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 Multi-Project (M) Instructions in the How to Apply - Application Guide, except where instructed to do otherwise (in this NOFO or in a Notice from the 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.
   
   



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

Purpose

The intent of this NOFO is to encourage applications from academic, biotechnology, biomedical device industry, or pharmaceutical industry investigators interested in participating with the National Institute of Mental Health (NIMH)  in a National Cooperative Drug/Device Discovery/Development Group (NCDDG) program. The objectives of this program are: to advance the discovery, preclinical development, early-stage human studies, and/or proof of concept (PoC) testing of new, rationally based candidate agents or devices to treat mental disorders; and to develop novel ligands and novel brain circuit-modulator technologies as tools to advance biological research on the function of genes, cells, biochemical pathways, distributed neural circuits, and neural oscillatory patterns implicated in the etiology and pathophysiology of mental disorders, and as potential new therapeutics. Partnerships between academia and industry are strongly encouraged.

Each NCDDG program should consist of a multidisciplinary team of scientists with appropriate expertise to further the development and evaluation of novel candidate agents or proposed biomedical devices. Scientists from both academia and the pharmaceutical industry are encouraged to participate within an NCDDG; scientists from foreign institutions and NIH Intramural laboratories may participate in some aspects. It is anticipated that the interaction of academic and non-profit research institutions with industry and NIH via the NCDDG model will: 1) accelerate the discovery and development of new therapeutics for mental disorders; 2) increase the availability of pharmacologic and device-based research tools (including imaging agents) for basic and clinical research; 3) facilitate the development and validation of neurophysiological and pharmacokinetic (PK) and pharmacodynamic (PD) measures to evaluate novel therapeutics for mental disorders; 4) increase the availability of new compounds, agents, and devices suitable for testing in humans; 5) facilitate the development and validation of new clinical measures or biomarkers suitable for use in human PoC trials of novel therapeutics for mental disorders; and/or 6) develop and validate novel neurostimulation technologies and protocols for mental disorders.

The goal of the NCDDG program is not to duplicate or compete with the private sector but to complement and accelerate the development of research tools for new molecular and circuit targets implicated in mental disorders, and effective compounds, agents, and devices for the prevention and treatment of psychiatric and addictive disorders, as well as core features of these illnesses, especially in areas of unmet medical need.

Background and Research Objectives

Significant advances in neuroscience, genomics, genetics, and related omics, behavioral neuroscience, together with technological developments (structural biology, in silico and high throughput screening (HTS), in vivo imaging methods), have provided a rich knowledge base for understanding pathophysiology, identifying new molecular targets for drug discovery, new circuit/oscillatory targets for device development, and developing rational pharmacotherapies and neuromodulation interventions for the treatment of psychiatric disorders. With the wealth of potential new drug/device targets, the opportunity exists to accelerate the process of target validation and medication discovery to make great strides toward novel and effective treatments for mental disorders.

An application submitted to this NOFO can include two to three scientific projects along with Scientific and/or Administrative Cores. Applications proposing only a single research project and no cores should respond to the companion NOFO utilizing the U01 mechanism (see  PAR-25-352).

Points to consider relevant to this announcement:

• The development of analogs of established or well-studied agents for the treatment of mental disorders is not appropriate for this NOFO.

NIMH's Objectives and Interests for the NCDDG Program

NIMH’s objective for the NCDDG program is to support innovative, high-impact research focused on the discovery of pharmacological agents selective for novel molecular targets and new neuromodulation devices targeting novel neural circuit and neural oscillatory targets with the potential to prevent or reverse pathophysiological processes underlying mood and anxiety disorders, schizophrenia, eating disorders, obsessive-compulsive disorder, fragile x, autism, and other mental illnesses. Public-private partnerships are particularly encouraged.

NIMH-relevant NCDDG research projects should focus on novel interventions, using either pharmacological agents or neuromodulation devices that interrogate a molecular, circuit, or clinical target that is linked to a biological mechanism or pathophysiology of the proposed mental disorder.

The NIMH strongly encourages an experimental medicine approach to therapeutic development. This NOFO will support up through First-in-Human (FIH) for devices or Phase Ia or Ib trials for pharmacological agents. For these trials, studies are expected to assess the agent/device for 1) safety and tolerability, 2) target engagement, and 3) pharmacodynamic effects on relevant circuits or systems. Data resulting from Phase I trials in healthy controls and in the target patient population are expected to determine optimal clinical dosing and to establish feasibility for further testing in PoC and efficacy trials. Agents/devices should 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 needs in psychiatric disorders. In support of this effort, NIMH recognizes the need for the timely development of new positron emission tomography (PET) radiotracers for targets that are of interest for assessing target engagement/dose selection for clinical trials of novel therapeutics and for studies of the pathophysiology of psychiatric disorders.

Consistent with NIMH’s Research Domain Criteria (RDoC) initiative, research projects directed towards ameliorating pathophysiology that is potentially more proximal to specific functional deficits (domains) than DSM diagnostic entities are encouraged. Additional information about the RDoC approach can be found on the RDoC website. The testing of functional domains not included specifically in RDoC may also be considered, if well justified.

NIMH encourages applications ranging from ligand discovery and testing in preclinical assays through human Phase I studies of novel agents. Examples include, but are not limited to:

• A multidisciplinary approach that integrates machine learning (ML) tools, including human-in-the-loop ML (an ML model that requires researcher interaction),  into drug discovery processes at any of its stages, from hit/lead identification to lead optimization.
  • Use of generative ML models in de-novo design of drug chemical structures with desired properties
  • Ligand-based virtual screening and computational hit expansion following high-throughput screening (HTS) campaigns.
  • Use of ML in the design of new molecules employing phenotypic and high content screening data and assessing their potency, selectivity, and binding affinity
  • Use of ML models for predicting bioactivity and ADMET parameters of compounds
• Ligand discovery for therapeutics development or as clinical research tools (e.g., imaging probes) for novel molecular targets implicated in mental illnesses.
• Biotechnology Products and Biologics including, but not limited to, large biologic macromolecules, (e.g., proteins, antibodies, and peptides), gene-based therapies (i.e., oligonucleotide- and viral-based), cell therapies, and novel emerging therapies (e.g., microbial and microbiome therapies).
• Development and application of novel assays for evaluating brain pharmacodynamic (PD)/pharmacokinetic (PK) relationships in preclinical and early phase human studies.
• Initial Good Laboratory Practice (GLP) toxicology, safety pharmacology, and pharmacokinetics to support an Investigational New Drug (IND) application to the Food and Drug Administration (FDA) to begin human clinical testing.
• Phase I studies (FIH pharmacology experiments) that include pharmacokinetic/ pharmacokinetic (PD/PK) biomarkers to assess target engagement, functional pharmacological activity or physiological effect, safety, and tolerability of new drugs.
• Novel tool and biomarker development to enable studies to assess target engagement, brain PD and PK for innovative drug targets; for example, PET tracers for evaluating receptor occupancy and interrogating dose-response relationships.
• Phase Ib studies in the proposed disease population to confirm target engagement, establish optimal dosing, PK/PD, CNS exposure, functional pharmacological or neurophysiological activity, and tolerability of the novel compound, agent, or device.
• The inclusion of PD measures to assess functional pharmacological activity of the agent is encouraged in dose-finding studies.
• The Phase IIa PoC study should provide sufficient objective data on CNS pharmacological activity and associations with functional measures for projects to be "de-risked" to attract public or private funding for further clinical and commercial development.

NIMH also encourages applications ranging from early-stage, pre-clinical, device development to FIH clinical trials. Examples include, but are not limited to:

• Regulatory activities, including pre-submission meetings with FDA, Investigational Device Exemption (IDE) submission, risk determinations, or other FDA regulatory submissions.
• Device, software, and firmware design verification and validation activities.
• Non-GLP animal studies to develop techniques relevant to the device, optimize relevant therapeutic parameters, and refine device design as necessary for subsequent GLP testing or additional clinical studies for regulatory approval.
• Bench-top and/or animal testing to demonstrate compliance with FDA Recognized Standards.
• GLP compliant large animal model safety and/or testing of an implanted device.
• Activities to become current Good Manufacturing Practice (GMP) compliant.
• Activities to bring the development process under Design and Quality Systems Control.
• Development of packaging, connectors, and other accessories necessary for the translation of this technology.
• FIH, PoC studies that may assess initial measures of safety and efficacy and lead to further refinement of the device.
• Linkage of behavior with brain recordings via high-density recordings of both.
• Modeling technologies capable of precisely characterizing delivered dose of neuromodulation technologies (e.g., electric field modeling) and accurately measuring the impact of the delivered dosage on neural functioning (e.g., simultaneous TMS-EEG, TMS-fMRI or other technologies to demonstrate engagement of the targeted distributed network or neural oscillatory target).

For PoC studies, priority will be given to novel agents that are IND-ready or IDE-ready with pre-clinical profiles suggesting the possibility of therapeutic effect in mental disorders. Testing of novel indications for already approved agents/devices will be considered, based on feasibility, strong theoretical rationale, and unmet clinical or medical need.

Summary

In summary, the NCDDG Program will support broad, innovative, multidisciplinary approaches to the discovery of new, rationally based treatments and research tools for mental disorders. Since the creative talents in the required scientific disciplines are rarely available in a single institution, a multi-institutional, group approach involving academic, nonprofit, commercial, and/or industrial institutions is envisioned. Academic, pharmaceutical, and biomedical technology scientists are strongly encouraged to form partnerships that take full advantage of their combined intellectual and material resources for drug discovery, lead optimization, model development, and clinical testing. Further, the interaction of academic and non-profit research institutions with the pharmaceutical and biomedical device industry and NIH is expected to facilitate subsequent development and marketing of new pharmacologic and device treatments, although these latter activities are not within the scope of this NOFO. Molecular targets for drug/device discovery, and the sources and types of chemical/circuit entities to be investigated will be selected by the applying group. Both novel mechanisms of action and disease-oriented approaches are of interest.

Research Scope

The objective of this NOFO is to establish NCDDG Groups to conduct innovative, high impact research focused on the discovery and testing of chemical entities for novel molecular targets, as well as novel devices for novel circuit/neural dynamic targets implicated in the pathophysiology of mental disorders. The NCDDG serves as a vehicle for pharmaceutical, biomedical device and academic scientists to pool intellectual and material resources for the translation of basic science findings into the conceptualization, discovery, and evaluation of new chemical entities and devices. Groups are encouraged to select molecular targets for drug discovery and circuit targets for device discovery based on recent findings in basic and clinical neuroscience, genetics, and proteomics relevant to the understanding of mental disorders.

The identification of lead compounds/candidate agents/devices and refining them for target validation and medication development are important goals of this initiative.

Applicants seeking additional sources of support for preclinical development activities such as toxicology and safety pharmacology assessment, bulk synthesis, GMP synthesis, and formulation development should consider the NIH Blueprint Neurotherapeutics Network program and/or the NIH Bridging Interventional Development Gaps (BrIDGs) Program.

Prior to submission of an application, applicants are strongly encouraged to contact the relevant Scientific/Research Contact listed in Section VII of this NOFO to determine if the proposed Research Project would be considered a priority for NIMH.

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

The NIMH has published updated policies and guidance for investigators regarding human research protection and clinical research data and safety monitoring (NOT-MH-19-027). 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.

Applications Not Responsive to this NOFO.

The following types of studies are not responsive to this NOFO. Applications proposing such studies will be considered non-responsive and will not be reviewed or considered for funding.

• Applications proposing Clinical Trials that lack a Clinical and Data Monitoring Plan
• Applications that lack a Milestone Plan
• Applications proposing Clinical Trials that lack the 'Common Data Elements Applicability' attachment

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.

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

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

Section II. Award Information

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 Organization) 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 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 registration; 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 his/her 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 and Notice of NIH's Interest in Diversity, NOT-OD-20-031.

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.

An NIH intramural scientist may not serve as the PD/PI of an NCDDG but may participate as a research collaborator or consultant (see Section IV.7 for more information).

2. Cost Sharing

This NOFO does not require cost sharing as defined in the NIH Grants Policy Statement Section 1.2- Definitions 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 or an institutional system-to-system solution. A button to apply using ASSIST is available in Part 1 of this NOFO. See the administrative office for instructions if planning to use an institutional system-to-system solution.

2. Content and Form of Application Submission

It is critical that applicants follow the Multi-Project (M) Instructions in the How to Apply - Application Guide, except where instructed in this notice of funding opportunity to do otherwise and where instructions in the How to Apply - Application Guide are directly related to the Grants.gov downloadable forms currently used with most NIH opportunities. 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 protected]

Page Limitations

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

Instructions for the Submission of Multi-Component Applications

The following section supplements the instructions found in How to Apply- Application Guide and should be used for preparing a multi-component application.

Revision applications must include an Overall component and the components affected by the revision.

Therefore, the component requirements listed above may not apply to the revision application.

Overall Component

When preparing the application, use Component Type ‘Overall’.

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

SF424(R&R) Cover (Overall)

Complete entire form.

PHS 398 Cover Page Supplement (Overall)

Note: Human Embryonic Stem Cell lines from other components should be repeated in cell line table in Overall component.

Research & Related Other Project Information (Overall)

Follow standard instructions.

Project/Performance Site Locations (Overall)

Enter primary site only.

A summary of Project/Performance Sites in the Overall section of the assembled application image in eRA Commons compiled from data collected in the other components will be generated upon submission.

Research and Related Senior/Key Person Profile (Overall)

Include only the Project Director/Principal Investigator (PD/PI) and any multi-PDs/PIs (if applicable to this NOFO) for the entire application.

It is anticipated that the NCDDG will include multi-disciplinary teams of scientists with appropriate expertise for the NCDDG project. Scientists from both academia and biotechnology or pharmaceutical industry are encouraged to participate in the project and may serve as the PD/PI or one of multiple PD/PI.

Applications should clearly describe the PD/PI leadership and track record in successfully leading the development, implementation, and management of comprehensive research programs.

Describe the scientific disciplines represented in the Research Projects and Scientific Cores to achieve the NCDDG Program objectives.

Where private sector collaborators and/or consultants are identified, provide evidence that they will contribute expertise to advance the project. If biotechnology or pharmaceutical partners are used, identify the key personnel who have authority within the company to allocate resources to ensure the successful completion of the proposed discovery and development efforts

A summary of Senior/Key Persons followed by their Biographical Sketches in the Overall section of the assembled application image in eRA Commons will be generated upon submission.

Budget (Overall)

The only budget information included in the Overall component is the Estimated Project Funding section of the SF424 (R&R) Cover.

A budget summary in the Overall section of the assembled application image in eRA Commons compiled from detailed budget data collected in the other components will be generated upon submission.

PHS 398 Research Plan (Overall)

Introduction to Application: For Resubmission and Revision applications, an Introduction to Application is required in the Overall component.

Specific Aims: Provide a concise description of overall NCDDG aims. Outline how the Projects and Core(s) will contribute to attaining objectives.

Research Strategy: The following information must be included:

• Describe plans to accommodate the stated NCDDG requirements, criteria, and NIMH involvement.
• Provide an overview of the proposed NCDDG Group, its central theme and goals; this overview should describe the general objectives, and explain the proposed contribution of each of the individual Research Project(s) and Scientific and Administrative Cores (if any) towards achieving the objectives of the Group.
• Provide a clear description of how each Research Project is required for the attainment of the NCDDG Program's objectives, including available professional and technical personnel to permit efficient and successful conduct of the proposed research and a description of the contribution of each to fulfillment of group objectives.
• Describe plans for ensuring effective intra-group communication, interaction, cohesiveness, and coordination among the PD/PI, Research Project Leaders, and NIH Project Scientists. Investigators must address their willingness to collaborate extensively within the NCDDG group and to fully share information.
• Where pharmaceutical or device partnerships are proposed, describe how these partnerships will facilitate the development and evaluation of candidate drugs or therapeutics, tools for clinical research, and model validation for testing therapeutics.
• Detail the staffing, governance, and organizational structure showing that it is appropriate for conducting the study as proposed and within specified timelines.
• Provide evidence that the strategy is likely to succeed and will produce and significantly advance a new candidate therapeutic for development.

Milestones and Timeline: Identify measurable milestones and a timeline of the research activities for the Research Project over the life of the project. Milestones should be well described, quantifiable, and scientifically justified. The milestones should be regarded as criteria for evaluating the progress and direction of the Research Project and should not be just a restatement of the specific aims.

• Where a Phase I study is included, describe the track record of the clinical research team in successfully recruiting subjects into clinical trials and research studies and completing proposed studies within the projected timelines. Cite prior relevant trials or systematic reviews that justify why this trial is needed and inform its design.
• Detail the current status of lead compounds and key lead optimization goals for a development program. (e.g., Lead Compound Report Card) as well as go-no-go criteria in a testing funnel for advancing compounds across stages (Sample Drug Development Testing Funnel).
• Include plans to report high-quality and reproducible studies to the scientific community in a transparent manner. Attention to principles of study design and transparency are essential to enable reviewers, the scientific community, and NIH to assess the quality of scientific findings.
• Provide milestones that are appropriate, evaluative, and clearly defined for the aims associated. These milestones should be feasible and quantifiable about specific aims and timelines.
• The proposed go/no-go milestone studies must be appropriately powered, and the statistical analyses adequately described.
• Provide clear go/no go decision-making points.
• Describe the potential challenges and corresponding solutions (e.g., strategies that can be implemented in the event of enrollment shortfalls).
• The timelines should be appropriate for the Research Projects and overall NCDDG program.
• If clinical studies are proposed, the recruitment goals must be appropriate.

Letters of Support:

Include letters of commitment to the collaboration and communication plan (described in the Research Strategy) by all Research Project Leaders.

Include letters of commitment to the collaboration by private sector partners or collaborators. If the application involves collaboration with an NIH intramural scientist, the intramural scientist must obtain written approval of his/her NIH Institute Scientific Director for the amount of resources that are allocated to the project; this amount must be specified in the letter. 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.

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.

The applicant must address a plan and timeline for sharing research tools generated by the NCDDG. 

Other Plan(s): 

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 (DMS Plan). All applications, regardless of the direct costs requested for any one year, must address a DMS Plan.
• In addition to the NIMH requirement to share data via the National Institute of Mental Health Data Archive, data from the NCDDG program must be made available to the research community through publications, or public website, consistent with achieving the goals of the Program.
• Positive or negative data from NIH supported clinical trials must be submitted to the appropriate NIMH Data Archive database as detailed in NOT-MH-23-100.
• As part of the DMS Plan, the applicant must address a plan and timeline for sharing chemical synthesis, preclinical and clinical trials data generated by the NCDDG.
• Key Elements that should be considered when developing such DMS Plan are detailed at: Home Page | Data Sharing
• Applicants are expected to include the following key elements:
  • Description of how protocols and data will be shared as well as schedule/timeline for sharing data. At a minimum, plans are expected to include annual submission of raw and summary data.
  • Description of project management of protocol and data sharing.

To advance the goal of advancing research through widespread data sharing among researchers, investigators funded by NIMH under this NOFO are expected to share those data via the National Institute of Mental Health Data Archive (NDA; see NOT-MH-23-100). Established by the NIH, 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. NDA links data across research projects through its Global Unique Identifier (GUID) and Data Dictionary technology. Investigators funded under this NOFO are expected to use these technologies to submit data to NDA.

To accomplish this objective, it will be important to formulate a) an enrollment strategy that will obtain the information necessary to generate a GUID for each participant, and b) a budget strategy that will cover the costs of data submission. The NDA website provides two tools to help investigators develop appropriate strategies: 1) the NDA Data Submission Cost Model which offers a customizable Excel worksheet that includes tasks and hours for the Program Director/Principal Investigator and Data Manager to budget for data sharing; and 2) plain language text to be considered in your informed consent available from the NDA's Data Contribution page. Investigators are expected to certify the quality of all data generated by grants funded under this NOFO prior to submission to NDA and review their data for accuracy after submission. Submission of descriptive/raw data is expected semi-annually (every January 15 and July 15); submission of all other data is expected at the time of publication, or prior to the end of the grant, whichever occurs first (see NDA Sharing Regimen for more information); Investigators are expected to share results, positive and negative, specific to the cohorts and outcome measures studied.For more guidance on submitting data to NDA, refer to the NDA Data Management and Sharing Plan on the NDA website. NDA staff will work with investigators to help them submit data types not yet defined in the NDA Data Dictionary. 

Appendix:

Only limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in How to Apply- Application Guide; any instructions provided here are in addition to the How to Apply - Application Guide instructions.

PHS Human Subjects and Clinical Trials Information (Overall)

When involving human subjects research, clinical research, and/or NIH-defined clinical trials 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, there must be at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record within the application. The study record(s) must be included in the component(s) where the work is being done, unless the same study spans multiple components. To avoid the creation of duplicate study records, a single study record with sufficient information for all involved components must be included in the Overall component when the same study spans multiple components.

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 (Overall)

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

Administrative Core

SF424 (R&R) Cover (Administrative Core)

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant’s Project
• Proposed Project Start/Ending Dates

PHS 398 Cover Page Supplement (Administrative Core).

Enter Human Embryonic Stem Cells in each relevant component

Research & Related Other Project Information (Administrative Core) 

Human Subjects: Answer only the Are Human Subjects Involved? and 'Is the Project Exempt from Federal regulations? questions.

Vertebrate Animals: Answer only the Are Vertebrate Animals Used? question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

Project /Performance Site Location(s) (Administrative Core)

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries

Research & Related Senior/Key Person Profile (Administrative Core)

• In the Project Director/Principal Investigator section of the form, use Project Role of ‘Other’ with Category of ‘Project Lead’ and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.
• It is anticipated that the NCDDG will include multi-disciplinary teams of scientists with appropriate expertise for the NCDDG project. Scientists from both academia and biotechnology or pharmaceutical industry are encouraged to participate in the project.
• Biotechnology or pharmaceutical partners should include key personnel who have authority within the company to allocate resources to ensure the successful completion of the proposed discovery and development efforts.
• The inclusion of a Project Manager in the Administrative Core appropriate to the complexity of the group is strongly encouraged.

Budget (Administrative Core)

Budget forms appropriate for the specific component will be included in the application package.

This program strongly encourages in-kind resource contributions of the partners within the NCDDG (e.g., biotechnology, pharmaceutical, or disease foundations).

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply

PHS 398 Research Plan (Administrative Core)

Introduction to Application: For Resubmission and Revision applications, an Introduction to Application is allowed for each component.

The most commonly referenced Research Plan attachments are listed below for your convenience. NOFO specific instructions are required for the Specific Aims and the Research Strategy in each component. NOFO-specific instructions are optional for Letters of Support. Delete Letters of Support if there are no NOFO-specific instructions.

Specific Aims: Provide a concise description of the Administrative Core aims.

Research Strategy: Describe how the Administrative Core will contribute to the goals of the overall NCDDG as well as any novel features of the Administrative Core that enhance the collaborative effort, including optimizing communication, decision-making, and sharing between the Project and/or Scientific Core teams. Describe how each Project or Scientific Core (as applicable) will draw upon the Administrative Core and how it in turn will respond to Project or Scientific Core needs. The description of the Core should clearly indicate the facilities, resources, services, and professional skills that the Core will provide. Moreover, information must be provided about how the collective operation of the Core will be effected in a coherent manner. Include plans for scheduling group meetings, notifying group members (including NIMH or NIAAA), and documenting and disseminating group meeting proceedings.

Applicants should summarize proposed plans for further development of promising compounds or clinical candidates that are generated and/or tested by the NCDDG program.

A plan should be described for decision-making regarding the identification and evaluation of promising drug candidates for development.

A plan to assure the maintenance of close collaboration and effective communication among members of the group.

Provide evidence of institutional support and competence of the applying Institution to serve as the Administrative Core for the Group.

Letters of Support: Provide any letters of support that are specific to the Administrative Core. Include letters of commitment to the collaboration by private sector partners or collaborators. 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.

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:

Note: Do not submit the Resource Sharing and Data Management and Sharing Plans (DMS Plan) here. The Resource Sharing and DMS Plan should be submitted only in the Overall component.

Appendix:

Only limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions

PHS Human Subjects and Clinical Trials Information (Administrative Core)

When involving human subjects research, clinical research, and/or NIH-defined clinical trials 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 a 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

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 SF424 (R&R) Application Guide must be followed.

Scientific Core

When preparing your application in ASSIST, use Component Type Scientific Core.

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

SF424 (R&R) Cover (Scientific Core)

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant’s Project
• Proposed Project Start/Ending Dates

PHS 398 Cover Page Supplement (Scientific Core)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Scientific Core)

Human Subjects: Answer only the Are Human Subjects Involved? and 'Is the Project Exempt from Federal regulations? questions.

Vertebrate Animals: Answer only the Are Vertebrate Animals Used? question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

Project /Performance Site Location(s) (Scientific Core)

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachments for additional entries.

Research & Related Senior/Key Person Profile (Scientific Core)

• In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Core Lead and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• It is anticipated that the NCDDG will include multi-disciplinary teams of scientists with appropriate expertise for the NCDDG project. Scientists from both academia and biotechnology or pharmaceutical industry are encouraged to participate in the project.
• Biotechnology or pharmaceutical partners should include key personnel who have authority within the company to allocate resources to ensure successful completion of the proposed discovery and development efforts.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.

Budget (Scientific Core)

Budget forms appropriate for the specific component will be included in the application package.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

PHS 398 Research Plan (Scientific Core)

Introduction to Application: For Resubmission and Revision applications, an Introduction to Application is allowed for each component.

Specific Aims: Provide a concise description of Core aims.

Research Strategy: Describe how the Core will contribute to the goals of the overall NCDDG as well as how each individual Research Project will draw upon the Core. The description of the Core should clearly indicate the facilities, resources, services and professional skills that the facility will provide. Moreover, information must be provided about how the collective operation of the Cores will be effected in a coherent manner. Identify measurable milestones and a time line of the research activities for the core over the life of the project.

Describe that the Core can provide essential facilities or services to two or more Research Projects and that the Core quality of the facilities or services can provide strong support to the Projects. The qualifications and experience of the personnel involved in the Core should be sufficiently strong to successfully conduct the work of the Core.

Letters of Support: Provide any letters of support that are specific to the Scientific Core. Include letters of commitment to the collaboration by private sector partners or collaborators. If the application involves collaboration with an NIH intramural scientist, 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; this amount must be specified in the letter. 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.

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, and NIMH Data Sharing Policy Notice NOT-MH-23-100, with the following modifications:

Note: Do not submit the Resource Sharing and Data Management andSharing Plans (DMS Plans) here. The Resource Sharing and DMS Plans should be submitted only in the Overall component.

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

PHS Human Subjects and Clinical Trials Information (Scientific Core)

When involving human subjects research, clinical research, and/or NIH-defined clinical trials 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 a 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.

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 SF424 (R&R) Application Guide must be followed

Research Project

When preparing your application in ASSIST, use Component Type ‘Project.’

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

SF424 (R&R) Cover (Research Project)

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant’s Project
• Proposed Project Start/Ending Dates

PHS 398 Cover Page Supplement (Research Project)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Research Project)

Human Subjects: Answer only the ‘Are Human Subjects Involved?’ and 'Is the Project Exempt from Federal regulations?’ questions.

Vertebrate Animals: Answer only the ‘Are Vertebrate Animals Used?’ question.

Project Narrative:  Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

Project /Performance Site Location(s) (Research Project)

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachments for additional entries.

Research & Related Senior/Key Person Profile (Research Project)

• In the Project Director/Principal Investigator section of the form, use Project Role of ‘Other’ with Category of ‘Project Lead’ and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.
• Biotechnology or pharmaceutical partners should include key personnel who have authority within the company to allocate resources to ensure the successful completion of the proposed discovery and development efforts.
• Where private sector collaborators and/or consultants are identified, provide evidence that they will contribute expertise to advance the project. 
• Where the proposed research plan includes a chemical series that was developed by a biotechnology or pharmaceutical industry, provide evidence of the involvement of industry chemists as collaborators or advisors in the project.

Budget (Research Project)

The Core Lead will be expected to devote at least 1.8 person-months of effort per year to the project. In an MPI application, each Core Lead will be expected to devote 1.8 calendar months of effort per year to the project.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

PHS 398 Research Plan (Research Project)

Introduction to Application: For Resubmission applications, an Introduction to Application is allowed for each component.

Specific Aims: Provide a concise description of each Project aim.     

Research Strategy:  The following information should be included in the Research Strategy:

• Describe how the proposed plan for discovery and testing of novel treatments, research tools, or clinical studies address unmet needs for the targeted disease. The biological targets, mechanisms, or measures considered should be novel.
• Describe contributions of the collaborating partners within the NCDDG (preclinical or clinical)

Where preclinical testing is proposed, the designs should be sufficiently detailed and rationalized, and such studies should be relevant to the clinical development path. Clearly show that the scientific disciplines represented in Research Projects are adequate to achieve the NCDDG Program objectives. Provide a sound scientific rationale for the proposed molecular or clinical targets. The proposed targets, screens, and preclinical models should be relevant to therapeutic discovery for mental disorders.

• Phase 1 clinical studies for mental disorders should be designed to assess target engagement, optimal dosing, safety, and tolerability. Phase 1b/IIa clinical studies for mental disorders should be designed to establish the relationship between the magnitude and duration of target modulation and the potential for clinical efficacy in the proposed study population.
• Proposed PD biomarkers should assess the functional pharmacological activity of the novel agent. Proposed pharmacogenetic or other biomarkers should be appropriate to the patient selection strategies for the proposed clinical studies of mental disorders.
• The proposed device capabilities and neural targets should be appropriate for the proposed clinical studies of mental disorders.
• Where a PET ligand development is included, the target should be novel. Provide a clear developmental strategy, a clear description of the desired properties of the radiotracer, and evidence of feasibility that the target can be detected in the brain region(s) of interest with a radiotracer.
• Where a device stimulation or biomarker development is included, the target circuit or neural dynamic signal should be novel. Provide evidence that the strategy is likely to succeed and evidence of feasibility that the target can be detected in the brain circuits of interest in the proposed physiological signal.
• Where a Phase I study is included, describe the track record of the clinical research team in successfully recruiting subjects into clinical trials and research studies and completing proposed studies within the projected timelines. Cite prior relevant trials or systematic reviews that would help to justify why this trial is needed and inform its design.
• Provide a clear description of the procedures for clinical data monitoring and quality control of data adequate and that standardized systems and controls in place for data monitoring to ensure data integrity and to assess the effect of the intervention.
• Define appropriate and evaluative milestones for the associated aims. The milestones should be feasible and quantifiable about specific aims and timeline. Potential challenges and corresponding solutions should be discussed (e.g., strategies that can be implemented in the event of enrollment shortfalls). Timelines should be appropriate for the Research Projects and overall NCDDG program. Applicants should propose definitive go/no-go milestones for the studies. Studies should be appropriately powered, and the statistical analyses should be clearly described. Appropriate, evaluative go/no go decision-making points and quantitative milestones should be clearly defined. The recruitment goals should be appropriate for the proposed clinical studies.

Where a clinical trial is proposed. Without duplicating information in the PHS Human Subjects and Clinical Trials Information Form, please provide the following:

• Clearly describe the administrative, data coordinating, enrollment, and laboratory/testing centers
• Clearly address the capability and ability to conduct the trial at the proposed site(s) or centers and the plans to add or drop enrollment centers, as needed.
• If international site(s) is/are proposed, address the complexity of executing the clinical trial.
• If multisites/centers are proposed, clearly describe 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.
• The study design should be justified and appropriate to address primary and secondary outcome variable(s)/endpoints; these endpoints should be clear, informative, and relevant to the clinical and statistical hypothesis being tested. Justify the proposed study populations (size, sex, gender, age, demographic group), proposed intervention arms/dose, and duration of the trial. Provide a plan to complete data analysis within the proposed period of the award.
• Ethical issues for the proposed research should be adequately addressed. Provide a plan to monitor accrual. Address the need for randomization (or not), masking (if appropriate), controls, and inclusion/exclusion criteria.

Letters of Support: Provide any letters of support that are specific to the Research Project. Include letters of commitment to the collaboration and contribution specifics by private sector partners or collaborators. If the application involves collaboration with an NIH intramural scientist, 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; this amount must be specified in the letter. 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.

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:

Note: Do not submit the Resource Sharing and Data Management and Sharing Plans (DMS Plans) here. The Resource Sharing and DMS Plans should be submitted only in the Overall component.

Appendix:

Only limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.

PHS Human Subjects and Clinical Trials Information (Research Project)

When involving human subjects research, clinical research, and/or NIH-defined clinical trials 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 a 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 5 - Other Clinical Trial-related Attachments

5.1 Other Clinical Trial-Related Attachments

1. The Clinical and Data Monitoring Plan is a required attachment.

The filename "Clinical and Data Monitoring Plan.pdf" must be used for this attachment. The file name should be appended with 1, 2, 3, etc., as needed.

For each clinical trial proposed, create a document entitled "Clinical and Data Monitoring Plan".

Each Plan includes 2 parts: The Clinical Monitoring Plan for the quality assurance of the proposed clinical trial through clinical monitoring activities, and the Data Monitoring Plan for the quality controls proposed through data monitoring activities.

The NIH requirements for monitoring clinical trials as described below are in addition to the application's Data and Safety Monitoring Plan (DSMP) which describes how patient safety in the trial will be monitored, and the regulatory requirement in 45 CFR 46 for ongoing review and approval of all non-exempt human subjects research by the IRB of record.

Part A: The purpose of the Clinical Monitoring Plan is to verify that the clinical trial is being conducted, and documented by the Protocol, Standard Operating Procedures (SOPs), Good Clinical Practice (GCP), and the applicable regulatory requirement(s).

Describe the persons/entity responsible for conducting the monitoring (e.g., contracted Clinical Research Associate, Data Coordinating Center, Independent study monitor from the Clinical Coordinating Center).

Describe the frequency of planned monitoring activities (e.g., Study Initiation, Interim Visits, Study Close Out), locations where the monitoring will occur (e.g., participating clinical sites, data center, clinical coordinating center), and what data will be reviewed.

• Provide an overall description of the monitoring plan to ensure adherence to the protocol, adequate documentation of the consenting process, and the quality and consistency of the study intervention(s), including fidelity monitoring for behavioral interventions. Include methods to monitor study intervention and a system to record and manage exceptions and deviations. If applicable, describe monitoring of participating facilities such as labs or pharmacies for adequate handling and storage of investigational product(s) and study specimens. Include a description to assure that the investigational product(s) accountability and reconciliation are performed adequately during and at the end of the trial per applicable regulatory requirements.
• Describe plans for handling any deficiencies that are uncovered and in cases of serious deficiencies the appropriate reporting to relevant authorities, including but not limited to the IRB of record, DSMB if one is assigned, FDA if applicable, institutional officials and the NIH.

Part B: The purpose of the Data Monitoring Plan is to ensure that validated systems and controls are in place to ensure the integrity of the clinical research data being collected for the proposed study:

• Describe methods and systems for data collection (e.g., Case Report Forms/CRFs), data entry, data verification, and data validation. Describe the data query process and frequencies and any planned mitigation strategies in the event of non-compliance.
• Describe methods and systems to ensure data confidentiality and subject privacy.
• Describe the process for locking the final trial datasets and the planned procedures on data access and sharing, as appropriate.

Applications proposing Clinical Trials that lack the Clinical and Data Monitoring Plan are considered incomplete and will not be peer-reviewed.

2. The Milestone Plan is a required attachment.

The filename "Milestone Plan.pdf" must be used for this attachment. The filename should be appended with 1, 2, 3, etc., as needed.

Applicants are required to provide detailed project performance and timeline objectives. This section must include an overview of the project timeline for the following general milestones, as applicable:

• Finalization of clinical protocol (with program agreement, if applicable)
• Registration of clinical trial in ClinicalTrials.gov
• Completion of regulatory approvals
• Enrollment of the first subject
• Enrollment and randomization, if applicable of 25%, 50%, 75% and 100% of the projected study population, including women, minorities, and children (as appropriate)
• Completion of data collection time period
• Completion of primary endpoint and secondary endpoint data analyses
• Completion of the final study report
• Reporting of results in ClinicalTrials.gov.

These milestones may be negotiated at the time of the award, as necessary.

Applications that lack the Milestone Plan are considered incomplete and will not be peer-reviewed.

3. Common Data Elements Applicability is a required attachment.

The filename "Common Data Elements Applicability.pdf" must be used for this attachment. The filename should be appended with 1, 2, 3, etc., as needed.

Applicants are required to describe their plans to consider the applicability of Common Data Elements (CDEs).

Investigators are encouraged to describe if NIH-supported CDEs will be used in the proposed clinical trial. If CDEs are not applicable, applicants are expected to explain why.

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. The 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 has released expectations for collecting common data elements when an application involves human research participants. Details can be found at NOT-MH-20-067 and the NIMH webpage on Data Sharing for Applicants and Awardees.

Applications proposing Clinical Trials that lack the 'Common Data Elements Applicability' attachment are considered incomplete and will not be peer-reviewed.

4. Clinical Protocol Schedule of Events

• The filename "Clinical Protocol Schedule of Events.pdf" must be used for this attachment. The file name should be appended with 1, 2, 3, etc., as needed.
• The clinical protocol schedule of events is to capture a snapshot of the time it takes for protocol procedures to be completed by an individual participant during the trial.

For example:

• Week 1 Screening/Baseline Visit (4 hours)- eligibility criteria, obtain informed consent, screening assessment(s), labs, etc.
• Week 2, 4, 6, 8, Study Visits (3 hours) –intervention(s), assessment(s), labs, scan(s), etc.
• Week 12, and 18 Follow-up Visits (3 hours)- assessment(s), labs, scan(s), etc.
• Week 24 End of study visit (2 hours)- assessment(s), labs, scan(s), etc.

This document may be provided in a tabular format.

5. Investigator Brochure or Package Insert

• The filename "Investigator Brochure or Package Insert.pdf" must be used for this attachment. The file name should be appended with 1, 2, 3, etc., as needed.
• The Investigator Brochure or package insert may be attached for a clinical trial testing a drug or biologic.

6. Material safety data sheet (MSDS)

• The filename "Material safety data sheet (MSDS).pdf" must be used for this attachment. The filename should be appended with 1, 2, 3, etc., as needed.
• Labeling information or summary of safety information from prior studies may be attached for a clinical trial testing a significant risk investigational device for which an application for a new Investigational Device Exemption (IDE) will be submitted.

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 SF424 (R&R) Application Guide must be followed.

FIH and Phase I studies may be reviewed by the appropriate NIH Institute's 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 from the NCDDG group on a regular basis to monitor subject enrollment and retention, safety, quality of data collection, and integrity of the study. Based on its review, the DSMB has the authority to stop the study after it has started.

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) using ASSIST or other electronic submission systems. 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 How to Apply- Application Guide.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

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.

For information on how applications will be automatically assembled for review and funding consideration after submission, refer to: http://grants.nih.gov/grants/ElectronicReceipt/files/Electronic_Multi-project_Application_Image_Assembly.pdf.

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) and component Project Leads 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.

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 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 components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

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.

Requests of $500,000 or more for direct costs in any year

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.

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.    Intellectual property will be managed in accord with established policy of 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. 

Recipients or subrecipients must submit any information related to violations of federal criminal law involving fraud, bribery, or gratuity violations potentially affecting the federal award. See Mandatory Disclosures, 2 CFR 200.113 and NIH Grants Policy Statement Section 4.1.35.

Send written disclosures to the NIH Chief Grants Management Officer listed on the Notice of Award for the IC that funded the award and to the HHS Office of Inspector Grant Self Disclosure Program at [email protected].

Post Submission Materials

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.

Section V. Application Review Information

1. Criteria

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

In addition, for applications involving clinical trials:

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.

Significance

Does the project address an important problem or a critical barrier to progress in the field? Is the prior research that serves as the key support for the proposed project rigorous? 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?

Specific to this NOFO:  

• To what extent does the proposed plan for discovery and testing of novel treatments, research tools, or clinical studies support the needs for the targeted disease?
• To what extent will the study produce and significantly advance a new candidate therapeutic for development?

In addition, for applications involving clinical trials

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?

Investigator(s)

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?

Specific to this NOFO:

• To what extent have collaborations been established or consultants identified to provide the appropriate depth and breadth of expertise required for the project?
• To what extent are the scientific disciplines represented in Research Projects and Scientific Cores adequate to achieve the NCDDG Program objectives?
• If private sector collaborators and/or consultants are identified, to what extent does the application lend assurance that they will contribute expertise to advance the project?
• To what extent are plans adequate for ensuring effective intra-group communication, interaction, cohesiveness, and coordination among the PD/PI, Research Project Leaders, and NIH Project Scientists?
• To what extent does the application state the investigator's willingness to collaborate extensively within the NCDDG group and share information fully?
• How effective are the contributions of the collaborating partners?

In addition, for applications involving clinical trials

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?

Innovation

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

In addition, for applications involving clinical trials

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?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed 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?

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 or gender, race, and ethnicity, as well as the inclusion or exclusion of individuals of all ages (including children and older adults), justified in terms of the scientific goals and research strategy proposed?

Specific to this NOFO:

• To what extent does the application adequately address whether the staffing, governance, and organizational structure are appropriate for conducting the study as proposed and within specified timelines?
• If preclinical testing is proposed, to what extent are the designs sufficiently detailed and rationalized, and are such studies relevant to the clinical development path?  To what extent does the application adequately address the scientific rationale for the proposed molecular or clinical targets, and the relevance of the proposed targets, screens, and preclinical models to therapeutic discovery for mental disorders?
• How well are the proposed Phase 1 clinical studies for mental disorders designed to evaluate target engagement, optimal dosing, safety, and tolerability? To what extent are the proposed Phase 1b/IIa clinical studies for mental disorders designed to establish the relationship between the magnitude and duration of target modulation and potential for clinical efficacy in the proposed study population? To what extent does the proposed PD biomarkers assess functional pharmacological activity of the novel agent? To what extent is the use of pharmacogenetic or other biomarkers as patient selection strategies appropriate to the proposed clinical studies of mental disorders? To what extent are the proposed device capabilities and neural targets appropriate for the proposed clinical studies of mental disorders?
• If PET ligand development is included, how adequate is the evidence of feasibility that the target can be detected in the brain region(s) of interest with a radiotracer? To what extent are the desired properties for the radiotracer clearly stated and reasonable for the proposed target?
• If device stimulation or biomarker development is included, how adequate is the evidence that the target can be detected in the brain circuits of interest in the proposed physiological signal?
• If pharmaceutical or device partnerships are proposed, to what extent does the proposed study facilitate the development and evaluation of candidate drugs or therapeutics, tools for clinical research, and model validation for testing therapeutics?

In addition, for applications involving clinical trials

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?

Environment

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

In addition, for applications involving clinical trials

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?

Additional Review Criteria - Overall

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.

Specific to this NOFO:

Additional Review Criteria - Administrative Core

• To what extent is the evidence of institutional support and competence of the applying Institution adequate to serve as the Administrative Core for the Group?

Additional Review Criteria - Scientific Cores

• How well do the Scientific Cores provide essential facilities or services to two or more Research Projects judged to have scientific merit? How adequate is the quality of the facilities or services provided by the Cores to support the Research Projects? To what extent are the qualifications and experience of the personnel involved in the Cores sufficiently strong to successfully conduct the work of the Cores?

Additional Review Criteria - Research Projects

• How well does the application cite relevant trials or systematic reviews that would help justify why the trial is needed and inform its design?
• To what extent has the clinical research team demonstrated a track record of successfully recruiting subjects into clinical trials and research studies and completing proposed studies within projected timelines?
• How appropriate, evaluative, and clearly defined are the proposed milestones for the associated aims?
• To what extent are the milestones feasible and quantifiable regarding specific aims and timelines? Are the go/no go decision-making points appropriate?
• To what extent are potential challenges and their corresponding solutions (e.g., strategies that can be implemented in the event of enrollment shortfalls) effectively discussed?
• To what extent are the biological targets, mechanisms, or measures novel?
• How appropriate are the timelines for the Research Projects and the overall NCDDG program?
• How appropriately powered are the go/no-go milestone studies, and are the statistical analyses adequately described?
• Are the proposed clinical studies and the recruitment goals appropriate?
• How well does the proposed research plan include a chemical series developed by a biotechnology or pharmaceutical industry, and is there adequate evidence of industry chemists' involvement as collaborators or advisors in the project?

Clinical Data Monitoring Plan

• How adequate are the procedures for clinical data monitoring and quality control of data for the proposed studies? How adequate are the standardized systems and controls for data monitoring in ensuring data integrity and assessing the effect of the intervention?

Study Timeline

Specific to applications involving clinical trials

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)?

Protections for Human Subjects

For research that involves human subjects but does not involve one of the 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 categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.

Inclusion of Women, Minorities, and Individuals Across the Lifespan

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 or gender, race, and ethnicity, as well as the inclusion (or exclusion) of individuals of all ages (including children and older adults) to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

Vertebrate Animals

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following three points: (1) a complete description of all proposed procedures including the species, strains, ages, sex, and total numbers of animals to be used; (2) justifications that the species is appropriate for the proposed research and why the research goals cannot be accomplished using an alternative non-animal model; and (3) interventions including analgesia, anesthesia, sedation, palliative care, and humane endpoints that will be used to limit any unavoidable discomfort, distress, pain and injury in the conduct of scientifically valuable research. Methods of euthanasia and justification for selected methods, if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals, is also required but is found in a separate section of the application. For additional information on review of the Vertebrate Animals Section, please refer to the Worksheet for Review of the Vertebrate Animals Section.

Biohazards

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

Resubmissions

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

Renewals

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

Revisions

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

Additional Review Considerations - Overall

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

Applications from Foreign Organizations

Not Applicable

Select Agent Research

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

Resource Sharing Plans

Reviewers will comment on whether the Resource Sharing Plan(s) (e.g., Sharing Model Organisms) or the rationale for not sharing the resources, is reasonable.

Authentication of Key Biological and/or Chemical Resources:

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.

Budget and Period of Support

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

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by 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.

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 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.

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 Section 2.5.1. Just-in-Time Procedures. This request is not a Notice of Award nor should it be construed to be an indicator of possible funding.

Prior to making an award, NIH reviews an applicant’s federal award history in SAM.gov to ensure sound business practices. 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 the Responsibility/Qualification records in SAM.gov to ascertain the applicant’s integrity, business ethics, and performance record of managing Federal awards per 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.

3. Anticipated Announcement and Award Dates

After the peer review of the application is completed, the PD/PI will be able to access their 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

A Notice of Award (NoA) is the official authorizing document notifying the applicant that an award has been made and that funds may be requested from the designated HHS payment system or office. The NoA is signed by the Grants Management Officer and emailed to the recipient’s business official.

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.

Recipients must comply with any funding restrictions described in Section IV.6. Funding Restrictions. Any pre-award costs incurred before receipt of the NoA are at the applicant's own risk.  For more information on the Notice of Award, please refer to the NIH Grants Policy Statement Section 5. The Notice of Award and NIH Grants & Funding website, see Award Process.

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).

Prior Approval of Pilot Projects

Recipient-selected projects that involve {clinical trials or studies involving greater than minimal risk to human subjects} require prior approval by NIH prior to initiation.

• The recipient institution will comply with the NIH Guidance on Changes That Involve Human Subjects in Active Awards and That Will Require Prior NIH Approval.
• The recipient institution will provide NIH with specific plans for data and safety monitoring, and will notify the IRB and NIH of serious adverse events and unanticipated problems, consistent with NIH DSMP policies.

2. Administrative and National Policy Requirements

The following Federal wide and HHS-specific policy requirements apply to awards funded through NIH:

• The rules listed at 2 CFR Part 200, Uniform Administrative Requirements, Cost Principles, and Audit Requirements for Federal Awards.
• All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the terms and conditions in the Notice of Award (NoA). The NoA includes the requirements of this NOFO. 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.
• 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.

All federal statutes and regulations relevant to federal financial assistance, including those highlighted in NIH Grants Policy Statement Section 4 Public Policy Requirements, Objectives and Other Appropriation Mandates.

Recipients are responsible for ensuring that their activities comply with all applicable federal regulations.  NIH may terminate awards under certain circumstances.  See 2 CFR Part 200.340 Termination and NIH Grants Policy Statement Section 8.5.2 Remedies for Noncompliance or Enforcement Actions: Suspension, Termination, and Withholding of Support.

Successful recipients under this NOFO agree that:

Where the award funding involves implementing, acquiring, or upgrading health IT for activities by any funded entity, recipients and subrecipient(s) are required to: Use health IT that meets standards and implementation specifications adopted in 45 CFR part 170, Subpart B, if such standards and implementation specifications can support the activity.  Visit https://www.ecfr.gov/current/title-45/subtitle-A/subchapter-D/part-170/subpart-B to learn more.

Where the award funding involves implementing, acquiring, or upgrading health IT for activities by eligible clinicians in ambulatory settings, or hospitals, eligible under Sections 4101, 4102, and 4201 of the HITECH Act, use health IT certified under the ONC Health IT Certification Program if certified technology can support the activity. Visit https://www.healthit.gov/topic/certification-ehrs/certification-health-it to learn more.

Pursuant to the Cybersecurity Act of 2015, Div. N, § 405, Pub. Law 114-113, 6 USC § 1533(d), the HHS Secretary has established a common set of voluntary, consensus-based, and industry-led guidelines, best practices, methodologies, procedures, and processes.

Successful recipients under this NOFO agree that:

When recipients, subrecipients, or third-party entities have:

1. ongoing and consistent access to HHS owned or operated information or operational technology systems; and
2. receive, maintain, transmit, store, access, exchange, process, or utilize personal identifiable information (PII) or personal health information (PHI) obtained from the awarding HHS agency for the purposes of executing the award.

Recipients shall develop plans and procedures, modeled after the NIST Cybersecurity framework, to protect HHS systems and data. Please refer to NIH Post-Award Monitoring and Reporting for additional information. 

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 (HHS) grant administration regulations at 2 CFR Part 200, 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 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 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 recipients of the project, 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 for:

• Define objectives, approaches, and plan and conduct the proposed research and assume responsibility and accountability to the applicant organization and to the NIMH for the performance and proper conduct of all research supported in this initiative, in accordance with the Terms and Conditions of Award.
• Provide interim progress updates when requested by NIMH.
• Provide leadership in thoughts, ideas, and actions, working with the Steering Committee for the cooperative agreement.
• Coordinate and attend at least monthly NCDDG meetings. The PD/PIs will be responsible for preparing concise proceedings or minutes (one to two pages), which will be delivered to all members within one week of the meeting.
• Attend and participate in in-person and/or virtual meetings amongst the PIs awarded under this initiative and the companion NOFO (U01), with the frequency determined by the Steering Committee.
• Accept close interaction with and participation of a NIMH Project Scientist in the NCDDG Steering Committee (SC).
• Communicate and publish major findings in a timely manner. Publication or oral presentation of work done under this agreement will be accompanied by an appropriate acknowledgment of NIMH support, including the assigned cooperative agreement award number.
• Share data and resources generated under this project with the scientific community, as permitted by law, in a timely manner and as directed under the applicable NIMH and NIH policies sharing policies.
• PD(s)/PI(s) agree to participate in the cooperative research program, including serving on the Steering Committee, participating in Steering Committee in person and virtual meetings, adhering to Steering Committee policies and decisions, and accepting the participation and assistance of NIMH staff in accordance with the guidelines described under Cooperative Agreement Terms and Conditions of Award: NIH Responsibilities.
• 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 HHS, PHS, and NIH policies.
• Participate as a voting member of the Steering Committee. In the case of MPI award, the PIs will have one combined vote.

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

The role of the NIMH Project Scientist will be to facilitate and not to direct the activities. It is anticipated that the NIMH Project Scientist will offer advisory input. The NIMH Project Scientist will:

• Provide guidance and support in the design of research activities.
• Serve as a resource for protocol design and development.
• Advise in the selection of sources or drug development resources (e.g., CNS receptor screening, NIH Blueprint Neurotherapeutics chemical synthesis or toxicology services).
• Advise in management and technical performance.
• Participate as a voting member in the Steering Committee (SC). Regardless of the number of Project Scientists, NIH has only one vote.

Additionally, an agency program official or IC program director will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.

The NIMH Program Official will:

• Provide the normal scientific and programmatic stewardship of the award, including programmatic monitoring of the overall project.
• Prior to award, negotiate the final Data Management and Sharing Plan (DMS Plan) and final Resource Sharing Plan and the milestones to ensure that the goals of the project are being met.
• Monitor Milestones and data sharing.
• Approve modifications to the research plan and/or study protocol(s), in consultation with the SC, based on emerging data and/or other issues that impact progress of the project.
• Reserve the right to obtain periodic external peer review and recommend reviewers for an assessment of progress and achievement of milestones and deliverables.
• May attend SC meetings as a non-voting observer

Areas of Joint Responsibility

• Steering Committee: A governing Steering Committee composed of the PD/PI(s), key research scientists, collaborators or consultants, outside experts, the NIH Project Scientist(s), will be established in each NCDDG to assist in monitoring and developing the scientific content and direction of the program. When included in the Steering Committee, outside experts are chosen by the PD/PI(s) in consultation with the NIH Project Scientist and Program Official. Each named member of the Steering Committee will have one vote.  In the case of MPI award, the PIs will have one combined vote.
• Coordination and facilitation of interactions among the recipients under this initiative.
• Facilitation of collaboration with other NIMH-supported research resources.
• Assist in avoiding unwarranted duplication of effort with other NIH efforts.
• Schedule and organize in-person and virtual meetings for dissemination of ideas and encouragement of scientific collaboration. The frequency of these meetings (annual, semi-annual, etc.) will be determined by the Steering Committee, which will be responsible for scheduling the time and place 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 recipient. This special dispute resolution procedure does not alter the recipient'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.

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. 

• 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 Section 8.4.1 Reporting. To learn more about post-award monitoring and reporting, see the NIH Grants & Funding website, see Post-Award Monitoring and Reporting.

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 Section 8.6 Closeout. 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.

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]

Yael Mandelblat-Cerf, Ph.D.
National Institute of Mental Health (NIMH)
Telephone: 301-793-7563
Email: [email protected]

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

Heather Weiss
National Institute of Mental Health (NIMH)
Telephone: 301-443-4415
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.