Early Stage Testing of Pharmacologic or Neuromodulatory Device-based Interventions for the Treatment of Mental Disorders (R61/R33 Clinical Trial Required)

Early Stage Testing of Pharmacologic or Neuromodulatory Device-based Interventions for the Treatment of Mental Disorders (R61/R33 Clinical Trial Required) is sponsored by National Institute of Mental Health (NIMH). Supports early-stage testing of interventions, including digital devices for mental health treatment.

PAR-25-184: Early Stage Testing of Pharmacologic or Neuromodulatory Device-based Interventions for the Treatment of Mental Disorders (R61/R33 Clinical Trial Required) This funding opportunity was updated to align with agency priorities. Carefully reread the full funding opportunity and make any needed adjustments to your application prior to submission. Department of Health and Human Services Part 1.

Overview Information Participating Organization(s) National Institutes of Health ( NIH ) Components of Participating Organizations National Institute of Mental Health ( NIMH ) Funding Opportunity Title Early Stage Testing of Pharmacologic or Neuromodulatory Device-based Interventions for the Treatment of Mental Disorders (R61/R33 Clinical Trial Required) R61 / R33 Exploratory/Developmental Phased Award Notices of Special Interest associated with this funding opportunity March 31, 2025 - This funding opportunity was updated to align with agency priorities.

Carefully reread the full funding opportunity and make any needed adjustments to your application prior to submission. April 4, 2024 - Overview of Grant Application and Review Changes for Due Dates on or after January 25, 2025. See Notice NOT-OD-24-084 .

August 31, 2022 - Implementation Changes for Genomic Data Sharing Plans Included with Applications Due on or after January 25, 2023. See Notice NOT-OD-22-198 . August 5, 2022 - Implementation Details for the NIH Data Management and Sharing Policy.

See Notice NOT-OD-22-189 . Funding Opportunity Number (FON) Companion Funding Opportunity Research Project (Cooperative Agreements) Exploratory/Developmental Grants Phase II Phase 1 Exploratory/Developmental Grant/ Exploratory/Developmental Grants Phase II Exploratory/Developmental Grants Phase II Phase 1 Exploratory/Developmental Grant/ Exploratory/Developmental Grants Phase II See Section III. 3.

Additional Information on Eligibility .

Assistance Listing Number(s) Funding Opportunity Purpose The purpose of this NOFO is to support the early stage testing of pharmacologic interventions with novel mechanisms of action or neuromodulatory device-based interventions for the treatment of symptoms or domains of altered functions in individuals with mental illness (e.g., schizophrenia, depression, autism, obsessive compulsive disorder, anxiety, bipolar disorder).

Early intervention studies are also encouraged where symptoms of a disorder have been identified in subjects (a prodromal phase) prior to full diagnostic criteria being met.

Ultimately, this NOFO is intended to support evaluation of pharmacologic or neuromodulatory device-based interventions using a protocol design where the presumed mechanism of action of the intervention is adequately tested, to provide meaningful information where target modulation yields a well-controlled, dose-dependent neurophysiological/clinical/behavioral effect.

Pediatric, adult, and geriatric-focused interventions are appropriate for this NOFO. The R61/R33 NOFOs are intended to support biphasic high-risk applications. Support for a single phased award that does not need the developmental (R61) phase is available in the companion R33, PAR-25-183 .

Applicants pursuing other stages of the clinical trial pipeline should consider one of the companion NOFOs listed above. Funding Opportunity Goal(s) The mission of the National Institute of Mental Health (NIMH) is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery, and cure.

Open Date (Earliest Submission Date) Renewal / Resubmission / Revision (as allowed) AIDS - New/Renewal/Resubmission/Revision, as allowed All applications are due by 5:00 PM local time of applicant organization. Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

Required Application Instructions It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide , except where instructed to do otherwise (in this NOFO or in a Notice from NIH Guide for Grants and Contracts ). Conformance to all requirements (both in the Application Guide and the NOFO) is required and strictly enforced.

Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

There are several options available to submit your application through Grants. gov to NIH and Department of Health and Human Services partners. You must use one of these submission options to access the application forms for this opportunity.

Use the NIH ASSIST system to prepare, submit and track your application online. Use an institutional system-to-system (S2S) solution to prepare and submit your application to Grants. gov and eRA Commons to track your application.

Check with your institutional officials regarding availability. Workspace to prepare and submit your application and eRA Commons to track your application. Part 1.

Overview Information Part 2. Full Text of Announcement Section I. Notice of Funding Opportunity Description Section II.

Award Information Section III. Eligibility Information Section IV. Application and Submission Information Section V.

Application Review Information Section VI. Award Administration Information Section VII. Agency Contacts Section VIII.

Other Information Part 2. Full Text of Announcement Section I. Notice of Funding Opportunity Description In the last several 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.

Likewise, a handful of new Food and Drug Administration (FDA) approvals in the neuromodulatory device space have also been balanced by the failure of large-scale invasive and non-invasive brain stimulation approaches and hesitancy by industry to invest in mental health treatments.

Given the high risk of failure for these Central Nervous System (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 engaged and modulated.

In response to these emergent issues, NIMH has developed this NOFO to encourage Phased Innovation (R61/R33) grant applications that support early-stage, novel pharmacologic and neuromodulatory 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-dependent manner; 2) if yes, do those doses (as reflected in plasma level of a drug, or neuromodulatory device dose received in the brain) enable target engagement (CNS functional response) independent of side effects and potential safety issues?

; and in the R33 phase, 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 NOFO 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 mechanism of target engagement or site of action (intervention's molecular/circuit-based target) before moving into the R33 phase of the award.

Specifically, the NOFO 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 NOFO strongly encourages the testing of interventions not previously approved/marketed for psychiatric disorders, including 1) interventions in active development; 2) pharmacologic and/or neuromodulatory device interventions repurposed from approved/marketed non-psychiatric indications; 3) pharmacologic agents and/or neuromodulatory devices discontinued from development in the indication where they were originally developed; 4) expanding uses of neuromodulatory devices to other indications and populations.

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 NOFO, as long as the pharmacologic agent or neuromodulatory device being tested is novel. A clear and careful description of the combination of therapies, and how the multitude of combination parameters will be assessed are expected to be included.

This includes evaluating the dosage of each modality of the combination intervention. Studies are expected to demonstrate how effects of the combined therapies on target engagement are positively synergistic (vs. negative or net-neutral), using appropriate control conditions (e.g., comparing the effects of the combined therapies relative to each monotherapy).

For all combination therapies, applicants should follow all other guidance/requirements of the NOFO to which they are applying, including defining measures of target engagement and describing how they will test various doses/combinations.

The rationale for the selection of doses/combinations being assessed should be well-supported by empirical evidence (i.e., preliminary data, clinical and/or preclinical studies, or existing evidence from the literature) . For multimodal interventions in pediatric populations , a novel intervention should be paired with a previously established intervention.

For drugs and neuromodulatory devices, an established intervention is defined through FDA approval/clearance of the intervention, for a specific indication, age range, and dosing. All drugs/devices to be tested must have passed Phase I/EFS safety studies (in healthy or patient populations).

In addition, responsive pediatric drug applications must be testing drugs that have already been approved for use in pediatric patients in non-psychiatric indications and are now being repositioned.

Applications to conduct First in Human testing of new chemical entities, or trials of novel first-in-children pharmacological agents or federally regulated devices designed for brain stimulation in pediatric populations (i.e., first exposure in children or first in pediatric indication) should instead apply to PAR-25-180 , "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-25-180 .

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 PAR-25-177 , “Full-Scale Hybrid Effectiveness-Implementation Trials for Mental Health Interventions (R01 Clinical Trial Required), or PAR-25-178 ,"Pilot Hybrid Effectiveness-Implementation Trials for Mental Health Interventions" (R01 Clinical Trial Required)", or any subsequent re-issuances of these NOFOs.

Applicants focused on large scale/pivotal trial 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)" ( PAR-25-179 ).

Applicants interested in conducting research investigating putative targets, target engagement markers, biomarkers of neurobiological processes, and mechanisms of action are encouraged to consider mechanistic clinical trial NOFOs (e.g., NIH Parent R01 Clinical Trial Required, NIH Parent R21 Clinical Trial Required, NIH Parent R01 Basic Experimental Studies with Humans, NIH Parent R21 Basic Experimental Studies with Humans).

NIMH is specifically interested in novel molecular or circuit-based 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.

NIMH Research Domain Criteria ( RDoC) principles and constructs should, as appropriate, inform subject eligibility or stratification, identification of intervention targets, and/or selection of outcome measures. Effective prevention and treatment of mental illness have the potential to reduce morbidity and mortality associated with intentional injury (i.e., suicide attempts and deaths, see: www. suicide-research-agenda.

org ). Lack of attention to the assessment of these outcomes has limited our understanding regarding the degree to which effective mental health interventions might offer prophylaxis. Where feasible and appropriate, NIMH strongly encourages intervention research that includes assessment of suicidal behavior using strategies that can facilitate data sharing (see NOT-MH-15-009 and https://www.

phenxtoolkit. org/ for example, constructs and corresponding assessment strategies) in order to advance understanding of how effective prevention and treatment of mental disorders might impact suicide relevant outcomes. Required components of R61/33: Applications proposing only the R61 phase or only the R33 phase are incomplete and will not be accepted under this NOFO.

Applicants who already have sufficient preliminary data to progress to the R33 phase (data demonstrating dose-dependent modulation of the target, an association between the target modulation, and neurophysiological/clinical/behavioral effects) should apply directly to PAR-25-183 , "Early Stage Testing of Pharmacologic or Neuromodulatory Device-based Interventions for the Treatment of Mental Disorders (R33 - Clinical Trial Required)".

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 and discuss whether the proposed project is consistent with NIMH program priorities.

The R61 phase focuses on testing whether the molecular/circuit-based target can be modulated by varying the dose of the drug or neuromodulatory device 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 the 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) for neuromodulatory devices, inclusion of a valid sham or control condition (e.g., active control) condition in the R61 phase to demonstrate target engagement beyond placebo; 4) demonstration of adequate target engagement with established dose selection; 5) feasibility data to indicate that an adequate dose for the intervention can be applied in the selected human population with good safety and tolerability; and 6) adequate and feasible recruitment plans to enable study completion in two years.

The criteria used to demonstrate adequate target engagement (i.e., the statistical test/threshold for the dose/control comparison) should be clearly outlined (prespecified) in the Go/No-Go criteria. Descriptions of how multiple comparisons will be accounted for should also be included. Funding for the R33 phase is contingent on successfully meeting the Go/No-Go milestones in the R61 phase (see Section VI.

Award Administration Information, 1. Award Notices for further information). 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.

It is not expected that the R33 phase would be powered for efficacy. In addition to the aims of testing safety and replicating R61 measures of target engagement, functional outcomes/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.

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, altered CNS physiology, and strength of the association between target engagement and change in symptoms/function.

Additional information for specific intervention types: Neuromodulatory devices: This NOFO supports trials for novel neuromodulatory medical devices as defined by Section 201(h) of the Food, Drug, and Cosmetic Act , with the intended use of treating or preventing mental illness. Clear measures of target engagement for device studies should be included.

Regions of interest are expected tobe rigorously defined, and statistical tests should be prespecified. Valid control/sham conditions are expected tobe included in the R61 phase, to ensure the Go/No-Go milestone is falsifiable.

Dose ranging studies (e.g., two stimulation paradigms compared) may be utilized, but if there is a strong case for why only one dose in comparison to control/sham is needed, this information should be clearly justified . Each condition tested should be sufficiently powered to inform the aims and Go/No-Go milestone criteria.

For neuromodulatory devices, all aspects of dose should be thoroughly defined, modeled, and where appropriate, measured, including its spatial and temporal components, as well as the context of its administration. The exact means of modeling and/or measurement will depend on the form of energy delivered by the device, or the approach’s intended impact on brain function as in the case of MRI-neurofeedback interventions..

Note that 'dose' includes all aspects of the delivered dose and the received dose.

Delivered dose refers to the specifications of the parameter settings on the neuromodulatory device (e.g. temporal parameters of pulse shape, pulse trains, duty cycle, etc), the specifications of the means of application (e.g. coil, electrodes, transducer, neuroimaging paradigm specifications in the case of MRI-neurofeedback, etc), the contextual aspects of when and how the dose is administered (e.g. brain state at time of delivery, phase of endogenous oscillations, simultaneous or sequential engagement in a task or psychosocial intervention, etc).

The received dose refers to the specifications of the dose received by each individual, which includes the spatial distribution of the energy once it enters the individual’s brain (e.g., where in the brain the energy is deposited, and its amplitude at each location).

Characterization of the spatial aspects of received dose for brain stimulation devices should use realistic head modeling to simulate the amplitude of the electric field induced or other form of energy applied across the brain and should evaluate the degree of target to non-target stimulation.

A figure must 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 the 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.

Focus should be placed on identifying the neuromodulatory 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 must be included in the R61 and R33 phases.

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 is expected tobe provided. In the event of implanted neurostimulators, blinded discontinuation designs may be particularly useful.

Pharmacological interventions: Pharmacological intervention studies should include a functional CNS pharmacodynamic (PD) readout to assess target engagement, 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.

Evaluation of target engagement can be achieved using a range of measures, including neurophysiological, fMRI, and PET. It should be noted that there is a hierarchy of target engagement “proof”, with measures most proximate to the molecular event preferred (e.g. receptor occupancy), when available. If receptor occupancy was previously established, it should be used with PK data to help inform the initial dose range in the R61.

Studies to adapt pharmacologic interventions to pediatric populations should be directed to PAR-25-180 , "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 the 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 PK, if appropriate, and a functional CNS PD readout of target engagement.

Adequate functional target engagement, in relationship to PK and dosing, is expected to be a key criterion of a "Go/No-Go" decision to move from the R61 to R33 phase. Applications must list the FDA regulatory oversight (e.g., IND/IDE) status or Nonsignificant risk (NSR) determination.

Applications Not Responsive to the NOFO Studies that are not responsive to this NOFO 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.

Applications that do not list the status of FDA regulatory oversight (e.g., Investigational New Drug (IND)/Investigational Device Exemption (IDE) status or Nonsignificant risk (NSR) determination status). Non-human animal studies. Applications that propose to test pharmacological or neuromodulatory 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 that do not clearly define a measure of CNS target engagement in the R61 phase (and replicate it in the R33 phase) or have a clearly defined and falsifiable Go/No-Go milestone.

Pharmacologic studies that lack: Inclusion of a functional CNS PD readout or plasma drug levels measure. Test of target engagement in a dose-dependent manner.

Neuromodulatory device studies that lack: Thorough description of all device settings and algorithms that would enable precise replication of the methods using units/metrics appropriate to the specific device being studied (e.g. stimulation parameters in the case of electromagnetic devices, or processing algorithms in the case of neurofeedback or closed-loop systems) Individualized modeling, and where appropriate, measurement, of the strength and distribution of the dose received by the individual subject, using methods appropriate to the specific device being studied in the case of devices that apply energy to the head or body (i.e. realistic head modeling of the electric field induced in the brain by electromagnetic devices) Specific contextual information regarding brain state when the dose is delivered.

For multimodal/combined interventions, this includes when each intervention is delivered with respect to the other. Clear description of the sham/control condition to be used in the R61 and R33 phases. Description of neuronavigation procedures indicating how individual patient anatomy will guide application.

To fully evaluate the study's scientific validity and the safety implications for participants, studies involving human participation are expected to include information on any planned or reasonably anticipated co-enrollment for participants in this study, including any studies participants are actively participating in at enrollment or any reasonably anticipated co-enrollment in additional studies during participation in the present study.

Applicants are encouraged to leverage existing resources and infrastructure, such as contract research organizations (CROs) or Clinical and Translational Science Awards (CTSAs) or similar groups with expertise in managing regulatory quality clinical trials and with expertise in the age range and intervention type proposed.

The NIMH is committed to enhancing the reliability of NIMH-supported research through rigorous study design and reporting ( NOT-MH-14-004 ). The NIMH has published updated policies and guidance for investigators regarding human research protection and clinical research data and safety monitoring ( NOT-MH-19-027 and Conducting Research with Participants at Elevated Risk for Suicide: Considerations for Researchers) .

The application’s PHS Human Subjects and Clinical Trials Information and, including the Data and Safety Monitoring Plans, should reflect the policies and guidance in this notice.

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.

Plans for the protection of research participants and data and safety monitoring will be reviewed by the NIMH for consistency with NIMH and NIH policies and federal regulations. Investigators proposing NIH-defined clinical trials may refer to the Research Methods Resources website for information about developing statistical methods and study designs. See Section VIII.

Other Information for award authorities and regulations. Section II. Award Information Grant: A financial assistance mechanism providing money, property, or both to an eligible entity to carry out an approved project or activity.

Application Types Allowed The OER Glossary and the How to Apply Application Guide provide details on these application types. Only those application types listed here are allowed for this NOFO. Required: Only accepting applications that propose clinical trial(s).

Need help determining whether you are doing a clinical trial? Funds Available and Anticipated Number of Awards NIMH intends to commit a total of $27,000,000 million for FY 2026 to fund this NOFO and the companion NOFOs listed in Part 1. Overview Information.

Future year amounts will depend on annual appropriations. Application budgets are not limited but need to reflect the actual needs of the proposed project. The scope of the proposed project should determine the project period.

The maximum period of the combined R61 and R33 phases is 5 years, with up to 2 years for the R61 phase and up to 3 years for the R33 phase. Applications with a project period less than 5 years are encouraged where feasible. NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from this NOFO.

Section III.

Eligibility Information Higher Education Institutions Public/State Controlled Institutions of Higher Education Private Institutions of Higher Education Nonprofits Other Than Institutions of Higher Education Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education) Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education) For-Profit Organizations (Other than Small Businesses) City or Township Governments Special District Governments Indian/Native American Tribal Governments (Federally Recognized) Indian/Native American Tribal Governments (Other than Federally Recognized).

Eligible Agencies of the Federal Government U.S. Territory or Possession Independent School Districts Public Housing Authorities/Indian Housing Authorities Native American Tribal Organizations (other than Federally recognized tribal governments) Faith-based or Community-based Organizations Non-domestic (non-U.S.) Entities (Foreign Organizations) Non-domestic (non-U.S.) Entities (Foreign Organizations) are eligible to apply.

Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply. Foreign components, as defined in the NIH Grants Policy Statement , are allowed. Applicant organizations must complete and maintain the following registrations as described in the How to Apply- Application Guide to be eligible to apply for or receive an award.

All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. Failure to complete registrations in advance of a due date is not a valid reason for a late submission, please reference the NIH Grants Policy Statement Section 2.

3. 9. 2 Electronically Submitted Applications for additional information.

System for Award Management (SAM) – Applicants must complete and maintain an active registration, which requires renewal at least annually . The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.

NATO Commercial and Government Entity (NCAGE) Code – Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM. Unique Entity Identifier (UEI) - A UEI is issued as part of the SAM. gov registration process.

The same UEI must be used for all registrations, as well as on the grant application. eRA Commons - Once the unique organization identifier is established, organizations can register with eRA Commons in tandem with completing their Grants. gov registrations; all registrations must be in place by time of submission.

eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application. Grants. gov – Applicants must have an active SAM registration in order to complete the Grants.

gov registration. Program Directors/Principal Investigators (PD(s)/PI(s)) All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons.

If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Eligible Individuals (Program Director/Principal Investigator) Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with their organization to develop an application for support.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the How to Apply-Application Guide. This NOFO does not require cost sharing as defined in the NIH Grants Policy Statement Section 1. 2 Definition of Terms .

3. Additional Information on Eligibility Applicant organizations may submit more than one application, provided that each application is scientifically distinct. The NIH