducting clinical and technical validation of the biomarker or signature using an optimized detection method (based on lessons learned in the UG3 study) to test the biomarker or signature's performance on an independent cohort in a large-scale clinical trial. The UG3 phase should clearly describe the technical and clinical validation milestones and define the performance criteria that need to be met for the biomarker and method of detection to be considered acceptable for further assessment in the UH3 phase.

Multiple Principal Investigator Organization Plan and Team Characteristics: Multi-disciplinary teams will be integral to the successful development of these tools; hence, multiple principal investigators (MPI) are required in this NOFO.  All MPIs should be involved in the development of the research plan and the coordination and execution of the project. The multi-disciplinary team, which should include the MPIs, should cover expertise in areas relevant to the proposed project, including but not limited to: biomarker and signature development; clinical expertise relevant for the clinical populations of interest (including clinical trial designs); computational, statistical, and/or bioinformatics analysis; experience with the use and development of the detection method technology, biosample, data, or tissue source standardization; and biological, behavioral, physiological expertise in the depression condition or conditions under investigation. Investigators are encouraged to form collaborations and seek additional consultants as needed for the project. Investigators should have access (or a feasible plan for access) to relevant clinical networks associated with the depressive condition(s) studied and/or the standardized samples and data, and describe how they plan to leverage existing NIH resources.

Research Objectives

Applications submitted to this NOFO must propose a research plan designed to develop biomarkers and signatures serving as tools to predict treatment selection between two or more well-established depression treatments. For this NOFO, well-established treatments for depression are those that are approved by the United States Food and Drug Administration (FDA) or, for non-regulated interventions, those that are well-validated, widely used, and recommended in treatment guidelines. The application is expected to provide a specific set of candidate biomarkers or signatures to be developed. The biomarker should reflect specific dimensional constructs in depression that may be modulated by a therapeutic intervention. The candidate biomarker or signature resulting from the completion of this research will need to undergo analytical and clinical validation. The application should also include centralized resource groups that will coordinate the clinical trials and standardize all sample or data collection methods, technology development, statistical analyses, and algorithm development.

Implementation

The NOFO will provide funding through the two-staged UG3/UH3 (Exploratory/Developmental Phased Award Cooperative Agreement) Phased Innovation Award cooperative agreement mechanism. As a cooperative agreement, implementation will involve the participation of NIMH program staff in the planning and execution of therapy-directed projects. The UG3 portion of the award is designed to support preparatory research for one to two years. Based on milestone progress, a limited number of projects will proceed to the UH3 phase for the remainder of the award period. The second (UH3) phase will include optimization and initial clinical validation studies of the predictive tool, to produce a promising tool that will provide evidence to inform treatment selection among two or more therapeutic agents at the end of the UH3 phase.

Project teams will share insights by presenting research projects at bi-annual UG3/UH3 phase meetings, where:

• Private-Public Partnerships (private sector commercial institutions): NIMH may invite relevant stakeholders from private sector companies to participate in network meetings to allow PIs to receive further input regarding product and business development, marketing, scalability. Individual NIMH, FDA, and diagnostic expert input may occur on a more regular basis as warranted.

Phased Award Mechanism

The UG3 phase will support preparatory research using existing data or a pilot study involving new data collection to assess whether the candidate biomarker or signature measured at baseline is predictive of treatment response at the individual level.

The goal of the preparatory/pilot phase is to perform an initial assessment of technical and clinical utility if the retrospective data is much smaller in sample size, such that subject-level data is less informative. For the UG3-phase studies involving new data collection, the sample size should be fewer than 50 subjects per study arm. The pilot study should focus on assessing the feasibility and practical limitations of biomarker data collection, such as the ability to standardize the data collection procedures across sites, maintain data quality, and evaluate psychometric issues (e.g., reliability, ceiling, floor effects).

The UH3 phase will support a proof-of-concept (POC) trial involving new data collection to test the ability of the candidate biomarker or signature to prospectively predict differential treatment response. Activities in both phases must include the use of samples or measures from patients with depressive disorders as data sources. Applications exclusively focused on samples or data from animal models will be deemed non-responsive.

Transition Milestones from the UG3 to the UH3 Phase

Projects must be organized systematically, including annual decision-making metrics throughout the entire period of the project. Additionally, the transition from the UG3 to the UH3 phase is contingent upon the successful completion of the Go/No Go milestones proposed for the UG3 phase. These milestones are required as a part of the application but may be further refined in collaboration with the PD/PI, NIH program staff, and subject-matter experts at the start of each project phase and updated as needed and mutually agreed upon. The NIH Program Official will contact the applicant to discuss the proposed milestones prior to the award. The transition milestones must be clearly defined, quantifiable, and scientifically justified to allow the investigators and program staff to assess progress in the UG3 phase and the potential for the development of a candidate biomarker or signature in the UH3 phase. At the end of the UG3 phase, NIH program staff will determine whether the project will advance to the UH3 phase. 

Project Characteristics

The tool can be developed for trans-diagnostic use or targeted for use in one of several depressive conditions that may have a common or distinct pathophysiology or biotype, within the NIMH mission.

Examples of Studies That would be Appropriate Under this NOFO Include, but Are Not Limited to:

• Identification and optimization of a biomarker or signature (including algorithms) that can accurately predict depression treatment response between two or more specific therapeutic agents or interventions for either:
  • A single diagnostic category, subgroup(s) within a diagnostic category, or a trans-diagnostic phenotype that spans diagnostic groups and may share the same underlying treatment-response biotype.
  • The tool/biomarker/signature would be measured at baseline (prior to treatment exposure). The clinical trial is required to determine which subjects respond to the treatment(s) at the individual level. Only well-validated or FDA-approved depression treatments will be allowed.
• Empirical optimization of the algorithm or signature to finalize the component(s) weighting in the signature that results in the most accurate treatment selection prediction tool for use in clinical treatment decisions.
• Development and evaluation of a candidate biomarker or signature algorithm from a set of exploratory biomarkers that have been described in peer-reviewed publications to optimize the algorithm, including establishing sample/data curation or collection procedures, followed by testing the optimized algorithm in an independent cohort in the UH3 phase for initial validation.
• Discovery approaches from one or more large multi-site datasets or sample repositories to identify new biomarkers and characterize their relationship to relevant biological processes and outcomes within a disease or condition, followed by prospective validation in the UH3 phase for a specific use.

Applications or Studies That Are Non-responsive to This NOFO:

Applications deemed to be non-responsive will not proceed to review and will be withdrawn. 

• Studies proposing to develop tools other than prediction biomarkers to inform the selection between two or more well-established treatments for depression based on predicted individual response, will be deemed not responsive. As an example, safety and/or effectiveness studies for the specific treatments and target engagement biomarkers, which are also pharmacodynamic/response biomarkers would not be responsive. Studies that exclusively focus on tools able to predict response to one treatment would not be responsive.
• Studies aimed at understanding disease pathophysiology, genetic, or epigenetic mechanisms in the absence of biomarker identification, development of detection technology, and early validation.
• Studies focused on the determination of efficacy and development of candidate therapeutics as the primary goal.
• Projects that do not include clinicians (e.g., treating psychiatrists, psychologists, physicians) and/or end-users as consultants. Clinicians and/or end-users must be included in the projects to provide input on practical limitations of using the tool in clinical settings and potential corrective approaches to increase the chance that the tool can be successfully implemented into clinical workflow and eventually adopted into practice.
• Studies that do not include Multiple Principal Investigators (MPI), with each MPI contributing expertise in distinct, predefined areas relevant to the proposed project. These areas could include, but are not limited to, experimental design, data analysis, and subject matter expertise.
• Studies that do not include detailed plans for both the UG3 and the UH3 phases.
• Studies that lack annual decision-making metrics throughout the entire project period (i.e., both UG3 and UH3 phases).
• Studies that lack transition milestones, i.e., UG3 phase technical and clinical validation quantitative milestones that define the performance criteria that need to be met for the biomarker and method of detection to be considered acceptable for further assessment in the UH3 phase.
• Studies that do not include the use of samples or measures from patients with depressive disorders as data sources. Applications exclusively focused on samples or data from non-depressive conditions, healthy subjects, or animal models will be deemed non-responsive.
• Studies that propose interventions that are not well-established depression treatments. For this NOFO, well-established treatments for depression are those that are FDA-approved or, for non-regulated interventions, those that are well-validated, widely used, and recommended in treatment guidelines.
• Studies that do not include a prospective clinical trial to validate the utility of their biomarker/tool for predicting differential response to two or more established treatments for depression in the UH3 phase.

Considerations for Clinical Trials

This NOFO supports the discovery of biomarker tools/signatures that can inform treatment selection between two or more existing depression therapeutics. Thus, while the studies outlined in an application may be defined as clinical trials, this NOFO is not designed/intended to support tests of the efficacy of novel interventions.

Data Sharing

NIMH requires all projects funded under this NOFO to deposit bi-annually all data generated by the project to the NIMH Data Archive (NDA). The data will be made available to qualified investigators with approved NDA data access agreements according to the NDA data sharing regimen.

Leveraging Existing Research Resources

NIMH encourages the use of existing resources and support to help drive this effort. Collaborations with mental health advocacy organizations, depression-focused networks, private research foundations, academic institutions, other government agencies, and the NIH Intramural program are strongly encouraged. Studies are also encouraged to leverage the resources of ongoing clinical trials or real-world clinical data supported through other federal or private funds and may include data and samples that can be accessed from existing bio-specimen, imaging, and data repositories. NIMH encourages the use of existing resources (e.g., Clinical and Translational Science Awards (CTSAs), practice-based research networks, electronic medical records, administrative databases, patient registries) to increase the efficiency of participant enrollment and data collection, as appropriate.

Technical Assistance

Prospective applicants are strongly encouraged to consult with NIMH staff when developing plans for an application (see Section VII. Agency Contacts). This early contact will provide an opportunity to discuss the goals of the NOFO, clarify NIMH policies and guidelines, and identify whether the proposed project is consistent with NIMH priorities.

 A web-based Technical Assistance (TA) Meeting will be held for prospective applicants to this NOFO on Thursday, July 11, 2024, from 2:00 pm - 3:00 pm ET. when NIMH staff will be available to answer questions related to this funding announcement. Prospective applicants can participate in the TA meeting and are encouraged to submit to the Agency Contacts listed in Section VII their questions or comments one week in advance of the TA meeting. Participation in the teleconference is neither required nor necessary for a successful application. A recording of the teleconference will be available after the TA meeting. Information on how to attend the pre-application webinar will be published through a Guide Notice. 

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). 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.

See Section VIII. Other Information for award authorities and regulations.

Investigators proposing NIH-defined clinical trials may refer to the Research Methods Resources website for information about developing statistical methods and study designs.

Section II. Award Information

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

1. Eligible Applicants

Higher Education Institutions

• Public/State Controlled Institutions of Higher Education
• Private Institutions of Higher Education

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

• Hispanic-serving Institutions
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions
• Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

• Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

• Small Businesses
• For-Profit Organizations (Other than Small Businesses)

Local Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)

Federal Governments

• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations
• Non-domestic (non-U.S.) Entities (Foreign 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

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 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.

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. Individuals from diverse backgrounds, including underrepresented racial and ethnic groups, individuals with disabilities, and women are always encouraged to apply for NIH support. See, Reminder: Notice of NIH's Encouragement of Applications Supporting Individuals from Underrepresented Ethnic and Racial Groups as well as Individuals with Disabilities, NOT-OD-22-019.

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.

2. Cost Sharing

This NOFO does not require cost sharing as defined in the NIH Grants Policy Statement NIH Grants Policy Statement Section 1.2 Definition of Terms.

3. Additional Information on Eligibility

Number of Applications

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 How to Apply - Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

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:

• Descriptive title of proposed activity
• Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
• Names of other key personnel
• Participating institution(s)
• Number and title of this funding opportunity

The letter of intent should be sent to:

Email: [email protected]

Page Limitations

All page limitations described in the How to Apply – Application Guide and the Table of Page Limits must be followed.

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.

SF424(R&R) Cover

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.

SF424(R&R) Senior/Key Person Profile

All instructions in the How to Apply - Application Guide must be followed.

R&R Budget

All instructions in the How to Apply - Application Guide must be followed.

R&R Subaward Budget

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.

PHS 398 Research Plan

All instructions in the How to Apply - Application Guide must be followed, with the following additional instructions:

All applications must include plans for both the UG3 and the UH3 phases.

Specific Aims:

Within the Specific Aims section, include headers titled UG3 Phase Specific Aims and UH3 Phase Specific Aims. Briefly provide the context for the proposed set of studies, with an emphasis on the research rationale for the treatment selection tool along with a cogent argument outlining its importance and unmet clinical need. Under each header, state the specific objectives of the efforts. In addition, state the major objectives of the proposed study, including the technical questions to be answered to further develop and validate the tool, biomarker, or signature.

Research Strategy:

In the Research Strategy Section, address for both the UG3 and UH3 phases the following areas:

1. Rationale and Unmet Need

• Define the depression condition or multiple related depression conditions to be addressed and the unmet need for therapeutic assignment in the specific area.
• Provide a strong rationale that supports the scheme for the development of the tool. For tool(s) investigated across several depression conditions, provide the basis for choice of the condition(s) and the treatments(s). Provide specific, precise, and empirically testable research hypotheses specifying how the relationship associations between the patient input variables and the treatment prediction outcome will be established.
• Describe the possible methods of detection and components for the tool and address the feasibility of this method of detection for use in decision-making in clinical practice.
• Describe how the inclusion of clinicians and/or end-users as partners in the project will ensure that the tool, if successfully developed, can be implemented into a clinical workflow for future adoption into clinical practice. Projects will be required to include clinicians and/or end-users as consultants to provide input on practical limitations of using the tool in clinical settings and potential corrective approaches to increase the chance that the tool can be successfully implemented into clinical workflow and eventually adopted into practice.
• Specify the intended clinical use (predictive individual treatment selection between two or more depression therapeutics) for the tool and its detection method; include information on characteristics of the sample (e.g., specimen, image, EEG, behavioral, physiological endpoint) to be used for the measurement and how the measurement result will be used.
• If applicable, provide a comparison to other tools, biomarkers, or signatures for the specified depression condition, discussing the advantages and disadvantages of the proposed biomarker approach and addressing the unmet need for a biomarker.
• Describe the potential for the proposed studies to significantly advance translational medicine in the depression indication area(s) described.
• Address the likelihood and challenges for the tool, biomarker, or signature and its detection method to be broadly adopted in clinical testing and/or by the healthcare community for use in treatment.

2. Preliminary Data

Provide:

• An outline of the preliminary data or literature supporting the rationale for the discovery scheme of the new tool. Describe the overall strengths, weaknesses, and rigor of the preliminary data.
• Any existing natural history data that is relevant to the tool discovery scheme.
• Data addressing the feasibility and utility of any existing detection method or biomarker that is related to the proposed discovery scheme.
• Data addressing the feasibility of measurement of the tool, biomarker, signature from a clinical perspective.
• Data addressing the treatment in terms of efficacy, effectiveness, use in the clinic, etc. Provide evidence that the tool associates with depression-related pathways.
• The preliminary rationale for the proposed clinical use.

3. Approach

Address the following items for both the UG3 and UH3 phases:

• Include plans for cross-functional coordination and execution of activities such as clinical therapeutic intervention, sample and/or data collection across one or several depression conditions, standardization of sample collection methods, harmonization of detection methods, algorithm/signature development and statistical analysis.
• Describe all activities relevant to the proposed tool approach, study design, etc.:
  • Execution and planning for the development and organization of clinical, technology, and statistical/modeling resource centers.
  • If the focus is on the development of a signature common to several depression conditions, execution and planning for sample collection from populations representing each depression condition and for selection of core signature components.
  • Execution and planning for a clinical trial as part of the tool/biomarker/signature identification process and as part of the initial clinical validation process.
  • Plan for ensuring standardization of data/sample collection. If retrospective samples or data are being used, provide details as to how they were collected and plans to address and evaluate differences across sites/sources.
  • Plan for resolution of pre-analytic variables in the detection method.
  • Biomarker detection methodology development (including algorithm development) and initial validation approach.
  • If a machine learning algorithm will be used to measure or detect the biomarker or signature, describe the training and testing procedures to be used and the rationale for the approach; address how overfitting will be avoided and what best practices for rigor and reproducibility will be employed. Describe how the algorithm stability and reliability will be tested, and the overall rationale for the approach(es)/model(s) selected. Describe how your ML algorithm will incorporate a stakeholders-in-the-loop (e.g., patients, caregivers, clinicians, FDA, CMS), interpretable solutions (beyond prediction and classification), and/or a continuous learning approach.
  • Bioinformatics and statistical designs for analysis or deconvolution of sample data and refinement of the biomarker or signature identity.
  • Plans to assemble a signature from several, possibly multi-modal, components.
  • Outline the biomarker/signature approach to enable the prediction of individual treatment selection between two or more interventions.
  • Plans to obtain proof of concept for the tool biomarker, signature, and/or signature components using clinical samples or measures.

4. Timeline and Proposed Milestones

Provide proposed milestones and timelines under the Milestones' heading at the end of the Research Strategy Section. Quantitative milestones and performance metrics are required to provide clear indicators of a project's feasibility, continued progress or emergent difficulties. Proposed milestones and timelines will be evaluated as part of the scientific and technical merit of the UG3/UH3 application.

The UH3 phase may include preliminary Clinical Validation of the biomarker or signature including metrics. The set of milestones should allow the evaluation of progress in the UG3 phase, and the successful completion of these milestones should provide confidence that the investigator will be able to successfully implement the UH3 phase and achieve its end goals within the timeline of this grant mechanism. Quantitative criteria should be justifiable, and the timelines proposed for achieving the milestones should be realistic and inclusive of necessary steps, but also efficient without adding unnecessary steps.

• Provide a detailed timeline for the anticipated attainment of each milestone and the overall goal. Indicate when it is anticipated that essential components of the project will be completed. The proposed timeline with specific milestones should be clearly delineated and should appear as the last element of the Research Strategy section.
• Identify any impediments that could require an addendum to the research plan, milestones, or timeline with a discussion of alternative approaches.

5. Investigators' Expertise and Team Management Plan

Describe:

• Applicant's and research team's (e.g., co-investigators, collaborators, consultants):
  • knowledge of and experience with the biological, physiological, behavioral, or other target and/or proposed as biomarker or signature;
  • expertise in the physiology, behavior, condition, clinical phenotype, computational modeling, bioinformatics, detection technology, etc. to design and implement a robust identification/validation plan for the biomarker tool/signature;
  • knowledge of analytical design and requirements necessary for the development and validation of the detection technology.
• Proposed multi-disciplinary team and its appropriateness for the approach and goals of the proposed project.
• Multiple Principal Investigators (MPIs) area of expertise, roles, and responsibilities.
• Each team member's area of expertise, role, and responsibility.
• The team's ability to design the details of the plans and experiments and to execute the research strategy.
• The plans for establishing and utilizing centralized research groups (e.g., Research/Clinical Coordination, Technology/Statistical Analysis) where all signature components are standardized across a specific depression condition or multiple conditions. How the team will work together (e.g., data generation, reporting of data and integrated review across teams with various disciplines, decision-making) throughout the project (and include letters of support below).

Letters of Support:

• Include letters of support from consultants, contractors, and collaborators.
• If applying from an academic institution, include a letter of support from the technology transfer official who will be managing intellectual property associated with this project.
• If research will be performed at more than one institution, include a letter of support from each institution clarifying how intellectual property will be shared or otherwise managed across the institutions.
• If collaborating with a private entity, include a letter of support that addresses any agreement to provide treatments, any limits on the studies that can be performed with said treatments, any limitations on sharing of data (including negative results), and whether a licensing agreement(s) will be needed and in place once the project is funded. This letter should be signed by a person or persons authorized to represent the private entity.
• If an application proposes to utilize the infrastructure or resources of existing projects, whether funded by the NIMH, other governmental, or non-governmental entities, letters of support detailing the terms of collaboration and data sharing must be included.
• If the utilization of extant samples is proposed as a component of the study, letters of support or approval for the use of those samples should be included.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the How to Apply - Application Guide.

Other Plan(s): Note: Effective for due dates on or after January 25, 2023, the Data Management and Sharing Plan will be attached in the Other Plan(s) attachment in FORMS-H application forms packages.

All instructions in the How to Apply - Application Guide must be followed, with the following additional instructions:

• All applicants planning research (funded or conducted in whole or in part by NIH) that results in the generation of scientific data are required to comply with the instructions for the Data Management and Sharing Plan. All applications, regardless of the amount of direct costs requested for any one year, must address a Data Management and Sharing Plan.
• The following modifications also apply:
  • NIMH intends to maximize the impact of these projects through broad and rapid data sharing, consistent with the NIMH Public Access and Data Sharing Policy (https://www.nimh.nih.gov/funding/managing-your-grant/nimh-data-sharing-for-applicants-and-awardees).
  • To maximize discoverability and value of NIMH datasets and studies, and facilitate data integration and collaboration, applications submitted in response to this NOFO are strongly encouraged to incorporate standards and resources where applicable:
    • Applicants are encouraged to ensure that data collected by the study conform to Findable, Accessible, Interoperable, and Reusable (FAIR) principles.
    • The NIH notices referenced below provide additional NIH guidance that should be considered in developing a strong data management and sharing plan. The list is instructive but not comprehensive.
    • NIH Policy for Data Management and Sharing (NOT-OD-23-053).
    • NIH has provided guidance around selecting a repository for data generated by NIH-supported research and has developed desirable characteristics for all data repositories (NOT-OD-21-016).
    • NIH encourages the use of data standards including the PhenX Toolkit (https://www.phenxtoolkit.org/) (for example, see NOT-DA-12-008,NOT-MH-15-009).
    • NIMH strongly encourages grantees with human subjects research studies to collect and bank biospecimens and associated phenotypic information from all consenting subjects (NOT-MH-21-265.
    • NIH encourages researchers to explore the use of the HL7 FHIR® (Fast Healthcare Interoperability Resources) standard to capture, integrate, and exchange clinical data for research purposes and to enhance capabilities to share research data (NOT-OD-19-122). The FHIR® standard may be particularly useful in facilitating the flow of data with EHR-based datasets, tools, and applications.
    • NIH encourages clinical research programs and researchers to adopt and use the standardized set of data classes, data elements, and associated vocabulary standards specified in the United States Core Data for Interoperability (USCDI) standards, as they are applicable (NOT-OD-20-146). Use of the USCDI can complement the FHIR® standard and enable researchers to leverage structured EHR data for research and enable discovery.
    • Recipients conducting research that includes collection of genomic data should incorporate requirements under the NIH Genomic Data Sharing Policy (NOT-OD-14-124, NOT-OD-15-086). 
    • NIMH requires all projects funded under this NOFO to deposit bi-annually all data generated by the project to the NIMH Data Archive (NDA). The data will be made available to qualified investigators with approved NDA data access agreements according to the NDA data sharing regimen.

Appendix: Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the How to Apply - Application Guide.

• No publications or other material, with the exception of blank questionnaires or blank surveys, may be included in the Appendix.

PHS Human Subjects and Clinical Trials Information

When involving human subjects research, clinical research, and/or NIH-defined clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the How to Apply - Application Guide, with the following additional instructions:

If you answered “Yes” to the question “Are Human Subjects Involved?” on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

All instructions in the How to Apply - Application Guide must be followed.

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start). All instructions in the How to Apply - Application Guide must be followed.

PHS Assignment Request Form

All instructions in the How to Apply - Application Guide must be followed.

Foreign Organizations

Foreign (non-U.S.) organizations must follow policies described in the NIH Grants Policy Statement, and procedures for foreign organizations described throughout the How to Apply Application Guide.

3. Unique Entity Identifier and System for Award Management (SAM)

See Part 2. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov

4. Submission Dates and Times

Part I. contains information about Key Dates and times. 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. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

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 and time.  If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications.

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 How to Apply – Application Guide.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

Applications Involving the NIH Intramural Research Program

The requests by NIH intramural scientists will be limited to the incremental costs required for participation. As such, these requests will not include any salary and related fringe benefits for career, career conditional or other Federal employees (civilian or uniformed service) with permanent appointments under existing position ceilings or any costs related to administrative or facilities support (equivalent to Facilities and Administrative or F&A costs). These costs may include salary for staff to be specifically hired under a temporary appointment for the project, consultant costs, equipment, supplies, travel, and other items typically listed under Other Expenses. Applicants should indicate the number of person-months devoted to the project, even if no funds are requested for salary and fringe benefits.

If selected, appropriate funding will be provided by the NIH Intramural Program. NIH intramural scientists will participate in this program as co-investigators in accord with the Terms and Conditions provided in this NOFO. Intellectual property will be managed in accord with established policy of the NIH in compliance with Executive Order 10096, as amended, 45 CFR Part 7; patent rights for inventions developed in NIH facilities are NIH property unless NIH waives its rights.

Should an extramural application include the collaboration with an intramural scientist, no funds for the support of the intramural scientist may be requested in the application. The intramural scientist may submit a separate request for intramural funding as described above.

Use of Common Data Elements in NIH-funded Research

Many NIH ICs encourage 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.

NIMH expects investigators for this funding announcement to collect Common Data Elements (CDEs) for mental health human subjects research. Unless NIMH stipulates otherwise during the negotiation of the terms and conditions of a grant award, this Notice applies to all grant applications involving human research participants. The necessary funds for collecting and submitting these CDE data from all research participants to the NIMH Data Archive (NDA) should be included in the requested budget. A cost estimator (https://nda.nih.gov/ndarpublicweb/Documents/NDA_Data_Submission_Costs.xlsx) is available to facilitate the calculation of these costs. NIMH may seek further information regarding CDEs prior to award. Additional information about CDEs can be found at the NIMH webpage on Data Management and Sharing for Applicants and Awardees.

6. 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 Section 7.9.1 Selected Items of Cost.

7. Other Submission Requirements and Information

Applications must be submitted electronically following the instructions described in the How to Apply - 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 How to Apply – Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile form. 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 NOFO for information on registration requirements.

The applicant organization must ensure that the unique entity identifier provided on the application is the same identifier used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the How to Apply - Application Guide.

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by NIMH, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

Post Submission Materials

Applicants are required to follow the instructions for post-submission materials, as described in the policy

Section V. Application Review Information

1. Criteria

Only the review criteria described below will be considered in the review process.  Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.

For this announcement, note the following:

This NOFO supports studies focused on the discovery of promising candidate prediction tools, biomarkers, or signatures to make individual-level treatment selection between two or more therapeutics for depression indications that will withstand rigorous validation and ultimately provide the tools necessary for evidence-based treatment assignment in depression.

.

A proposed Clinical Trial application may include study design, methods, and intervention that are not by themselves innovative but address important questions or unmet needs. Additionally, the results of the clinical trial may indicate that further clinical development of the tool/biomarker is warranted or lead to new avenues of scientific investigation.

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).

Reviewers will consider each of the review criteria below in the determination of scientific merit and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

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 Timelines

• Evaluate the robustness of proposed milestones and the association with clear and quantitative criteria that will allow for successful go/no-go decisions at the UG3/UH3 transition point and during each year of the grant period.
• Evaluate the appropriateness of the set of milestones to determine progress in the UG3 phase, and provide confidence that the investigator will be able to successfully implement the UH3 phase and achieve its end goals within the timeline of this grant mechanism.
• Evaluate the strength of the transition milestone criteria to support progress assessment and the potential for the development of a candidate biomarker or signature in the UH3 phase, e.g., how strong is the scientific justification, how clearly are they defined, how quantifiable are they. If a transition criterion is not to be used for go/no-go decisions, how strong is the justification for not using that criterion?
• Evaluate the appropriateness of the timelines to efficiently achieve the milestones.
• Evaluate the adherence of proposed milestones, where applicable, to rigorous principles, including statistically adequate sample sizes with biologically relevant effect sizes, randomization, blinding, control of bias, independent replication, and adequate reporting of experimental details and results.
• Evaluate the strength of the plan for a UH3 phase preliminary Clinical Validation of the biomarker or signature including metrics, e.g., quantifiable criteria, realistic and efficient timelines for achieving milestones, and progress evaluation.

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.

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by NIMH, in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

As part of the scientific peer review, all applications will receive a written critique.

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

Appeals of initial peer review will not be accepted for applications submitted in response to this NOFO.

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this NOFO. Following initial peer review, recommended applications will receive a second level of review by the appropriate national Advisory Council or Board. The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.

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. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

Information regarding the disposition of applications is available in the NIH Grants Policy Statement Section 2.4.4 Disposition of Applications.

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. This request is not a Notice of Award nor should it be construed to be an indicator of possible funding. 

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 recipient's business official.

Recipients must comply with any funding restrictions described in Section IV.6. 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 NOFO will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website.  This includes any recent legislation and policy applicable to awards that is highlighted on this website.

The NIMH has published policies and guidance for investigators regarding human research protection, data and safety monitoring, Independent Safety Monitors and Data and Safety Monitoring Boards, reportable events, and participant recruitment monitoring (NOT-MH-19-027). The application’s PHS Human Subjects and Clinical Trials Information should reflect the manner in which these policies will be implemented for each study record. These plans will be reviewed by the NIMH for consistency with NIMH and NIH policies and federal regulations. The NIMH will expect clinical trials to be conducted in accordance with these policies including, but not limited to: timely registration to ClinicalTrials.gov, submission of review determinations from the clinical trial’s data and safety monitoring entity (at least annually), timely submission of reportable events as prescribed, and establishment of recruitment milestones and progress reporting.

Individual awards are based on the application submitted to, and as approved by, the NIH and are subject to the IC-specific terms and conditions identified in the NoA.

ClinicalTrials.gov: If an award provides for one or more clinical trials. By law (Title VIII, Section 801 of Public Law 110-85), the "responsible party" must register and submit results information for certain “applicable clinical trials” on the ClinicalTrials.gov Protocol Registration and Results System Information Website (https://register.clinicaltrials.gov). NIH expects registration and results reporting of all trials whether required under the law or not. For more information, see https://grants.nih.gov/policy/clinical-trials/reporting/index.htm

Institutional Review Board or Independent Ethics Committee Approval: Recipient institutions must ensure that all protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the recipient must provide NIH copies of documents related to all major changes in the status of ongoing protocols.

Data and Safety Monitoring Requirements: The NIH policy for data and safety monitoring requires oversight and monitoring of all NIH-conducted or -supported human biomedical and behavioral intervention studies (clinical trials) to ensure the safety of participants and the validity and integrity of the data. Further information concerning these requirements is found at http://grants.nih.gov/grants/policy/hs/data_safety.htm and in the application instructions (SF424 (R&R) and PHS 398).

Investigational New Drug or Investigational Device Exemption Requirements: Consistent with federal regulations, clinical research projects involving the use of investigational therapeutics, vaccines, or other medical interventions (including licensed products and devices for a purpose other than that for which they were licensed) in humans under a research protocol must be performed under a Food and Drug Administration (FDA) investigational new drug (IND) or investigational device exemption (IDE).

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, Recipients, and Activities, including of note, but not limited to:

• Federalwide Standard Terms and Conditions for Research Grants
• Prohibition on Certain Telecommunications and Video Surveillance Services or Equipment
• Acknowledgment of Federal Funding

If a recipient is successful and receives a Notice of Award, in accepting the award, the recipient agrees that any activities under the award are subject to all provisions currently in effect or implemented during the period of the award, other Department regulations and policies in effect at the time of the award, and applicable statutory provisions.

If a recipient receives an award, the recipient must follow all applicable nondiscrimination laws. The recipient agrees to this when registering in SAM.gov. The recipient must also submit an Assurance of Compliance (HHS-690). To learn more, see the Laws and Regulations Enforced by the HHS Office for Civil Rights website.

HHS recognizes that NIH research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research. For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this NOFO.

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to System for Award Management (SAM.gov) requirements. SAM.gov requires Federal agencies to review and consider information about an applicant in the designated integrity and performance system (currently SAM.gov) prior to making an award. An applicant can review and comment on any information in the responsibility/qualification records available in SAM.gov. NIH will consider any comments by the applicant, in addition to the information available in the responsibility/qualification records in SAM.gov, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 2 CFR Part 200.206 “Federal awarding agency review of risk posed by applicants.” This provision will apply to all NIH grants and cooperative agreements except fellowships.

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at  2 CFR 200, and other DHHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the recipients is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the recipients for the project as a whole, although specific tasks and activities may be shared among the recipients and the NIH as defined below.

The PD(s)/PI(s) will have the primary responsibility to:

• Define the details for the project within the guidelines of this NOFO.
• Performance and proper conduct of all research in accordance with the Terms and Conditions of Award.
• Accept close coordination, cooperation, and participation of NIH program staff in the scientific, technical, and administrative management of the grant.
• Administratively manage the grant.
• Oversee the overall budget.
• Oversee and perform the scientific activities and conduct of the research; this includes implementing the research protocol, obtaining IRB approval, establishing and implementing approaches for data integration and harmonization, quality control, data analysis and interpretation, and publication of results.
• Submit data for quality assessment and/or validation in any manner specified by the Steering Committee and/or the NIMH program staff to ensure scientific rigor.
• Deposit all data generated by the project in the NIMH Data Archive (NDA). All data will be deposited into NDA bi-annually.
• Submit progress reports summarizing project activities and achievement of project milestones to NIMH staff as requested.
• Accept and implement the common guidelines and procedures approved by the Steering Committee and NIMH.
• Provide administrative leadership and coordination of all meetings with NIMH staff.
• Chair and coordinate the activities of the Steering Committee.  The chair will be chosen by a majority vote of the Steering Committee, with years of service as chair determined by the committee. The Chair is responsible for preparing meeting agendas, scheduling and chairing meetings, and preparing concise minutes which will be delivered to Steering Committee members within 2 weeks of the meeting. Virtual meetings are appropriate.
• Serve as a member of the Steering Committee and fulfill related duties outlined below in Areas of Joint Responsibility; inform the NIMH Program Official of all major interactions with other members of the Steering Committee.
• Sharing data and resources consistent with the DMS Plan and according to the approved sharing policies for the NIH, including preparation of a final harmonized prevention trial dataset that will be deposited into the NIMH Data Archive (NDA).
• Appropriately acknowledge NIMH support in publications or oral presentations of work done under this agreement, including the assigned cooperative agreement award number.
• Recipients will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.

NIH staff have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:

NIMH Program Officials and Program Staff

• A Program Official and an NIMH Project Scientist(s) will be assigned to this award.
• NIMH staff will interact with the PD(s)/PI(s) on a regular basis to monitor progress. Monitoring may include: regular communication with the PD(s)/PI(S) and his/her staff, periodic site visits for discussion with the awardees research team, fiscal reviews, and other relevant stewardship activities.
• The NIH reserves the right to terminate or curtail the award (or an individual part of the award) in the event of inadequate progress or data reporting.
• NIMH staff will make recommendations for continued funding based on overall study progress, including meeting of planned milestones.
• NIMH program staff will conduct annual administrative reviews of the transition milestones throughout the project.

Program Officer

• The Program Officer will be responsible for milestone negotiations to ensure that the milestones are achieved and goals are met.
• The Program Officials will be responsible for normal scientific and programmatic stewardship and guidance for the overall project within the NIMH.
• The Program Officer is responsible for monitoring the agreed timelines and Data Management and Sharing Plan (DMS Plan).

Program Scientist

• The NIMH will assign a Project Scientist(s) as the point of contact to work with the PD(s)/PI(s) to ensure the objectives of the program are being met. The primary responsibility for the program resides with the awardee, although specific tasks and activities will be shared among the awardee and the NIH Project Scientist(s).
• The role of the NIMH Project Scientist(s) is to assist, participate in deliberations, and facilitate discussion, but not to direct activities. This level of staff involvement does not alter the awardee’s dominant role and prime authority in conducting the activities of the project. The NIMH Project Scientist(s) may cooperate with the awardee as author or co-author of resulting publications in accordance with publication policies developed by the Steering Committee. Publications involving NIMH staff must follow NIH and NIMH publication policies.
• The NIMH Project Scientist(s) will be named to the Steering Committee as a voting member (NIMH will hold one vote on the Steering Committee, regardless of the number of NIMH Project Scientists). The role of the NIMH Project Scientist(s) is one of substantial involvement above and beyond the normal program stewardship role of a Program Official. The participation of the NIMH Project Scientist(s) is intended to assist the Steering Committee in its efforts to ensure that the broad scientific goals of NIMH are reflected in the final design, implementation, and reporting of results from project activities.

Areas of Joint Responsibility include:

• Ensuring that sites and investigators as well as NIH and other research partners fully comply with federal regulatory requirements. This includes, but is not limited to, those relating to human subjects protections and informed consent.
• A Steering Committee will be established to assist in monitoring progress over time. The Steering Committee will be composed of the PD(s)/PI(s); key personnel; the NIMH Project Scientist(s); and additional members with expertise in the overall goals of the project.
• Steering Committee members will meet periodically, but not fewer than twice per year, to plan and design research activities, review and monitor study progress, and establish priorities, policies, and procedures. Each member will have one vote in any decision to be made by the Steering Committee with respect to study policies and procedures. The NIMH Project Scientist(s) will be a voting member of the Steering Committee. The NIMH Project Scientist(s) has a total of one vote on the Steering Committee, regardless of the number of NIMH Project Scientists. Adoption of policies and procedures will require a majority vote.
• NIMH Program Official may attend Steering Committee meetings as non-voting participants.

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. It will have three members: the PI, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

All costs requested and all changes in budgets after the first year should be clearly identified and justified.

3. Data Management and Sharing

Consistent with the 2023 NIH Policy for Data Management and Sharing, when data management and sharing is applicable to the award, recipients will be required to adhere to the Data Management and Sharing requirements as outlined in the NIH Grants Policy Statement. Upon the approval of a Data Management and Sharing Plan, it is required for recipients to implement the plan as described.

4. Reporting

When multiple years are involved, recipients will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

A final RPPR, 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. NIH NOFOs outline intended research goals and objectives. Post award, NIH will review and measure performance based on the details and outcomes that are shared within the RPPR, as described at 2 CFR Part 200.301.

The Federal Funding Accountability and Transparency Act of 2006 as amended (FFATA), includes a requirement for recipients of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later.  All recipients 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 the threshold.  See the NIH Grants Policy Statement for additional information on this reporting requirement.

In accordance with the regulatory requirements provided at 2 CFR Part 200.113 and Appendix XII to 2 CFR Part 200, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period.  The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (Responsibility/Qualification in SAM.gov, formerly FAPIIS).  This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313).  As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available.  Full reporting requirements and procedures are found in Appendix XII to 2 CFR Part 200 – Award Term and Condition for Recipient Integrity and Performance Matters.

Section VII. Agency Contacts

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

eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten submission by the due date, and post-submission issues)

Finding Help Online: https://www.era.nih.gov/need-help (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: [email protected] (preferred method of contact)
Telephone: 301-480-7075

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: [email protected]

Michele Ferrante, PhD
National Institute of Mental Health (NIMH)
Telephone: 301-793-2634
Email: [email protected]

Nicholas Gaiano, PhD
National Institute of Mental Health (NIMH)
Telephone: 301-827-3420
Email: [email protected]

Rita Sisco
National Institute of Mental Health (NIMH)
Telephone: 301-443-2805
Email:[email protected]

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.

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 2 CFR Part 200.