It is critical that applicants follow the Research (R) Instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

Part 1. Overview Information
Part 2. Full Text of the Announcement

Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

Although many promising novel therapeutic targets for treating psychiatric disorders have been discovered in recent years, the translation into effective treatments has been unacceptably slow. For those Agents advancing to clinical testing, the success rate of new drug and device approvals for psychiatric disorders has been poor, with candidates often failing in late stage clinical trials after significant investment. In too many cases, the reasons for trial failures remain unclear but might include, for example, patient heterogeneity, unfavorable drug characteristics (toxicity, poor target engagement, sub-optimal pharmacokinetic (PK)/pharmacodynamics (PD) parameters), or inappropriate biological targets for the disorder. This situation has contributed to the decrease in pharmaceutical companies investment in psychiatric drug development and enlarged the valley of death for drug development.

The NIMH and NIH provide funding support and research resources to facilitate drug and device intervention development. Drug discovery and the development of novel medications for psychiatric disorders are supported through several avenues (see https://www.nimh.nih.gov/research-priorities/therapeutics/index.shtml). A report of the National Advisory Mental Health Council’s Workgroup, entitled, From Discovery to Cure: Accelerating the Development of New and Personalized Interventions for Mental Illness, evaluated NIMH’s portfolio, and funding opportunities/resources for drug discovery/development in light of the current trend of pharmaceutical companies and venture capital to decrease their investments in clinical trials for central nervous system (CNS) disorders. One of the recommendations of this workgroup was for NIMH to invest in early stage clinical trials of novel Agents that act on novel molecular pathways (receptors, enzymes, second messengers, etc.) that are not targeted with currently available psychiatric drugs, and that have a strong justification as a novel mechanism for the treatment of psychiatric disorders. In addition, a recommendation was made that such trials include biological measures to assess target engagement in brain and evaluate the Agent’s mechanism of action in humans. The incorporation of these additional measures into early stage trials is intended to provide very early signs of potential failure or success of the Agent and help inform whether further later stage trials should be considered.

The NIMH is also interested in encouraging the nascent field of neuromodulation and neurostimulation devices for mental health conditions. Therefore, this FOA also supports early stages of clinical trials for devices including first in human (FIH) and early feasibility studies (EFS). Both invasive and non-invasive devices are included in this FOA. The NIMH expects that objective CNS measures of the device’s action on the brain be included in the trial. Only FDA-regulated devices (including those with non-significant risk designations) are included in this initiative, not computer-based devices.

The intent of this FOA is to test new mechanism of action interventions (defined as investigational drugs, drug candidates, rescued or repurposed drugs, or neuromodulation devices) in early stage trials (i.e., first in human (FIH), early feasibility studies (EFS), Phase Ib, and Phase II/proof of concept (PoC) studies) using experimental medicine approaches to address unmet medical need for the treatment of psychiatric disorders. For this FOA, Phase Ib and Phase II/PoC trials are defined as follows: Phase Ib trials are defined as studies usually conducted in the target patient population to establish feasibility (e.g., target engagement, pharmacodynamics/pharmacokinetics (PD/PK), optimal dosing of the Agent) for a Phase II/PoC. Phase II/PoC trials are defined as studies designed to explore new hypotheses and to assess whether the Agent demonstrates an early signal of efficacy in the targeted patient population. In addition to clinical benefit, Phase II/PoC trials also include assessments of safety, tolerability, and PD/PK response of the Agent. Strategies to inform the selection of patients for Phase II/PoC studies of the novel candidate Agent (e.g., approaches to segment or enrich subjects for inclusion in the trial) are strongly encouraged. For this FOA, FIH and EFS are defined as small clinical investigations of a device early in development, typically before the device design has been finalized, for a specific indication (e.g., innovative device with initial pre-clinical safety data or marketed device for a novel clinical application). It may be used to evaluate the device design concept with respect to initial clinical safety and device functionality in a small number of subjects (generally fewer than 10 initial subjects) when this information cannot practically be obtained through additional nonclinical assessments or appropriate nonclinical tests are unavailable (see FDA Guidance Notice on Early Feasibility Studies: http://www.fda.gov/downloads/medicaldevices/deviceregulationand%20guidance/guidancedocuments/ucm279103.pdf). Target engagement and initial efficacy should be evaluated along with device safety.

The overall objective of this FOA is to facilitate rapid collection of data to "de-risk" novel mechanism of action investigational drugs or devices, rescued, or repurposed drugs for use in psychiatric disorders, in order to attract private funding for further clinical development and FDA approval of the intervention. In addition to the adult FIH, EFS, Phase Ib, and Phase II/PoC studies, support is also provided for novel, first in children intervention testing in pediatric populations (i.e., first exposure in children or first in pediatric indication). A key aspect of this FOA is the formation of collaborative partnerships between the biomedical researchers and biotechnology or industry partners to facilitate psychiatric drug and device development. In cases where the Phase II/PoC studies are successful, it is anticipated that the biotechnology or pharmaceutical company partner will pursue further clinical development of the intervention whenever feasible.

The FOA will support stand-alone FIH, EFS, Phase Ib or Phase II/PoC studies or a combination of these, with rigorous milestone-based go/no go decisions to progress from one study to the next if multiple trials are proposed.

Pharmacologic Agents

For pharmacological Agents, the duration of the project must be appropriate for the proposed project with a maximum of 1 year allowed for completion of a FIH or Phase Ib study and 3 years for a Phase II/PoC study (4-year maximum for applications to complete both phases). FIH studies should assess Agent: 1) safety and tolerability, 2) target engagement, and 3) pharmacological effects on relevant circuits or systems. Data resulting from FIH studies and Phase Ib trials in the target patient population are expected to determine optimal clinical dosing and to establish feasibility for further testing in Phase II/PoC and efficacy trials. Agents must be sufficiently potent and selective for critical evaluation of target engagement and brain exposure. The Agent/indication (if successful) should have a major, not merely incremental, impact on unmet medical need in psychiatric disorders.

Phase II/PoC studies must assess the clinical efficacy signal of novel Agents using pharmacologically-based dosing, with validation of target engagement and exposure in brain, and must include biological measures of impact of the Agent on clinically relevant physiological systems to assess the link between hypothesized drug mechanism/target and clinical effect. Phase II/PoC studies must be sufficiently powered to assess Agent impact (magnitude and duration of target modulation) on a physiological process that is associated with the clinical outcome measure (e.g., cognition, social function) and an outcome measure to assess clinical benefit must be included. Examples of available novel Agents for adult testing can be found at https://ncats.nih.gov/ntu/assets/2017#Adult_Indications and

examples of available novel Agents for pediatric testing can be found at https://ncats.nih.gov/ntu/assets/2017#Pediatric_Indications.

FDA-regulated devices

This FOA also supports FIH and EFS trials for novel FDA-regulated devices. For devices, the same experimental medicine strategy is expected to demonstrate that CNS stimulation produces a dose dependent CNS effect, but under regulatory safety considerations for devices instead of drugs. The duration and budget of the device trial(s) must be appropriate for the proposed project, with a maximum of four years. For the purpose of this FOA, both FIH and EFS device studies are analogous studies and include a maximum of 10 subjects. Information regarding FDA regulatory approval process for obtaining IDEs in FIH/EFS studies can be found at https://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm279103. Documentation of non-significant risk (NSR) determination from an IRB and/or the FDA may also be submitted for device studies that do not require an IDE.

FIH/EFS studies should evaluate both safety and early signs of clinical efficacy of device interventions, both which can inform future device development. Further information required for device studies is included in the Research Strategy section below and requires realistic head modeling and descriptions of the parameter space and dose/response capability. The experimental medicine approach requires that medical devices demonstrate target engagement via neural activity changes. Neural activity can be assessed by means of EEG, fMRI, or a variety of other electrophysiological or neuroimaging modalities. The dose dependent CNS effect should be explored and target engagement should be optimized throughout the study to inform future interventional study parameters.

Goal for all trials

Overall, the goal for all trials funded under this FOA is to "de-risk" novel mechanism of action investigational drugs or devices in order to attract private funding for further clinical development as FDA-approved treatments. These studies will: 1) accelerate the testing of new therapeutics for psychiatric disorders, 2) facilitate the validation of biological targets for therapeutic development, and 3) provide data assessing the relationship between clinical measures and biological indicators (mechanistic or PD biomarkers) of effect.

It is expected that successful applications will likely include multi-disciplinary teams of scientists with appropriate expertise for experimental evaluation and the clinical development of novel treatments. Scientists from both academia and biotechnology or pharmaceutical/device industry are encouraged to participate on the project. As an example, while an academic institution may be submitting the application, the company would be providing the therapeutic, input on trial design, and therapeutic know-how into the project. It is anticipated that the interaction of academic and non-profit research institutions with NIH and pharmaceutical industry will facilitate timely clinical evaluation and development of novel therapeutics. Applicants should outline proposed plans for further development of promising clinical candidates that are tested in the FIH, EFS, Phase Ib, and/or PhaseII/PoC studies through this program.

Given the diversity of expertise needed to conduct pediatric drug trials, it is required that a pediatric pharmacologist and pediatric psychiatrist would jointly participate. Additionally, it is required that Contract Research Organizations (CROs) or CTSAs, with expertise in first in pediatric PK/PD bridging studies, will conduct the trial(s).

For information on NIMH’s interest in pediatric pharmacological clinical trials, as well as the requirements, goals and priorities of pediatric drug trials please see: Notice of NIMH's Interest to Highlight High-Priority Pediatric Pharmacologic Trial Research Areas (NOT-MH-17-039) and Notice of NIMH's Interest in Pediatric Pharmacologic Trials in Autism Spectrum Disorders, directed at testing selective GABAergic agents (NOT-MH-17-044).

Additionally, for all other trials that fit the goals of this FOA, it is required that CROs or CTSAs with expertise in the age range and intervention type, conduct the trials.

Prior to award, it is expected that an IND or IDE be in place with the FDA for the proposed intervention. In addition, there should be documentation verifying the full participation of the pharmaceutical or biotechnology partner for rescue/repurpose studies and sufficient Agent/device supply to complete the study, and additional required documentation (e.g., confidential disclosure agreements (CDAs), collaborative research agreements (CRAs), licensing agreements). Timelines for submission of all documentation are critical for this project. It is expected that such documentation would be initiated early in the process of developing the application. Lack of appropriate documentation at the time of award could influence funding decisions.

For multi-site trials, use of a centralized IRB is expected. The number of trial sites should be limited to minimize variability of the data.

Strong subject recruitment is expected in these trials due to shortened timelines allowed for conducting the trials. Therefore, the recruitment plan provided in the application package will be included in the notice of award and monitored closely

The testing of established or well-studied Agents for the treatment of psychiatric disorders is not the focus of this FOA. Such applications would be considered of very low priority. Only FIH, EFS, Phase Ib, and Phase II/PoC studies of novel Agents on the regulatory path are appropriate for this announcement. Please refer to www.clinicaltrials.gov for a listing of Agents/mechanisms of action that are currently in trials in order to determine if the trial(s) is: 1) relevant to the proposed work, and could help inform the design of the U01 application; or 2) may be duplicative of the proposed application and therefore limit the innovation in the proposed application. Relevant trials should be acknowledged in the application.

Applicants are strongly encouraged to contact the relevant Scientific/Research Contact listed in Section VII of this FOA to determine: 1) if the proposed Agent/mechanism of action and clinical indication would be considered a priority for NIMH; and 2) if this, or other clinical trials FOAs, may be more appropriate for the proposed work. Applicants are also strongly encouraged to review the information on the NIMH website focused on clinical trials and Frequently Asked Questions http://www.nimh.nih.gov/funding/clinical-trials-for-researchers/index.shtml.

The NIMH has published updated policies and guidance for investigators regarding human research protection and clinical research data and safety monitoring (NOT-MH-15-025). The application’s Protection of Human Subjects section and data and safety monitoring plans should reflect the policies and guidance in this notice. Plans for the protection of research subjects and data and safety monitoring will be reviewed by the NIMH for consistency with NIMH and NIH policies and federal regulations.

The NIMH is committed to enhancing the reliability of NIMH-supported research through rigorous study design and reporting (NOT-MH-14-004).

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

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

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)
• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations

Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are not allowed.

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• System for Award Management (SAM) (formerly CCR) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
• NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
• eRA Commons - Applicants must have an active DUNS number and SAM registration in order to complete the eRA Commons registration. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

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

All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.

For pediatric drug trials, the application must include the joint participation of a pediatric pharmacologist and pediatric psychiatrist, as multiple PD/PIs.

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

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

The NIH will not accept duplicate or highly overlapping applications under review at the same time. This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101).

Buttons to access the online ASSIST system or to download application forms are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

It is critical that applicants follow the Research (R) Instructions in the SF424 (R&R) Application Guide, except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

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

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]

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

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.

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

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

It is required that Contract Research Organizations (CROs) or CTSAs, with expertise in first in pediatric PK/PD bridging studies, will conduct the trial(s).

Additionally, for all other trials that fit the goals of this FOA, it is required that CROs or CTSAs with expertise in the age range and intervention type, conduct the trials.

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

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

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

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

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

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

Research Strategy: For FIH, Phase Ib, and Phase II/PoC pharmacological studies, a clear description should be included of the approach for determining pharmacological dose/response relationships and target engagement of the drug candidate. Beyond these requirements, Phase II/PoC studies should present a compelling scientific rationale for the biological measures (mechanistic biomarkers) used to assess the link between hypothesized drug mechanism/target and clinical effect.

FIH studies should assess Agent: 1) safety and tolerability, 2) target engagement, and 3) pharmacological effects on relevant circuits or systems. Data resulting from FIH studies and Phase Ib trials in the target patient population are expected to determine optimal clinical dosing and to establish feasibility for further testing in Phase II/PoC and efficacy trials. Agents must be sufficiently potent and selective for critical evaluation of target engagement and brain exposure. The Agent/indication (if successful) should have a major, not merely incremental, impact on unmet medical need in psychiatric disorders.

For FIH/EFS device studies, the clinical impact and feasibility should be clearly defined. Describe the current state of knowledge of the etiology, clinical characteristics, and current and projected prevalence of the proposed disease indication where appropriate. Briefly discuss available alternatives, their limitations, and how the proposed project would provide benefits over existing therapies or diagnostics, regardless of therapeutic class (i.e., agents and devices). Identify one or more clinically meaningful device outcome measures based on input from both clinicians and patients. Discuss how the proposed project relates to therapy or diagnostic development efforts underway in academia and industry, including both agents and devices. Explain the rationale for the minimally acceptable and ideal results. Briefly comment on the feasibility of conducting clinical trials toward these goals (e.g., availability of clinical trial networks).

The overall plan for device testing should include:

• A clear description of the device and method of neurostimulation.
• A compelling rationale that the mode of stimulation will have a direct effect on brain regions of interest. Characterization of the spatial aspects of delivered dose for electromagnetic and other stimulating devices should use realistic head modeling to simulate the amplitude of the electric or related fields induced across the brain, and should evaluate degree of target to non-target stimulation.
• A plan for testing the target engagement/neural stimulation of a target brain region by means of neuroimaging/neurophysiology such as EEG, fMRI, MEG, or other devices.
• A plan for testing and describing dose/response characteristics of the delivered dose.
• A description of the temporal and spatial characteristics of the stimulation parameter space.
• A clearly stated device testing timeline that includes practical, achievable goals in support of the proposed clinical study.
• Anticipated risks in the device testing process, including potential needs for design changes, and mitigations based on initial test results.
• Clinical considerations including, but not limited to, description of the tools and process for device insertion and method for evaluating the functional integrity of the device. This plan will often involve collaboration between the investigators, clinical researchers, and may include the participation of private-sector companies.
• A discussion of why the target population is an appropriate group to address the hypotheses.

Applicants should clearly articulate what the next step will be in device development assuming a successful outcome of the clinical study, and justify the outcome metrics for the proposed clinical study in terms of quantifiable minimum-success criteria necessary to enable this next step.

For all interventions, subject selection must be well justified and would ideally ensure the individuals have the abnormality in the CNS pathway being studied; objective, biological measures should be used when feasible for subject selection. Phase II/PoC studies should incorporate FDA-accepted clinical outcome measures to assess potential efficacy in addition to the biological measures. In selecting biological measures, applicants are encouraged to incorporate measures consistent with the goals of the NIMH RDoC framework (http://www.nimh.nih.gov/research-funding/nimh-research-domain-criteria-rdoc.shtml). Overall, the inclusion of biomarkers in the design of the study is encouraged, when appropriate: e.g., the inclusion of PK/PD biomarkers to assess target engagement, brain exposure and functional pharmacological activity of the Agent or the use of molecular markers of disease, pharmacogenomics, or other biomarkers as patient selection strategies. The goals of the Phase II/ PoC trials are to determine that the Agent modulates the target/mechanism and shows potential for efficacy in the proposed disease population, thereby building scientific data to "de-risk" the further clinical development of the Agent for a new therapeutic use that has not previously been explored.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

• All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.
• Positive or negative data from NIH supported clinical trials are expected to be made available to the research community through ClinicalTrials.gov, publications, or public website, consistent with achieving the goals of the Program. The applicant is expected to address a plan and timeline for sharing clinical trials data.
• In order to advance the goal of advancing research through widespread data sharing among researchers, investigators funded under this FOA are expected to share those data via the National Institute of Mental Health Data Archive (NDA; https://data-archive.nimh.nih.gov). Established by the NIMH, NDA is a secure informatics platform for scientific collaboration and data-sharing that enables the effective communication of detailed research data, tools, and supporting documentation. A cost estimation tool for data sharing is available at https://ndct.nimh.nih.gov/preplanning/budget. Researchers should use that cost estimation tool when preparing budgets for applications submitted to NIMH.

Appendix:

Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

Use only for applications with due dates on or after January 25, 2018. When involving NIH-defined human subjects research, clinical research, and/or clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) 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 SF424 (R&R) Application Guide must be followed with the following additional instructions:

Section 2 - Study Population Characteristics

2.5 Recruitment and Retention Plan

A plan for robust subject recruitment must be included that addresses the shorter trial duration. Failure to maintain the planned recruitment rate could result in trial termination.

The application must include a clear description of the procedures to avoid bias in allocation of subjects to treatment and in assessment of outcomes; and subject follow-up procedures.

2.7 Study Timeline

The timeline should address reaching important study milestones such as: 1) obtaining IRB approval and regulatory clearance for the protocol, 2) establishing agreements with participating industry partners, 3) obtaining adequate supply of the investigational Agent or device, 4) finalizing the study procedures and training participating clinical site staff, and 5) enrolling 25%, 50%, 75% and 100% of the sample size.

The timeline should include a plan for decision-making regarding identification and evaluation of promising drug candidates or devices for development. All applications must include clearly-specified, well-defined milestones, go/no go decision points, and timelines for assessing progress. In addition, if the proposed research includes plans for FIH/EFS with progression to Phase Ib or Phase II/PoC studies in patients, specific milestones and go/no-go criteria should be described for assessing the appropriateness of advancing to Phase 1b or Phase II/PoC studies in patients.

Section 3 - Protection and Monitoring Plan

Section 3.5 Overall Structure of Study Team

For device testing, include descriptions of the organization of the study and how the trial will be managed, the role of any internal and external committees (e.g., executive committee, endpoint adjudication committee), and the responsibilities and oversight of any central laboratories/reading centers or resource centers.

Section 4 - Protocol Synopsis

Section 4.3 Outcome Measure

For FIH/EFS device studies, include one or more clinically meaningful device outcomes measures along with a strong rationale for the measures.

Section 4.4 Statistical Design and Power

Statistical methods must be proposed that are appropriately matched to the study design. Sample size, power calculations, and plans for analyses, data management, and quality control must be included.

Section 4.6 Will the study use an FDA-regulated intervention?

Section 4.6.a. If yes, describe the availability of Investigational Product (IP) and Investigational New Drug (IND)/Investigational Device Exemption (IDE) status

The application must include the status of all regulatory clearances necessary to conduct the proposed trial (e.g., status of the IND/IDE). The application should include evidence of contact with appropriate U.S. regulatory bodies (e.g., FDA in the form of Pre-submission meetings and IDE submission). Documentation of non-significant risk (NSR) determination from an IRB and/or the FDA may also be submitted for device studies that do not require an IDE. IRB approval is not required at the time of application submission, but is required prior to funding, so NIMH encourages investigators to begin this process as early as possible.

Delayed Onset Study

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

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

See Part 1. 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

Part I. Overview Information 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 Policy on Late Application Submission.

Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.

This initiative is not subject to intergovernmental review.

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Pre-award costs are allowable only as described in the NIH Grants Policy Statement.

Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide. Paper applications will not be accepted.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Guidelines for Applicants Experiencing System Issues. 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 Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.

The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

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

In order to expedite review, applicants are requested to notify the NIMH Referral Office by email at [email protected] when the application has been submitted. Please include the FOA number and title, PD/PI name, and title of the application.

Applicants requesting $500,000 or more in direct costs in any year (excluding consortium F&A) must contact a Scientific/ Research Contact at least 6 weeks before submitting the application and follow the Policy on the Acceptance for Review of Unsolicited Applications that Request $500,000 or More in Direct Costs as described in the SF424 (R&R) Application Guide.

NIH encourages the use of common data elements (CDEs) in basic, clinical, and applied research, patient registries, and other human subject research to facilitate broader and more effective use of data and advance research across studies. CDEs are data elements that have been identified and defined for use in multiple data sets across different studies. Use of CDEs can facilitate data sharing and standardization to improve data quality and enable data integration from multiple studies and sources, including electronic health records. NIH ICs have identified CDEs for many clinical domains (e.g., neurological disease), types of studies (e.g., genome-wide association studies (GWAS)), types of outcomes (e.g., patient-reported outcomes), and patient registries (e.g., the Global Rare Diseases Patient Registry and Data Repository). NIH has established a Common Data Element (CDE) Resource Portal" (http://cde.nih.gov/) to assist investigators in identifying NIH-supported CDEs when developing protocols, case report forms, and other instruments for data collection. The Portal provides guidance about and access to NIH-supported CDE initiatives and other tools and resources for the appropriate use of CDEs and data standards in NIH-funded research. Investigators are encouraged to consult the Portal and describe in their applications any use they will make of NIH-supported CDEs in their projects.

Applicants are required to follow the instructions for post-submission materials, as described in the policy. Any instructions provided here are in addition to the instructions in the policy.

Important Update: See NOT-OD-18-228 for updated review language for due dates on or after January 25, 2019.

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

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 intervention is unwarranted 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.

Does the project address an important problem or a critical barrier to progress in the field? Is there a strong scientific premise for the project? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Will sufficient data be collected to "de-risk" the candidate therapeutic for further clinical development? Does the therapeutic drug candidate or device address an area of unmet medical need for interventions for psychiatric disorders? Does the experimental Agent or device represent a potentially significant advancement over existing treatments? Does the experimental Agent or device hold promise of being utilized in clinical practice?

Are the scientific rationale and need for a clinical trial to test the proposed hypothesis or intervention well supported by preliminary data, clinical and/or preclinical studies, or information in the literature or knowledge of biological mechanisms? For trials focusing on clinical or public health endpoints, is this clinical trial necessary for testing the safety, efficacy or effectiveness of an intervention that could lead to a change in clinical practice, community behaviors or health care policy? For trials focusing on mechanistic, behavioral, physiological, biochemical, or other biomedical endpoints, is this trial needed to advance scientific understanding?

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or those in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

Is there evidence of proven expertise in recruiting subjects and in performing pharmacological and functional measures of target engagement? Is there a letter of support or other evidence of involvement of the private sector partner providing the investigational drug, drug candidate or device for the proposed studies, if a partner is proposed? Is the staffing, governance, and organizational structure appropriate for conducting the study as proposed and within specified timelines? Is there a description of the expertise needed by any potential consultants?

With regard to the proposed leadership for the project, do the PD/PI(s) and key personnel have the expertise, experience, and ability to organize, manage and implement the proposed clinical trial and meet milestones and timelines? Do they have appropriate expertise in study coordination, data management and statistics? For a multicenter trial, is the organizational structure appropriate and does the application identify a core of potential center investigators and staffing for a coordinating center?

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?

Are the therapeutic targets, mechanisms, or measures to assess target biology considered to be novel?

Does the design/research plan include innovative elements, as appropriate, that enhance its sensitivity, potential for information or potential to advance scientific knowledge or clinical practice?

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

Is there a strong justification for the approach for determining pharmacological effects and target engagement of the drug candidate? Is there a compelling scientific rationale for the biological measures (mechanistic biomarker) used to assess the hypothesized drug or device mechanism/target?

Are the clinical measures appropriate? Are plans for analyses, data management, and quality control adequate?

If the application plans to progress from FIH/ EFS studies in normal subjects to Phase Ib studies or to Phase II/PoC studies in patients, are specific milestones and go/no-go criteria described for assessing the biological validity and feasibility of progressing to Phase II/PoC studies?

Does the application adequately address the following, if applicable

Study Design

Is the study design justified and appropriate to address primary and secondary outcome variable(s)/endpoints that will be clear, informative and relevant to the hypothesis being tested? Is the scientific rationale/premise of the study based on previously well-designed preclinical and/or clinical research? Given the methods used to assign participants and deliver interventions, is the study design adequately powered to answer the research question(s), test the proposed hypothesis/hypotheses, and provide interpretable results? Is the trial appropriately designed to conduct the research efficiently? Are the study populations (size, gender, age, demographic group), proposed intervention arms/dose, and duration of the trial, appropriate and well justified?

Are potential ethical issues adequately addressed? Is the process for obtaining informed consent or assent appropriate? Is the eligible population available? Are the plans for recruitment outreach, enrollment, retention, handling dropouts, missed visits, and losses to follow-up appropriate to ensure robust data collection? Are the planned recruitment timelines feasible and is the plan to monitor accrual adequate? Has the need for randomization (or not), masking (if appropriate), controls, and inclusion/exclusion criteria been addressed? Are differences addressed, if applicable, in the intervention effect due to sex/gender and race/ethnicity?

Are the plans to standardize, assure quality of, and monitor adherence to, the trial protocol and data collection or distribution guidelines appropriate? Is there a plan to obtain required study agent(s)? Does the application propose to use existing available resources, as applicable?

Data Management and Statistical Analysis

Are planned analyses and statistical approach appropriate for the proposed study design and methods used to assign participants and deliver interventions? Are the procedures for data management and quality control of data adequate at clinical site(s) or at center laboratories, as applicable? Have the methods for standardization of procedures for data management to assess the effect of the intervention and quality control been addressed? Is there a plan to complete data analysis within the proposed period of the award?

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of children, justified in terms of the scientific goals and research strategy proposed?

Are subject inclusion criteria well justified and likely to show abnormality in the CNS pathway being studied? Are the recruitment strategy and plan well justified and feasible? Are clear, actionable study milestones proposed, including feasible subject accrual goals? Are likely problems anticipated?

For applications proposing device studies reviewers should address the following: Is the potential clinical impact clearly described? Has the current state of knowledge of the etiology, clinical characteristics, and current and projected prevalence of the proposed disease indication been described?

Does the application include a compelling plan for device testing that includes:

• A clear description of the device and method of neurostimulation.
• A compelling rationale that the mode of stimulation will have a direct effect on brain regions of interest.
• A plan for testing the target engagement/neural stimulation of a target brain region by means of neuroimaging/neurophysiology such as EEG, fMRI, MEG, or other devices.
• A plan for testing and describing dose/response characteristics of the delivered dose.
• A description of the temporal and spatial characteristics of the stimulation parameter space.
• A clearly stated device testing timeline that includes practical, achievable goals in support of the proposed clinical study.
• A clearly stated device testing timeline that includes practical, achievable goals in support of the proposed clinical study.
• Evidence of contact with appropriate U.S. regulatory bodies (e.g., FDA in the form of Pre-submission meetings and IDE submission).
• Anticipated risks in the device testing process, including potential needs for design changes, and mitigations based on initial test results.
• One or more clinically meaningful device outcomes measures included along with a strong rationale for the measures.
• Clinical considerations including, but not limited to, description of the tools and process for device insertion and method for evaluating the functional integrity of the device. This plan will often involve collaboration between the investigators, clinical researchers, and may include the participation of private-sector companies.
• A description of the target population, and why it is an appropriate group to address the hypotheses.
• Descriptions of the organization of the study and how the trial will be managed, the role of any internal and external committees (e.g., executive committee, endpoint adjudication committee), and the responsibilities and oversight of any central laboratories/reading centers or resource centers.

Have investigators clearly articulated what the next step will be in device development assuming a successful outcome of the clinical study, and justify the outcome metrics for the proposed clinical study in terms of quantifiable minimum-success criteria necessary to enable this next step?

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

When pharmaceutical or biotechnology industry partners are involved, are key personnel included who have authority within the company to allocate resources to ensure successful completion of the proposed discovery and development efforts? Are the necessary agreements in place? Is there evidence that all necessary regulatory clearances and permissions (e.g., IND or IDE, permissions for rating scales) have been obtained or will be in place before funding?

If proposed, are the administrative, data coordinating, enrollment and laboratory/testing centers, appropriate for the trial proposed?

Does the application adequately address the capability and ability to conduct the trial at the proposed site(s) or centers? Are the plans to add or drop enrollment centers, as needed, appropriate?

If international site(s) is/are proposed, does the application adequately address the complexity of executing the clinical trial?

If multi-sites/centers, is there evidence of the ability of the individual site or center to: (1) enroll the proposed numbers; (2) adhere to the protocol; (3) collect and transmit data in an accurate and timely fashion; and, (4) operate within the proposed organizational structure?

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.

Study Timeline

Is the study timeline described in detail, taking into account start-up activities, the anticipated rate of enrollment, and planned follow-up assessment? Is the projected timeline feasible and well justified? Does the project incorporate efficiencies and utilize existing resources (e.g., CTSAs, practice-based research networks, electronic medical records, administrative database, or patient registries) to increase the efficiency of participant enrollment and data collection, as appropriate?

Are potential challenges and corresponding solutions discussed (e.g., strategies that can be implemented in the event of enrollment shortfalls)?

For research that involves human subjects but does not involve one of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.

When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of children to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

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

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

For Renewals, the committee will consider the progress made in the last funding period.

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

As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.

Not Applicable

Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: (1) Data Sharing Plan; (2) Sharing Model Organisms; and (3) Genomic Data Sharing Plan (GDS).

For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.

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

As part of the scientific peer review, all applications:

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

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 .Following initial peer review, recommended applications will receive a second level of review by the National Advisory Mental Health Council. The following will be considered in making funding decisions:

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

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons. 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.

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the grantee’s business official.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

Any application awarded in response to this FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this website.

Additionally, ICs may specify any special reporting requirements for the proposed clinical trial to be included under IC-specific terms and conditions in the NoA. For example: If the proposed clinical trial has elevated risks, ICs may require closer programmatic monitoring and it may be necessary to require the awardee to provide more frequent information and data as a term of the award (e.g., to clarify issues, address and evaluate concerns, provide documentation). All additional communications and information related to programmatic monitoring must be documented and incorporated into the official project file. 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 of all trials whether required under the law or not. For more information, see http://grants.nih.gov/ClinicalTrials_fdaaa/

Institutional Review Board or Independent Ethics Committee Approval: Grantee institutions must ensure that the application as well as all protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the awardee 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).

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person’s race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency. HHS recognizes that 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 FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/index.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html; and https://www.hhs.gov/civil-rights/for-providers/laws-regulations-guidance/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

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 the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, 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 45 CFR Part 75.205 Federal awarding agency review of risk posed by applicants. This provision will apply to all NIH grants and cooperative agreements except fellowships.

Cooperative Agreement Terms and Conditions of Award

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 45 CFR Parts 75, and other HHS, 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 awardees 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 award 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 awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

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

The PD(s)/PI(s) will have primary authority and responsibility to define objectives and approaches and to plan and conduct the proposed research. She/he will assume responsibility and accountability to the applicant organization and to the NIMH for performance and proper conduct of all research, including the NIH intramural component, if applicable, in accordance with the Terms and Conditions of Award.

The Principal Investigator will be a member of the Steering Committee and will be responsible for scheduling Steering Committee meetings and disseminating meeting notes to all participants within 2 weeks of each meeting (see below under Collaborative Responsibilities).

The Awardee Institution and/or Research Project Leader's Institution will retain primary custody of and have primary rights to data as specified under the NIMH approved Intellectual Property Patent Rights Agreements for New Chemical Entities or the data and research resource sharing plans (described below). The PD/PI will provide to the NIMH Program Official and Project Scientist(s) access to data generated under this cooperative agreement to allow them to periodically review the data consistent with current DHHS, PHS, and NIH policies.

Timely publication of major findings by the Steering Committee members is encouraged. Publication or oral presentation of work done under this agreement will require appropriate acknowledgment of NIMH support, including the assigned cooperative agreement award number.

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

The Project Scientist(s) interacts scientifically with the funded PIs and the collaborators on their cooperative agreement grants, and may provide appropriate assistance, including: 1) assisting in research planning, 2) suggesting studies within the scope of the cooperative agreement objectives and research activities, 3) presenting experimental findings from published sources or from relevant contract projects, 4) participating in the design of experiments, 5) participating in the analysis of results, and 6) advising in management and technical performance.

The Project Scientist(s) will be a member(s) of the Steering Committee.

FIH, EFS, Phase Ib and Phase II/PoC studies will be reviewed by an appropriate NIMH Data and Safety Monitoring Board (DSMB) to ensure the safety of participants and the validity and integrity of the data. The study protocol(s) and consent form(s) will be reviewed by the DSMB prior to initiation of the project. The DSMB will review study reports on a regular basis to monitor subject enrollment and retention, safety, quality of data collection, and integrity of the study. Applicants should refer to NIH’s policy on data and safety monitoring (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html) as well as the NIMH Guidelines for Data and Safety Monitoring (http://www.nimh.nih.gov/funding/grant-writing-and-application-process/nimh-policy-on-data-and-safety-monitoring-in-extramural-investigator-initiated-clinical-trials.shtml.

Additionally, an NIMH Program Official will be responsible for the normal scientific and programmatic stewardship of the award, including monitoring implementation of the data and research resource sharing plans and will be named in the award notice.

As noted previously, both NIMH Project Scientist and Program Official will be given access to the data generated under this cooperative agreement, which will allow them to periodically review the data to ensure consistency with current DHHS, PHS, and NIH Policies.

Participation of NIH Intramural Scientists:

An NIH intramural scientist may not serve as the PD(s)/PI(s) but may participate as a collaborator, or consultant. However, an Intramural scientist may not receive salary, equipment, supplies, or other remuneration from awards resulting from this FOA. The Intramural scientist must obtain written approval of his/her NIH Institute Scientific Director for the amount of resources that may be allocated to the project. The approval must also specify that the conduct of the project will comply with the DHHS regulations for research involving human subjects (if applicable) and with the PHS policy on vertebrate animal research. The participation of an intramural scientist is independent of and unrelated to the role of the NIMH Project Scientist. For applications that include NIH intramural components, the intramural resource level will be included in the total cost of the overall application. The involvement of Intramural scientists needs to be consistent with NIH Policy. http://www1.od.nih.gov/oir/sourcebook/ethic-conduct/ethical-conduct-toc.htm

Intramural research scientists participating as collaborators have the same rights and responsibilities as other researchers who are participating investigators in the funded cooperative agreement grants. Most often these investigators will be members of the Steering Committee, since they will likely be considered as key personnel.

Areas of Joint Responsibility include:

A governing Steering Committee composed of the PD(s)/PI(s), a CRO lead or CTSA lead (as applicable), key personnel, NIMH Project Scientist(s), and NIMH Program Official will be established to assist in monitoring and developing the scientific content and direction of the program. The total membership by NIMH staff will not exceed one-third (1/3) of the membership of the Steering Committee. In all cases, the role of NIMH will be to assist, participate in deliberations, and facilitate discussion and not to direct activities.

Steering Committee will serve as the governing board for awardees. All awardees under this initiative program are bound by the policies and procedures developed by the Steering Committee; adoption of such policies and procedures requires a majority vote. Awardees under this FOA will be required to accept and implement policies approved by the Steering Committee.

Membership in the Steering Committee will include the PD(s)/PI(s) of each U01 award, or a designated representative in the case of Multiple PD/PI award. Each member will have one vote.

The NIMH Project Scientist will be a voting member 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, for scheduling and chairing meetings, and for preparing concise minutes which will be delivered to Steering Committee members within 30 days of the meeting. Virtual meetings are appropriate. The NIMH Project Scientist may not serve as the Chair of the Steering Committee.

The Steering Committee members will meet periodically to review progress, plan and design research activities, and establish priorities. The frequency of meetings, not fewer than two per year, will be determined by the PD(s)/PI(s) who will be responsible for scheduling the time and place (generally at one of the performance sites) and for preparing concise proceedings or minutes (action items and one-two page summary) which will be delivered to the members of the Committee within 2 weeks of the meeting.

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: a designee of the Steering Committee chosen without NIH staff voting, 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.

Intellectual Property and Patent Rights for New Chemical Entities or Devices

Since the development of new pharmacological treatments for psychiatric disorders is a major objective of this effort and active involvement by pharmaceutical laboratories is encouraged and would be facilitated by the existence of appropriate patent coverage, it is expected that applicants provide plans to address the handling of intellectual property for new chemical entities or devices under this FOA.

Under the earlier National Cooperative Drug Discovery/Development Groups (NCDDG) for the Treatment of Mental Disorders, Drug or Alcohol Addiction program, successful applicants were required to supply the following confidential materials to the NIMH Program Official listed under Section VII. Agency Contacts. Similar to the NCDDG, applicants are expected to address the three items noted below under this FOA, consistent with achieving the goals of this program:

1. Each applicant are expected to provide a detailed description of the approach to be used for handling intellectual property and for licensing where appropriate, in particular where the invention may involve investigators from more than one institution. Procedures are expected to be described for resolution of legal problems should they arise, consistent with achieving the goals of the program. Your attention is drawn to the NIH Extramural Technology Transfer Policies and Documents [https://grants.nih.gov/grants/intell-property.htm].

2. A formal statement of Intellectual Property among the PD(s)/PI(s) and their institutions as well as a detailed description of procedures to be followed for resolution of legal problems which may develop, is expected to be signed and dated by the organizational official authorized to enter into intellectual property arrangements for each PD(s)/PI(s) and their institution(s). The signed agreement is expected to be submitted prior to award to the appropriate NIMH staff at the addresses provided under Section VII. Agency Contacts.

3. Prior to the award, the PD(s)/PI(s) is expected to provide a signed statement of acceptance of the participation of NIMH staff during performance of the award as outlined under "NIH Staff Responsibilities" in Section VI.2 - Cooperative Agreement Terms and Conditions of Award.

Note: Do NOT submit documents 1-3 above with the application. However, awards will not be made until these documents are received and approved by NIMH.

Progress Reviews

Progress of the project will be reviewed annually by the NIMH Project Officer at the time of each non-competing continuation application to assure that satisfactory progress is being made in achieving the project objectives, especially with respect to enrollment and quality of data collection, timely data sharing as appropriate and consistent with achieving the goals of the program, and to ensure the site is following the procedures recommended and approved by the project Steering Committee.

By acceptance of these awards, the awardees agree to abide by decisions and policies of the project Steering Committee and the other terms and conditions listed above or referenced in the Notice of Grant Award.

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

A final 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.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.

In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, 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 (currently 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 45 CFR Part 75 Award Term and Conditions for Recipient Integrity and Performance Matters.

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

eRA Service Desk (Questions regarding ASSIST, eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact Center Telephone: 800-518-4726
Email: [email protected]

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: [email protected] (preferred method of contact)
Telephone: 301-945-7573

Questions about first in human and Phase I studies of novel therapeutic drug candidates or devices should be directed to:

Lois Winsky, Ph.D.
National Institute of Mental Health (NIMH)
Telephone: 301-443-5288
Email: [email protected]

Questions about proof of concept studies for novel therapeutics drug candidates for psychiatric disorders in adult populations should be directed to:

Mi Hillefors, M.D., Ph.D.
National Institute of Mental Health (NIMH)
Telephone: 301-443-2738
Email: [email protected]

Questions about FIH or EFS studies for devices for psychiatric disorders in adult populations should be directed to:

David McMullen, M.D.
National Institute of Mental Health (NIMH)
Telephone: 301-451-0180
Email: [email protected]

Questions about proof of concept studies for novel therapeutic drug candidates or devices for psychiatric disorders in children and adolescents (first exposure in children or first in pediatric indication), or in adults with early developmental onset disorders including Tourette Syndrome, Attention Deficit Disorder, and Autism Spectrum Disorder should be directed to:

Margaret Grabb, Ph.D.
National Institute of Mental Health (NIMH)
Telephone: 301-443-3563
Email: [email protected]

Nick Gaiano, Ph.D.
National Institute of Mental Health (NIMH)
Telephone: 301-827-3420
Email: [email protected]

Terri Jarosik
National Institute of Mental Health (NIMH)
Telephone: 301-443-3858
Email: [email protected]

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75.