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

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

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

In the last few years, pharmaceutical companies have shifted their focus away from psychiatric indications, due to the high failure rate of drug approvals, with many of the failures occurring in late stage development after significant funding and testing had occurred. Meanwhile, neuromodulatory device companies have received FDA clearance for novel approaches to treat serious mental illness (e.g., transcranial magnetic stimulation (TMS) for depression and deep brain stimulation (DBS) for obsessive compulsive disorder), and improvements in the safety and durability of electroconvulsive therapy have been studied. However, promising leads for the use of invasive and non-invasive neuromodulatory devices for a broader range of medication-resistant conditions await definitive evaluation. Two large multi-center trials evaluating promising leads for deep brain stimulation in the treatment of depression did not result in a deeper mechanistic understanding of why those trials did not meet expected outcomes, despite encouraging studies leading up to and subsequent to these trials.

Given the high risk of failure for these CNS intervention studies, there is a need to re-design early stage trials to incorporate objective measures that adequately test both the delivered dosage and the proposed mechanism of action of the intervention in humans and determine if the intervention target has been modulated. In response to these emergent issues, NIMH has developed this Funding Opportunity Announcement (FOA) to encourage Phased Innovation (R61/R33) grant applications that support early stage, novel pharmacologic and device-based intervention studies that incorporate an experimental medicine approach to validate molecular/circuit-based targets and evaluate their association with neurophysiological/behavioral/clinical benefit, as measured through improvements in a symptom or a domain of clinical function. In this approach, clinical studies should be designed so that even negative results will provide meaningful information: 1) does the intervention selectively engage/modulate the target in a dose/stimulus- dependent manner (here, 'selectively' means ratio of action between target and non-target is high enough to support a clinically acceptable risk/benefit ratio)?; 2) if yes, are those doses that enable target engagement independent of side effects and potential safety issues?; and 3) if target engagement occurs, is a measurable change in function demonstrated (i.e., is clinical benefit observed as detected through functional domains or clinical measures)? If these results are not obtained, the molecular/circuit-based mechanism has not been validated and should not be pursued further.

This FOA uses a phased innovation approach (R61/R33) to manage the risk associated with these early stage clinical studies, by requiring a demonstration of the intervention's effect on the proposed site of action (intervention's molecular/circuit-based target) before moving into the R33 phase of the award. Specifically, the FOA provides support for up to two years (R61 phase) for milestone-driven testing, refinement, and/or validation of the intervention's engagement with an empirically-supported, measurable molecular/circuit-based target. If milestones are successfully obtained, the grantee can be awarded up to 3 additional years of support (R33 phase) for studies to confirm target engagement in a larger sample and assess the relationship between target engagement and changes in functional outcomes or clinical symptoms/functional domains. Results from the R33 phase should provide enough evidence to determine whether further development of the intervention is warranted. This FOA strongly encourages the testing of interventions not previously approved/marketed for psychiatric disorders, including: 1) interventions in active development; 2) pharmacologic interventions repurposed from approved/marketed non-CNS indications; 3) pharmacologic agents discontinued from development in the indication where they were originally developed (see http://www.ncats.nih.gov/ntu/assets/current for a list of examples provided through the NCATS 2014 Industry-Provided Assets); and 4) expanding uses of stimulation devices.

Studies testing multimodal interventions (e.g., a novel pharmacologic agent/device designed to augment a psychosocial intervention such as exposure therapy) are acceptable under this FOA, as long as the pharmacologic agent or the device being tested is novel.

All drugs/devices to be tested must have passed Phase I safety studies. In addition, responsive pediatric applications must be testing drugs that have already been approved for use in pediatrics in non-psychiatric indications, and are now being repositioned. Applications to conduct Phase Ia First in Human testing of new chemical entities or trials of novel first-in-children pharmacological agents or federal regulated devices designed for brain stimulation in pediatric populations (i.e., first exposure in children or first in pediatric indication) are accepted to PAR-17-327 "First in Human and Early Stage Clinical Trials of Novel Investigational Drugs or Devices for Psychiatric Disorders (U01)". Applications that combine industry and academic effort into the design and management of the trial should also apply to PAR-17-327. Applications focused on clinical trials to establish the effectiveness of interventions where efficacy has already been demonstrated, and to test hypotheses regarding moderators, mediators, and mechanisms of action of these interventions should be directed to RFA-MH-18-701 "Clinical Trials to Test the Effectiveness of Treatment, Preventive, and Services Interventions (R01)", RFA-MH-18-700 "Clinical Trials to Test the Effectiveness of Treatment, Preventive, and Services Interventions (Collaborative R01)" or RFA-MH-18-706 "Pilot Effectiveness Trails for Treatment, Preventive and Services Interventions (R34)", or any subsequent re-issuances of these FOAs. Applicants focused on device-based interventions including but not limited to behavioral, cognitive, interpersonal, and device-based (both invasive/surgically implanted as well as noninvasive/transcranial) approaches, or a combination thereof are encouraged to apply to "Confirmatory Efficacy Clinical Trials of Non-Pharmacological Interventions for Mental Disorders (R01)" (RFA-MH-18-707).

Applicants are also strongly encouraged to review the information on the NIMH website focused on clinical trials trials and Frequently Asked Questions section: http://www.nimh.nih.gov/funding/clinical-trials-for-researchers/index.shtml.

NIMH is specifically interested in novel molecular targets (for drugs) and circuit-based targets (for brain stimulation devices) and how they relate to functional domains or symptom(s) of mental disorders as opposed to broad diagnostic categories in which not all subjects may share the same underlying disease process. For example, NIMH Research Domain Criteria (RDoC) constructs may be helpful in considering subject stratification, in clinical targets, or as intermediate outcome measures. It's important to note that other non-RDoC constructs may be suitable as well, especially if they maximize the probability that subjects share the same mechanism of disorder.

Where feasible and appropriate, applicants are strongly encouraged to include assessment of suicidal behavior (attempts or ideation) using strategies that can facilitate the sharing of data (e.g., see NOT-MH-15-009 and https://www.phenxtoolkit.org/ for constructs and corresponding assessment strategies).

Examples of studies that are not responsive to this FOA and will not be reviewed include the following:

• Applications whose scope of work does not include the objective measurement of molecular/circuit-based target engagement, the choice of which is supported by empirical evidence of its potential relationship in the functional domain(s) or symptoms, and of its potential to address an unmet therapeutic need.
• Animal studies.
• Applications that propose to test pharmacological or device-based interventions where there are studies already underway to test them in that population and with the same target. Applicants should check ClinicalTrials.gov to determine if the project they are considering is innovative or not.

Applications using only the R61 mechanism or only the R33 mechanism are incomplete and will not be accepted under this FOA. Applicants who already have sufficient preliminary data to progress to the R33 phase should apply directly to RFA-MH-18-703 "Early Stage Testing of Pharmacologic or Device-based Interventions for the Treatment of Mental Disorders (R33)".

Applicants are strongly encouraged to consult with NIMH staff when developing plans for an application (see Agency Contacts, Section VII). This early contact will provide an opportunity to clarify NIMH policies and guidelines, identify whether the proposed project is consistent with NIMH program priorities, and to discuss how to develop an appropriate project timeline, which is subject to peer review.

For multi-site trials, use of single IRBs is expected.

The R61 Phase

The R61 phase focuses on testing whether the molecular/circuit-based target can be modulated by varying the dose or stimulation exposure in clinical studies. Target modulation needs to be measured objectively and may assess intervention effects at the molecular, circuit, neural oscillatory, or system level (i.e., target engagement), and may also include a preliminary assessment of symptoms/domains if an acute study is not feasible due to a safety need for incremental dosing. The specific activities and milestones appropriate for the R61 phase will depend on the type of intervention under study and its stage of development. Generally, these activities and milestones include: 1) objective measures of the molecular/circuit-based target and hypothesized mechanism of action (including ratio of target versus non-target activity); 2) evidence that the measure(s) of target engagement can be reliably and validly manipulated in a dose-dependent fashion; 3) demonstration of adequate target engagement with established dose selection or stimulus range; 4) feasibility data to indicate that an adequate dose range for the intervention can be applied in the selected human population with good safety and tolerability; and 5) adequate and feasible recruitment plans to enable study completion in two years.

The R33 Phase

Funding for the R33 phase is contingent on successfully meeting the milestones in the R61 phase (see Section VI. Award Administration Information, 1. Award Notices for further information).

Pilot studies supported by the R33 phase should be powered for testing the link between the degree of the intervention's target engagement and functional outcomes in a patient population. In addition to the aims of testing safety and measuring target engagement, functional/symptoms will be measured and evaluated for how they associate with target engagement. Specific R33 activities may also include: 1) evaluating how the molecular/circuit-based target relates to biomarkers/measures of brain function and domains of functions, as well as symptom/functional measures; 2) further testing of the intervention's feasibility, safety, and acceptability; 3) evaluating the feasibility of recruitment, randomization (if appropriate), retention, assessments, and reporting of adverse events; and 4) developing target engagement, brain functional and symptom/functional measures. It is not expected that the R33 phase would be powered for efficacy.

The results of the R33 phase should inform a decision about whether the intervention has the potential to substantially improve functional/symptom outcomes, including evidence of safety, tolerability; alter CNS physiology; and strength of the association between target engagement and change in symptoms/function.

Additional information for specific intervention types

Medical devices: All aspects of delivered dose should be thoroughly defined, modeled, and where appropriate, measured, including its spatial and temporal components, as well as the context of its administration. Characterization of the spatial aspects of delivered dose for electromagnetic devices should use realistic head modeling to simulate the amplitude of the electric field induced across the brain, and should evaluate degree of target to non-target stimulation. A figure should be provided demonstrating this head modeling, including labeled axes/on figure legends/scale/color bars and demarcating a threshold for activation, when relevant. If multiple targets are proposed, models should be provided to demonstrate stimulation capabilities at each site (if individualized targets are to be used, models covering multiple general targets may be used). Additionally, individualized targeting should be used throughout the proposed application, not just for the example figure. Each subject should be given individualized stimulation that matches unique aspects of their anatomy. Characterization of temporal elements of dosage should specify pulse shape, pulse direction, frequency, train duration, inter-train interval, etc. Characterization of the context of delivered dosage should specify brain state at time of administration, engagement in on-line or off-line cognitive/behavioral therapies, social context of device delivery, concomitant pharmacological intervention, etc. Evaluation of target engagement should use on-line (e.g., TMS/fMRI interleaving, TCS-EEG, TMS-PET, DBS-EEG) or off-line (e.g., PET, fMRI/rsfcMRI, MRS) approaches, depending on the nature of the spatial anatomical and/or neural oscillatory targets. Note that 'dose' of neuromodulatory devices refers to all aspects of the administered electric field or alternative form of energy, including the spatial distribution (e.g., where in the brain the electric field or other form of energy is deposited, and its amplitude at each location), the temporal characteristics (e.g., pulse shape, pulse direction, frequency, train duration, inter-train interval), and the contextual aspects of when and how the dose is administered (e.g., temporal correspondence to underlying neural oscillations in an open or closed-loop fashion, brain state at time of administration, engagement in on-line or off-line cognitive/behavioral therapies, social context of device delivery, concomitant pharmacological intervention).

Focus should be placed on identifying the stimulation paradigm (including the spatial, temporal, and contextual features) that most effectively results in a CNS modification, based on the proposed mechanism of action of the intervention to improve symptoms/domains. Subjects randomized should be the patient population (not healthy controls). Careful attention should be paid to time-course of action. In the event of rapidly acting interventions, where clinical change is expected acutely during administration (as in the case of intra-operative stimulation with DBS), it is necessary to use outcome measures that are sensitive to rapid clinical change (e.g., neurocognitive task performance, quantification of behavioral/speech/facial measures).

Additionally, sham/control--stimulus comparators should be included. In the event that a sham is used, demonstration not only of adequate masking procedures but also lack of biological action that would exert CNS effects must be provided. In the event of implanted neurostimulators, blinded discontinuation designs may be particularly useful.

Pharmacological interventions: Evaluation of target engagement should use positron emission tomography (PET), if available, to establish receptor occupancy (RO). If RO was previously established, it should be used together with PK data to help inform initial dose range in the R61. Pharmacological intervention studies must include a functional pharmacodynamic (PD) readout as well as plasma drug levels (which can be compared to existing pharmacokinetic (PK) data). The PD readout may be based on acute dosing and if appropriate, may be tested in healthy controls or in patients. Studies to adapt pharmacologic interventions to pediatric populations should be directed to PAR-17-327 "First in Human and Early Stage Clinical Trials of Novel Investigational Drugs or Devices for Psychiatric Disorders (U01)". Studies of multi-target drugs or dietary supplements will be considered only if the study design can provide non-ambiguous results about all the CNS targets of interest.

The R61 phase will support development of novel interventions, including testing safety and determining an optimal dose/stimulus range for a subsequent trial by assessing dose-response with respect to pharmacokinetic (PK), if appropriate, and a functional pharmacodynamic (PD) readout of target engagement. Adequate functional target engagement, in relationship to PK and dosing must be a key criterion of a "go/no-go" decision to move from the R61 to R33 phase.

Other Resources

Applicants are encouraged to leverage existing resources and infrastructure such as those provided by institutions with Clinical and Translational Science Awards (CTSAs) and/or other existing consortia/networks to promote efficient cross-disciplinary collaborations.

Applicants with data collection plans that involve multiple respondent groups (e.g., clients/patients, therapists/providers, supervisors, administrators) should address provisions for human subject protections and consenting procedures for all participant groups, accordingly. The NIMH has published updated policies and guidance for investigators regarding human research protection and clinical research data and safety monitoring (NOT-MH-15-025). The application's Protection of Human Subjects section and data and safety monitoring plans should reflect the policies and guidance in this notice. Plans for the protection of research subjects and data and safety monitoring will be NIMH for consistency with NIMH and NIH policies and federal regulations. See Section VIII. Other Information for award authorities and regulations.

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

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

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

Higher Education Institutions

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

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

o Hispanic-serving Institutions

o Historically Black Colleges and Universities (HBCUs)

o Tribally Controlled Colleges and Universities (TCCUs)

o Alaska Native and Native Hawaiian Serving Institutions

o Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Governments

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

Other

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

Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Applicant Organizations

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

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

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

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

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

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

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

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

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

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

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

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

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

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.

By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:

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

The letter of intent should be sent to:

Email: nimhpeerreview@mail.nih.gov

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

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

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

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

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

Facilities and Other Resources: The description of the resources and environment should address how the study utilizes existing infrastructure (e.g., CTSAs, practice-based research networks, electronic medical records, administrative data bases, patient registries) or utilizes other available resources to increase the efficiency of participant recruitment and data collection or provide a justification in the event that such efficiencies cannot be incorporated.

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

As appropriate, Senior/Key Personnel should demonstrate their expertise and track record in pharmacologic or device-based clinical trials, including expertise in industry-funded trials, recruitment and retention of trial subjects and methodological and statistical expertise. Also include recent collaborative clinical research efforts among members of the proposed team, if any. Describe the expertise within the research team in the measurement methods proposed (e.g., PET, fMRI, MRS, task based measures).

Provide evidence that the PD(s)/PI(s) successfully carried out studies of similar structure and complexity as in the current application in the specified setting.

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

The R61 and R33 cannot be funded in the same fiscal year.

Budget Justification: For each budget year, indicate if the requested budget is for the R61 phase or the R33 phase. Describe the staffing for conducting the study as proposed and within specified timelines.

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

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

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

Specific Aims: Include headers titled R61 Specific Aims and R33 Specific Aims and state the specific objectives of the research effort in the two phases of this project, on the single Specific Aims attachment. Provide a concise description of the experimental medicine-designed clinical study(s) as well as how the proposed intervention could fill an important unmet need for those living with mental disorders.

Research Strategy: Applicants should include the following sections as part of the single Research Strategy attachment. Applications should not duplicate information provided in the attachment described in the PHS Human Subjects Clinical Trial Information form but may reference it to provide context as needed.

Significance: In this section of the Research Strategy, the application should:

• Describe the unmet therapeutic need that will be addressed by the intervention. Describe the intervention's potential to significantly reduce the burden of serious mental illness.
• Propose a novel intervention with a strong, well-supported theoretical rationale that is ready for early-phase testing.
• Propose clear hypotheses that are refutable. Describe how the project will advance knowledge of intervention and its potential mechanism of action, whether the trial results are positive or negative.
• Present a clear rationale for the effect size for the proposed study.

Investigators:

• Describe the combined expertise of the research team as a whole in terms of its ability to promote synergy and cover the critical elements of clinical trials expertise, track record in successfully conducting early clinical trials (e.g., subject recruitment and retention rates, reporting in clinicaltrials.gov, publications, experience in industry-funded trials), methodological and statistical expertise, and experience in all measures to be included in the study. (e.g., handling repeated measures designs, missing data, effect size).
• Describe the governance for conducting the study as proposed and within specified timelines

Innovation: In this section of the Research Strategy, the application should:

• Propose compelling rationale that the intervention selected is highly innovative (not already approved for a psychiatric indication, not ones used in standard practice such as SSRIs and ECT) and addresses an unmet therapeutic need, or otherwise has the potential for substantially improving outcomes for people with mental disorders. Innovation is reflected in the choice of a novel molecular/CNS target.

Approach: In this section of the Research Strategy, the application should:

• Provide a compelling scientific rationale for the protocol chosen. Present a clearly-specified molecular/circuit-based target and how target engagement relates to biomarkers/measures of brain function and domain of function as well as symptoms/function. Present a clear conceptual framework that includes relevant empirical support for the intervention, its mechanism of action, and how the mechanism of action should lead to functional improvement.
• Provide a clear rationale for the choice of clinical domain or measure of function in a clinical population (it may be a population that is selected or enriched on the basis of a measure of function or biomarker.)

Describe both the R61 and R33 phases:

• For the R61 phase, the study design will include the approach to determine dose/stimulus response relationships, PK (for drugs), electric field modeling (for devices) and target engagement, to determine a narrower dose range that adequately engages the target, for use in the R33 phase. Note: for electric field modeling, a figure should be provided to demonstrate it, including labeled axes on figure legends/scale bars and demarcating a threshold for activation, when relevant. If multiple targets are proposed, models should be provided to demonstrate stimulation capabilities at each site (if individualized targets are to be used, models covering multiple general targets may be used).
• Address whether a tolerable and safe dose range has been proposed that will adequately test the mechanism, with sufficient target exposure. Present a sufficiently robust and reproducible body of evidence to support the study hypothesis and rationale. When appropriate, include pre-clinical data supporting the intervention approach. Provide information on the specificity, safety, pharmacokinetics, pharmacodynamics, and brain penetration to support the study, to provide evidence that this is the right intervention to test the hypothesis. Note: Drugs must be sufficiently potent and selective for critical evaluation of target engagement and brain exposure. Studies of multi-target drugs (e.g., triple re-uptake inhibitors) will only be considered if the study design can provide non-ambiguous results about the CNS targets of interest, where each molecular target is measured for engagement, not just one. Devices must be appropriately designed to selectively reach the anatomical target. For deep penetrating devices, it must be demonstrated that deep targets are effectively and selectively reached, with a clinically acceptable target-to-nontarget ratio. Claims of deep targeting using noninvasive devices must be accompanied with rigorous pre-clinical and modeling data supporting the claims.
• Propose a rigorous test of target engagement and strong milestones (Go/No-Go Criteria) in the R61 phase. The research strategy should utilize reliable, objective and valid measures of target engagement, including dose and/or stimulus optimization to definitively test the intervention's ability to modulate the target. Additionally, safety and side effects need to be carefully monitored.
• In the R33 Phase, further validate the dose or stimulus range needed for target engagement, based on the R61 results, and collect additional data using reliable outcome measures that quantify changes in the disorder, functional domain, or symptom(s) within the context of a trial.
• Describe how the properly controlled, GCP standard, validation study will be conducted, not limited to these examples of methodologies: placebo controlled, PK, plasma levels of drugs, safety, and tolerability. Additionally, describe: a) how the stimulation/dose exposure range will be narrowed in the R33 phase based on the initial target engagement findings in the R61 phase and how replication and extension will be conducted and b) how this phase will evaluate associations between target engagement and subsequent symptom or functional change. Describe how sufficient data will be collected in the R33 phase in order to determine molecular/CNS target validation, based on relationships between target engagement, measures of brain function and clinical or functional effects.
• Describe the feasibility of the approach in terms of having in place all the necessary elements to carry out data acquisition and analysis in a timely manner. This information is critical because of the shorter timelines required for these studies.

Where feasible and appropriate, applicants are strongly encouraged to include assessment of suicidal behavior (attempts or ideation) in applications responding to this FOA using strategies that can facilitate the sharing of data (see NOT-MH-15-009 and https://www.phenxtoolkit.org/ for constructs and corresponding assessment strategies).

Milestones (Go/No-Go Criteria): Applications must provide a section titled "Milestones (Go/No-Go Criteria)", which addresses the following issues:

Adequate functional target engagement must be a key criterion of a "go/no-go" decision to move from the R61 to R33 phase. This section should include a clear description of the R61 phase milestones that, if met, will justify taking the proposed intervention into the R33 pilot study. The milestones proposed in the application must be pre-specified, objective, quantifiable, rigorously defined, feasible (in terms of timeline and approach), and scientifically justified to assess milestone achievement and operational feasibility relevant to advancing from the R61 to the R33 phase. Criteria of success in target engagement must be defined in terms of outcomes achieved (e.g., specific measures of target engagement) rather than as tasks completed, and quantitative threshold values should be specified for the proposed measures. The criteria for success should be designed to: (a) demonstrate that the intervention displays dose/stimulation-dependent effects at the proposed site of action (thus providing an initial proof of mechanism), and (b) provide preliminary evidence that at the same dose/stimulation range that modulates the CNS, safety issues and side effects impacting tolerability are not evident to the patients. Conditions should be clearly spelled out under which the PD/PI would not proceed to the R33 phase.

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:

In order to advance the goal of advancing research through widespread data sharing among researchers, investigators funded under this FOA are expected to share those data via the National Database for Clinical Trials related to Mental Illness (NDCT; http://ndct.nimh.nih.gov/; see NOT-MH-14-015 and NOT-MH-15-012). Established by the NIH, NDCT is a secure informatics platform for scientific collaboration and data-sharing that enables the effective communication of detailed research data, tools, and supporting documentation. NDCT links data across research projects through its Global Unique Identifier (GUID) and Data Dictionary technology. Investigators funded under this FOA are expected to use these technologies to submit data to NDCT.

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 NDCT web site provides two tools to help investigators develop appropriate strategies: 1) the NDCT Budgeting Spreadsheet http://ndct.nimh.nih.gov/preplanning/budget - 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 http://ndct.nimh.nih.gov/preplanning/informed-consent. Investigators are expected to certify the quality of all data generated by grants funded under this FOA prior to submission to NDCT 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 Data Sharing Expectation http://ndct.nimh.nih.gov/preplanning/#tab-1 for more information); Investigators are expected to share results, positive and negative, specific to the cohorts and outcome measures studied by using the Study functionality(see http://ndct.nimh.nih.gov/results). The NDCT Data Sharing Plan is available for review on the NDCT web site (http://ndct.nimh.nih.gov/wp-content/uploads/NDCT_Data_Sharing_Policy_20141002.pdf ). NDCT staff will work with investigators to help them submit data types not yet defined in the NDCT Data Dictionary http://ndct.nimh.nih.gov/submit/data-dictionary.

Appendix:

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

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

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

Study Record: PHS Human Subjects and Clinical Trials Information

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

Section 2 - Study Population Characteristics

2.5 Recruitment and Retention Plan

: Applications must provide a clear description of:

1. Recruitment and Referral sources, including detailed descriptions of the census/rate of new cases and anticipated yield of eligible participants from each source;

2. Procedures that will be used to monitor enrollment and track/retain participants for follow-up assessments;

3. Strategies that will be used to ensure a diverse, representative sample;

4. Potential recruitment/enrollment challenges and strategies that can be implemented in the event of enrollment shortfalls (e.g., additional outreach procedures, alternate/back-up referral sources);

5. Evidence to support the feasibility of enrollment, including descriptions of prior experiences and yield from research efforts employing similar referral sources and/or strategies.

2.7 Study Timeline

Applications must provide a timeline for reaching important study benchmarks such as: (1) finalizing the study procedures and training participating clinical site staff; (2) finalizing the intervention manual and assessment protocols, including fidelity measures/procedures, where applicable; (3) enrollment benchmarks; (4) completing all subject assessments and data collection activities, including data quality checks; (5) analyzing and interpreting results; and (6) preparing de-identified data and relevant documentation to facilitate data sharing, as appropriate.

Section 4 - Protocol Synopsis

4.6 Will the study use an FDA-regulated intervention? (yes/no)4.6.a. If yes, describe the availability of Investigational Product (IP) and Investigational New Drug (IND)/Investigational Device Exemption (IDE) status:

For studies of pharmacologic compounds and devices, at the time of the application's submission, there must be either an open Investigational New Drug application (IND) or Investigational Device Exemption (IDE) in place, or a documented FDA-submitted application/request for an IND or IDE. The grant application must describe the status of any such pending regulatory submissions. If an FDA IND or IDE application/request has not yet been submitted by the time of the grant application submission due date, the grant application must describe the plan and timeline for submitting the request for and obtaining the IND/IDE. If the drug/device is exempt from the IND/IDE, the grant application must include the justification and documentation for why the drug/device would be exempt.

5.1 Other Clinical Trial-related Attachments

Applicants must upload the attachments for Intervention Manual/Materials as separate files, as applicable. Applicants must use the "Intervention Manual/Materials" to name these other attachments files. As appropriate, this may include screenshots of mobile interventions, technological specifications, training manuals or treatment algorithms

Delayed Onset Study

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

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

Foreign (non-U.S.) institutions must follow policies described in the NIH Grants Policy Statement, and procedures for foreign institutions.

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

Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH's electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.

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

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

This initiative is not subject to intergovernmental review.

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

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

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

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

For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Guidelines for Applicants Experiencing System Issues. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.

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

See more tips for avoiding common errors.

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

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

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

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

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

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

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

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

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

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

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?

Could the intervention fill an important unmet therapeutic need for those living with a mental disorder, or substantially (not incrementally) improve clinical care?

Does the proposed project have the potential to validate or reject the molecular/CNS target being tested? Does it propose a novel intervention with a strong, well-supported theoretical rationale that is ready for early-phase testing? Will the project advance knowledge of the intervention and its potential mechanism of action, whether the trial results are positive or negative?

Is there a clear rationale for the effect size?

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?

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?

Is there sufficient evidence that the investigators can work as a team? Does the research team have demonstrated industry-funded clinical trials expertise and a track record in successfully conducting early clinical trials (e.g., subject recruitment and retention rates, reporting in clinicaltrials.gov, publications, GCP training and maintenance, blinding to randomization assignment, rater reliability assessments, effective management of all of the activities listed here)? Does the investigative team have sufficient methodological and statistical expertise in the study to evaluate target engagement, brain functional effects and functional outcomes (e.g., association of these different measures, handling repeated measures designs, missing data, effect size)? Does the investigative team include sufficient expertise in the measurement methods proposed, e.g., PK/PD, PET, fMRI, MRS, task-based measures? Does the investigative team have sufficient expertise in measurement methods to ensure consistent application of those measures to limit site drift during data collection?

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?

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?

Does the application introduce a novel, well-specified intervention (not ones used in standard practice such as SSRIs and ECT), and address an unmet therapeutic need, or otherwise have the potential for substantially improving outcomes for people with mental disorders? Innovation is also reflected in the choice of a novel molecular/CNS target. Is the rationale for the intervention and molecular/CNS target based on empirical evidence about how the mechanism may be involved in producing an improvement in symptoms or function?

Is it clearly-specified how molecular/circuit-based target engagement relates to biomarkers/measures of brain function and domain of function as well as symptoms/function? Does the application include a clear conceptual framework, and relevant empirical support, for the intervention, its mechanism of action, and how the mechanism of action should lead to functional improvement?

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

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?

Is the study design properly controlled including variables such as (but not limited to) PK, blinded control arm, GCP standards, sufficient safety and tolerability monitoring?

Is there a strong conceptual rationale, including empirical support, for choice of the intervention, the molecular/CNS target, how the target affects brain function, and potential for the intervention to alter the target and how it should lead to clinical improvement? Is there a clear rationale for the choice of clinical domain or measure of function in a clinical population (note: it may be a population that is selected or enriched on the basis of a measure of function or biomarker)? Is the rationale for the selection of the intervention in terms of potency, selectivity and mechanism of action strong? Is there a compelling scientific rationale for the biological measures (RO, PK, PD, and intermediate outcome measures) used to assess the link between target engagement and clinical effect?

Does the R61 phase of the study include the approach to determine dose response relationships, PK (for drugs), electric field modeling (for devices) and target engagement to determine a narrower dose range that adequately engages the target, in the R33 phase? Is the need for the R61 phase well justified; is there a need to test target engagement in a proof of concept phase?

Has a tolerable and safe dose range been proposed that will adequately test the mechanism, with sufficient target exposure? Does the applicant present a sufficiently robust and reproducible body of evidence to support the study hypothesis and rationale? When appropriate, were pre-clinical data included to support the intervention approach? Was sufficient information provided on the specificity, safety, e-field modeling, pharmacokinetics, pharmacodynamics, and brain penetration to support the study, to provide evidence that this is the right intervention to test the hypothesis? Note: Drugs and devices must be sufficiently potent and selective for critical evaluation of target engagement and brain exposure. If multi-target drugs are proposed (e.g., triple re-uptake inhibitors), does the study design provide non-ambiguous results about the CNS targets of interest, such that each molecular target is measured for engagement, not just one target?

Is a rigorous test of target engagement and strong go/no-go milestones in the R61 phase included in the application? Does the research strategy utilize reliable, objective and valid measures of target engagement, including dose and/or stimulus optimization to definitively test the intervention's ability to modulate the target? Does the strategy include careful monitoring of safety and side effects?

In the R33 Phase, is there a plan for further validation of the dose or stimulus range needed for target engagement, based on the R61 results, and will additional data be collected using reliable outcome measures that depict changes in the disorder, functional domain, or symptom(s) within the context of a trial?

Has the applicant described how the properly controlled, GCP standard, validation study will be conducted, not limited to these examples of methodologies: placebo controlled, PK, plasma levels of drugs, safety, and tolerability? Additionally, have they described: a) how the stimulation/dose exposure range will be narrowed in the R33 phase based on the initial target engagement findings in the R66 phase and how replication and extension will be conducted, and b) how this phase will evaluate associations between target engagement and subsequent symptom or functional change? Will sufficient data be collected in the R33 phase in order to determine molecular/CNS target validation, based on relationships between target engagement, measures of brain function and symptom or functional effects? Is there a clear strategy for tracking recruitment and facilitating retention?

Is there sufficient detail about intervention delivery and monitoring? Will results from the R33 phase definitively validate or reject the clinical target (through associations between target engagement and subsequent clinical or functional change)? Is there evidence of safety, tolerance, protocol feasibility; preliminary signal of symptom or functional improvement; and strength of the association between target engagement and change in clinical status?

Are all the necessary elements in place to carry out data acquisition and analysis in a timely manner? This information is critical because of the shorter timelines required for these studies.

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

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?

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?

Does the environment support timely subject recruitment and completion of each of the two phases (R61 and R33)?

As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.

Milestones (Go/No-Go Criteria)

Are quantitative criteria pre-specified and rigorously defined to assess milestone achievement and operational feasibility relevant to advancing from the R61 to the R33 phase? Are success criteria defined in terms of outcomes achieved (e.g., specific measures of target engagement) rather than as tasks completed? Are R61 milestones feasible, well developed and quantifiable with regard to the specific aims of each stage to assess optimal dosing? Are quantitative threshold values specified for the proposed measures? Are the criteria rigorous enough in: (a) demonstrating that the intervention displays dose/stimulation-dependent effects at the proposed site of action (thus providing an initial proof of mechanism), and (b) providing preliminary evidence that at the same dose/stimulation range that modulates the CNS, safety issues and side effects impacting tolerability are not evident to the patients? Does the application specify conditions under which they would not proceed to the R33 phase?

Study Timeline

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

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

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

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

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

Not Applicable

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

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

Not Applicable

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

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

Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.

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

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

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

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

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

As part of the scientific peer review, all applications:

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

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

Applications will be assigned to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the National Advisory Mental Health Council. The following will be considered in making funding decisions:

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

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

Information regarding the disposition of applications is available in the NIH Grants Policy Statement.

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

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

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

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

Additionally, ICs may specify any special reporting requirements for the proposed clinical trial to be included under IC-specific terms and conditions in the NoA. For example: If the proposed clinical trial has elevated risks, ICs may require closer programmatic monitoring and it may be necessary to require the awardee to provide more frequent information and data as a term of the award (e.g., to clarify issues, address and evaluate concerns, provide documentation). All additional communications and information related to programmatic monitoring must be documented and incorporated into the official project file. Individual awards are based on the application submitted to, and as approved by, the NIH and are subject to the IC-specific terms and conditions identified in the NoA. ClinicalTrials.gov: If an award provides for one or more clinical trials. By law (Title VIII, Section 801 of Public Law 110-85), the "responsible party" must register and submit results information for certain "applicable clinical trials" on the ClinicalTrials.gov Protocol Registration and Results System Information Website (https://register.clinicaltrials.gov). NIH expects registration of all trials whether required under the law or not. For more information, see http://grants.nih.gov/ClinicalTrials_fdaaa/

Institutional Review Board or Independent Ethics Committee Approval: Grantee institutions must ensure that the application as well as all protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the awardee must provide NIH copies of documents related to all major changes in the status of ongoing protocols. Data and Safety Monitoring Requirements: The NIH policy for data and safety monitoring requires oversight and monitoring of all NIH-conducted or -supported human biomedical and behavioral intervention studies (clinical trials) to ensure the safety of participants and the validity and integrity of the data. Further information concerning these requirements is found at http://grants.nih.gov/grants/policy/hs/data_safety.htm and in the application instructions (SF424 (R&R) and PHS 398).

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

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

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person's race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency. HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator's scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research.

For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/index.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html; and https://www.hhs.gov/civil-rights/for-providers/laws-regulations-guidance/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant's integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 "Federal awarding agency review of risk posed by applicants." This provision will apply to all NIH grants and cooperative agreements except fellowships.

Cooperative Agreement Terms and Conditions of Award

Not Applicable

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

A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

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

In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period. The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 Award Term and Conditions for Recipient Integrity and Performance Matters.

Recruitment Reporting and Trial Registration

NIMH requires reporting of recruitment milestones for participants in clinical trials as noted at http://grants.nih.gov/grants/guide/notice-files/NOT-MH-05-013.html. While trials in response to this FOA may not seek 150 subjects or more (the level at which this reporting has been required), we expect reporting for all trials, even those with less than 150 subjects.

The NIMH expects the registration and results reporting for all NIMH-supported clinical trials in ClinicalTrials.gov, regardless of whether or not they are subject to FDAAA (see http://grants.nih.gov/ClinicalTrials_fdaaa/at-a-glance.htm). We plan to include language regarding this expectation in the notice of grant award.

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

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

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact Center Telephone: 800-518-4726
Email: support@grants.gov

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-945-7573

For Pediatric Studies

Margaret Grabb, Ph.D.
National Institute of Mental Health (NIMH)
Telephone: 301-443-3563
Email: mgrabb@mail.nih.gov

For Adult Studies

Mi Hillefors, M.D., Ph.D.
National Institute of Mental Health (NIMH)
Telephone: 301-443-2738
Email: mi.hillefors@nih.gov

For Geriatric Studies

Jovier Evans, Ph.D.
National Institute of Mental Health (NIMH)
Telephone: 301-443-6328
Email: jevans1@mail.nih.gov

Nick Gaiano, Ph.D.
National Institute of Mental Health (NIMH)
Telephone: 301-827-3420
Email: nick.gaiano@nih.gov

Tamara Kees
National Institute of Mental Health (NIMH)
Telephone: 301-443-8811
Email: tkees@mail.nih.gov

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

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