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

Early Stage Testing of Pharmacologic or Neuromodulatory Device-based Interventions for the Treatment of Mental Disorders (R33- Clinical Trial Required) is sponsored by National Institute of Mental Health (NIMH). Supports Phase II clinical trials for pharmacologic or device-based interventions targeting mental disorders, including mood disorders.

PAR-25-183: Early Stage Testing of Pharmacologic or Neuromodulatory Device-based Interventions for the Treatment of Mental Disorders (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 (R33- Clinical Trial Required) R33 Exploratory/Developmental Grants Phase II.

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 Phase 1 Exploratory/Developmental Grant/ 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.

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 early-stage testing 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. This R33 NOFO supports single-phased clinical trial awards. Applicants proposing high-risk projects are encouraged to apply to one of the companion NOFOs, PAR-25-184 or PAR-25-180 .

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 field of neuromodulation have also been offset by failed large-scale invasive and non-invasive brain stimulation trials 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 Exploratory/Developmental Phase II 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) Do dose-dependent pharmacologic/neuromodulatory device actions enable target engagement independent of side effects and potential safety issues?

; and 2) 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 an Exploratory/Developmental Grant Phase II approach (R33) to manage the risk associated with these early-stage clinical studies, but does require a demonstration of the intervention's effect on the proposed mechanism of target engagement or site of action (intervention's molecular/circuit-based target) as preliminary data in the grant application.

Specifically, the NOFO requires supporting data that demonstrates milestone-driven testing, refinement, and/or validation of the intervention's engagement with an empirically supported, measurable molecular/circuit-based target. This application will support clinical studies to confirm target engagement and assess the relationship between target engagement and changes in functional outcomes or clinical symptoms/functional domains.

Results from the project 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-CNS indications; 3) pharmacologic agents and/or neuromodulatory devices 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 2020 Industry-Provided Assets), and 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 is 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 applications must be testing drugs that have already been approved for use in pediatric populations 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 federal 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 their subsequent reissuances.

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)”, PAR-25-179 .

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. Pilot studies supported by this NOFO 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 projects would be powered for efficacy. 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 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 project 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.

For this NOFO, preliminary data need to include positive results that demonstrate the molecular/circuit-based target can be modulated by varying the dose or stimulation exposure in clinical studies. If sufficient preliminary data are not included, then this NOFO is not appropriate.

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 included in the preliminary study will depend on the type of intervention under study and its stage of development.

Generally, these activities 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; and 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.

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 must be rigorously defined, and statistical tests should be prespecified. Valid control/sham conditions should be included. 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, and NIMH program staff and reviewers will determine appropriateness.

Each condition tested should be sufficiently powered to inform the aims (go/no go decisions for future testing). 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 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 (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 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: The preliminary data must include a functional CNS pharmacodynamic (PD) readout that assessed 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 in the preliminary study phase 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.

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.

Preliminary data should include evaluation of safety and determination of an optimal dose/stimulus range to inform the R33 design 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 must be a key criterion to determine if an R33 grant is warranted.

Applications must list the FDA regulatory oversight (e.g., IND/IDE) status or Non-significant risk (NSR) determination status.

Applications Not Responsive to this 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 lack preliminary data on the proposed measure of target engagement.

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.

Pharmacologic studies that lack inclusion of a functional CNS PD readout and evaluation of plasma drug levels.

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 that will be used. 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 must 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 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.

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 are encouraged to work with contract research organizations (CROs) or 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 ).

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.

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, including the Data and Safety Monitoring Plan, 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 is 3 years. 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 will not accept duplicate or highly overlapping applications under review at the same time, per NIH Grants Policy Statement Section 2.

3. 7. 4 Submission of Resubmission Application .

This means that the NIH will not accept: A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application. A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.

An application that has substantial overlap with another application pending appeal of initial peer review (see NIH Grants Policy Statement 2. 3. 9.

4 Similar, Essentially Identical, or Identical Applications ). Section IV. Application and Submission Information 1.

Requesting an Application Package The application forms package specific to this opportunity must be accessed through ASSIST, Grants. gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.

gov Workspace are available in Part 1 of this NOFO. See your administrative office for instructions if you plan to use an institutional system-to-system solution. 2.

Content and Form of Application Submission It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide except where instructed in this notice of funding opportunity to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced.

Applications that are out of compliance with these instructions may be delayed or not accepted for review. All page limitations described in the How to Apply- Application Guide and the Table of Page Limits must be followed. Instructions for Application Submission The following section supplements the instructions found in the How to Apply- Application Guide and should be used for preparing an application to this NOFO.

All instructions in the How to Apply - Application Guide must be followed. SF424(R&R) Project/Performance Site Locations All instructions in the How to Apply- Application Guide must be followed. SF424(R&R) Other Project Information All instructions in the How to Apply- Application Guide must be followed.

SF424(R&R) Senior/Key Person Profile All instructions in the How to Apply- Application Guide must be followed. As appropriate, Senior/Key Personnel descriptions 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. Provide the expertise within the research team in the measurement methods