Part 1. Overview Information

Key Dates

All applications are due by 5:00 PM local time of applicant organization. 

Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

It is critical that applicants follow the 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.

IMPORTANT: Per NOT-OD-24-086 updated application forms (FORMS-I) will be used for this opportunity. The updated forms are not yet available and will be posted 30 calendar days or more prior to the first application due date. Once posted, you will be able to access the forms using one of the following submission options:

1. NIH ASSIST
2. An institutional system-to-system (S2S) solution
3. Grants.gov Workspace

Part 2. Full Text of Announcement

Section I. Notice of Funding Opportunity Description

Background

Substance Use Disorders (SUDs) continue to have a substantial adverse impact in the United States, resulting in costs of more than $700 billion annually due to health care expenditures, lost earnings, and expenses associated with crime and accidents. There are effective pharmacological and behavioral treatments, but the long-term success rate is low and not all individuals are responsive. Furthermore, approved treatments are not available for cannabis, methamphetamine, cocaine use and polysubstance use disorders. The development of safe and effective therapeutic devices for SUDs represents an opportunity to address the significant public health need for new SUD interventions.

With the approval of neuromodulatory devices for treatment of mental health disorders such as depression and obsessive compulsive disorder, interest has rapidly grown around applying these and related technologies to SUDs. Studies examining the effects of neuromodulation on nicotine, alcohol, cocaine, and other SUDs have reported some therapeutic effects. Further work, however, is needed to strengthen and build upon these results. High priority areas of research include understanding the relationship between changes in brain circuitry and behavioral responses, what SUD behavioral activities are responsive, how long does the altered behavioral response last, how can devices be used together with FDA approved treatments, and are subsequent treatments needed to maintain the behavioral response.

Research Objectives

This notice of funding opportunity (NOFO) seeks to support research into neuromodulatory technologies to treat SUDs. These technologies include, but are not limited to, transcranial magnetic stimulation, transcranial direct current stimulation, vagal stimulation, deep-brain stimulation, focused ultrasound, and others. Also of interest are technologies that may not directly modify neuronal function but report on or alter neurophysiology that affect outcomes. This NOFO strongly encourages the testing of device-based interventions previously approved/marketed for non-SUD disorders, as well as new interventions in active development.

Understanding how these new treatment modalities work is of primary importance to this NOFO. In neuromodulatory technologies, for example, there are multiple coil types which can result in different breadths and depths of biologic effect. For studies that seek to understand how the neuromodulatory and neurophysiological interventions function, early stage endpoints should incorporate objective measures that examine both the delivered dosage/treatment duration and the proposed mechanism of action of the intervention, and should determine if the intervention target has been modulated.

Areas of interest to this NOFO include understanding the effect of the intervention on circuit-based targets, as well as to characterizing the breadth and stability of the behavioral effect. The questions may include, but are not limited to:

1. Does the intervention preferentially and reproducibly engage/modulate a circuit-based target in a dose/stimulus-dependent manner?
2. If circuit-based target engagement is verified, is there a measurable clinical benefit as detected through functional domains or clinical measures?
3. What is the relationship between changes in brain circuitry and behavioral responses?
4. What types of SUD behavioral activities are responsive to the intervention?
5. How long does the altered behavioral response last?
6. Are subsequent treatments needed to maintain the behavioral response?
7. Are there potential side effects and safety issues associated with the doses?

All aspects of dose delivered by a device should be thoroughly defined. This includes, when applicable,

1. The spatial distribution of dose delivered by electromagnetic devices, using anatomically-accurate computational head models to simulate the distribution of electromagnetic field in the brain;
2. The temporal characteristics, including pulse shape, pulse direction, frequency, train duration, inter-train interval, and other aspects where appropriate;
3. The contextual aspects of when and how the dose is administered, including specification of brain state at time of administration, engagement in cognitive/behavioral therapies, social context of device delivery, and others.

Studies are strongly encouraged, when appropriate, to include evaluation of circuit-directed target engagement, using on-line (e.g., TMS/fMRI interleaving, EEG, PET) or off-line (e.g., PET, fMRI/rsfcMRI, MRS) approaches, depending on the nature of the spatial anatomical and/or neural oscillatory targets. Careful attention should be paid to the time-course of action. For rapidly acting interventions, where changes in circuit-based targets occur acutely during administration, it may be most appropriate to use pharmacodynamic outcome measures (e.g. neurocognitive task performance, craving).

Sham/placebo stimulus comparators should be included when appropriate. If a sham is used, demonstration must be provided not only of adequate masking procedures but also lack of biological action that would exert CNS effects.

If applicable, investigators should design studies to evaluate potential sex/gender differences. When appropriate, methods to evaluate subjects' compliance with the study treatments should be included, such as when integrative pharmacologic or behavioral approaches are used.

For studies that include device development, applications are required to include a go/no-go decision tree regulatory pathway with clear milestones. Prospective applicants are encouraged to discuss the development plan with the appropriate regulatory authorities at the FDA.

For studies requiring an Investigational Device Exemption (IDE), applicants are expected to provide confirmation of an existing IDE, or describe the status of any such pending regulatory submissions. If an IDE application is not submitted by the time of the grant application submission, the applicant is expected to describe the plan and timeline for submitting the request and obtaining the IDE prior to the initiation of a grant award. If the device is exempt from the IDE, the grant application is expected to include the justification and documentation for why the device would be exempt.

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

UG3/UH3 Phases of Research

This NOFO uses a phased innovation approach (UG3/UH3). In the UG3 phase, milestones must be designed around the next stage of device or treatment development. The UG3 phase provides support for up to two years with specific milestones determined by the investigator and expected to be accomplished by the end of the UG3 phase. At that time, the grant will undergo administrative review by NIDA staff to determine if the milestones are successfully accomplished. If they are, then the application may be awarded for up to three additional years of support (UH3 phase).

Milestones and UG3/UH3 Transition: Applicants must plan for both the UG3 and UH3 phase. The UG3 section must include a description of an entry point and the milestone(s) that will be reached at the end of the phase. The milestones must include quantifiable metrics to determine success of the UG3. To successfully transition to the UH3 phase, the project must reach the milestones outlined in the application. Additional milestone(s) may be negotiated before or after funding decisions are made.

The UG3 Phase

The UG3 phase must provide an entry and exit point (milestone) for the device and treatment in the FDA approval pathway. The focus should be on moving forward to the next stage of testing and validation.

The specific activities and milestones appropriate for the UG3 phase will depend on the type of intervention under study and its stage of development. Grant applications must provide clear, measurable milestones to be accomplished at the end of the UG3. Generally, these activities and milestones may include:

• Objective measures of the circuit-based target, including selectivity, and mechanism of action 
• Evidence that the measure(s) of target engagement can be reliably and validly manipulated in a dose-dependent fashion 
• Demonstration of adequate target engagement with established dose selection or stimulus range 
• Evidence that the intervention effects efficacy related endpoints, such as craving, dependence, or days of abstinence 
• Evidence that the intervention effects behavioral related endpoints, such as measures of working memory, impulsivity, risk-taking propensity, distress tolerance, self-regulation, or stress reactivity 
• Evidence that an adequate dose range/treatment duration for the intervention(s) can be applied with acceptable safety and tolerability 
• Completion of initial safety studies
• Q-submission to obtain FDA feedback on regulatory pathway
• Completion of pre-clinical and clinical IDE-enabling studies 
• Filing an IDE
• Completion of a proof-of-concept, feasibility clinical trial

The UH3 Phase

Funding for the UH3 phase is contingent on successfully meeting the milestones in the UG3 phase (see Section VI. Award Administration Information, 1. Award Notices for further information). The UH3 phase supports the next step in the development of the intervention. Applicants must provide the entry and exit points of the proposed research in the development continuum. The application is required to provide quantifiable milestones to determine success of the UH3.

Activities for the UH3 may include:

• Demonstration of the relationship between target engagement and functional outcomes, preferentially using dose-ranging studies;
• Demonstration of the relationship between changes in the circuit-based target and biomarkers/measures of brain function, domains of functions, and symptom/functional measures;
• Development of target engagement, brain function and symptom/functional measures. Endpoints may include measures of abstinence and decreased use, as well behavioral measures such as craving and dependence;
• Demonstration of the efficacy of the intervention based on generally accepted measures, such as abstinence;
• If a behavioral treatment is used integratively, demonstration of its effect on the outcome measure

Special Considerations

NIDA applicants are strongly encouraged to review the guidelines and adhere to the requirements applicable to their research listed in the Special Considerations for NIDA Funding Opportunities and Awards. Upon award, these considerations will be included in the Notice of Grant Award. 

Applications Not Responsive to this NOFO 

The following types of studies are not responsive to this NOFO and will not be reviewed:

• Any application without quantifiable milestones
• Applications that  do  not propose the inclusion of a device to treat SUDs either, alone or in combination with alcohol use disorder. 
• Applications that only involve alcohol use disorder

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

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

Section II. Award Information

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

Section III. Eligibility Information

1. Eligible Applicants

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Local Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized).

Federal Government

• 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 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

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.

• System for Award Management (SAM) – Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
  • NATO Commercial and Government Entity (NCAGE) Code – Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
  • Unique Entity Identifier (UEI) - A UEI is issued as part of the SAM.gov registration process. The same UEI must be used for all registrations, as well as on the grant application.
• eRA Commons - Once the unique organization identifier is established, organizations can register with eRA Commons in tandem with completing their Grants.gov registration; all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov – Applicants must have an active SAM registration in order to complete the Grants.gov registration.

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

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

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with their organization to develop an application for support. Individuals from diverse backgrounds, including underrepresented racial and ethnic groups, individuals with disabilities, and women are always encouraged to apply for NIH support. See, Reminder: Notice of NIH's Encouragement of Applications Supporting Individuals from Underrepresented Ethnic and Racial Groups as well as Individuals with Disabilities, NOT-OD-22-019.

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.

2. Cost Sharing

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

Number of Applications

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

The NIH will not accept duplicate or highly overlapping applications under review at the same time, per NIH Grants Policy Statement Section 2.3.7.4 Submission of Resubmission Application. This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see NIH Grants Policy Statement 2.3.9.4 Similar, Essentially Identical, or Identical Applications).

Section IV. Application and Submission Information

1. Requesting an Application Package

The application forms package specific to this opportunity must be accessed through ASSIST, 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.

Letter of Intent

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

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

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

The letter of intent should be sent to: NIDALetterofIntent@mail.nih.gov

Page Limitations

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

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.

SF424(R&R) Cover

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.

R&R Budget

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

R&R Subaward Budget

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

PHS 398 Cover Page Supplement

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

PHS 398 Research Plan

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

Research Strategy:

Investigators should describe how the project addresses an important problem or a critical barrier to progress in the field. Describe the scientific premise and indicate how scientific knowledge, technical capability, and/or clinical practice will be improved if the aims are achieved. Describe how successful completion of the aims may change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field. A strong design to allow for the validation or rejection of the neural target or device being tested must be integral to the study. Indicate how the characteristics and rationale of the project make it ready for the proposed phase of testing.

Without duplicating information in the biosketches, descriptions are required to show the investigators can work as a team and have the necessary methodological and statistical expertise to evaluate the proposed outcomes. The environment are required to support timely subject recruitment and completion of both the UG3 and UH3 phases.

Go/no-go milestones for the UG3 phase must be clear, quantitative and achievable. A successful UG3 phase should set the stage for the larger UH3 phase. Describe how the research strategy for the UG3 phase utilizes reliable, objective and valid measures of target engagement to definitively test the intervention's ability to modulate the target. The application is required to demonstrate how the UH3 phase plans to include a more focused study that will move the intervention forward. 

For applications proposing clinical trials

The scientific rationale and need for a clinical trial must be supported by preliminary data and information in the literature. Describe how the clinical trial is 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. If the trial focuses on mechanistic, behavioral, physiological, biochemical, or other biomedical endpoints, describe how the trial will advance scientific understanding.

Without duplicating information in the biosketches, address how 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. Describe the expertise in study coordination, data management and statistics. If the study involves a multicenter trial, describe how the organizational structure is appropriate and identify a core of potential center investigators and staffing for a coordinating center.

The study should be appropriate to address primary and secondary outcome variable(s)/endpoints that are clear, informative and relevant to the hypothesis being tested. Explain how the study is adequately powered and designed efficiently to answer the research question(s), test the proposed hypothesis/hypotheses, and provide interpretable results. The study should be appropriate and well justified for the populations (size, gender, age, demographic group), proposed intervention arms/dose, and duration of the trial. Address differences, if applicable, in the intervention effect due to sex/gender and race/ethnicity.

 Address the need for randomization (or not), masking (if appropriate), controls, and inclusion/exclusion criteria. Applications should discuss the plans to standardize, assure quality of, and monitor adherence to, the trial protocol and data collection or distribution guidelines.

The planned analyses and statistical approach should be appropriate for the proposed study design, methods used to assign participants, and deliver interventions. Include procedures for data management and quality control of data. Describe the methods for standardization of procedures for data management to assess the effect of the intervention and quality control. Data analysis should be completed within the proposed period of the award.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the How to Apply- Application Guide. 

Other Plan(s): 

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

• All applicants planning research (funded or conducted in whole or in part by NIH) that results in the generation of scientific data are required to comply with the instructions for the Data Management and Sharing Plan. All applications, regardless of the amount of direct costs requested for any one year, must address a Data Management and Sharing Plan.

Appendix: Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the How to Apply- Application Guide.

• No publications or other material, with the exception of blank questionnaires or blank surveys, may be included in the Appendix.

PHS Human Subjects and Clinical Trials Information

When involving human subjects research, clinical research, and/or NIH-definedclinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the How to Apply- Application Guide, with the following additional instructions:

If you answered “Yes” to the question “Are Human Subjects Involved?” on the R&R Other Project Information form, 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 How to Apply- Application Guide must be followed.

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).All instructions in the How to Apply-Application Guide must be followed.

PHS Assignment Request Form

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

Foreign Organizations

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

3. Unique Entity Identifier and System for Award Management (SAM)

See Part 2. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov.

4. Submission Dates and Times

Part I. 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 Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications.

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

Information on the submission process and a definition of on-time submission are provided in the How to Apply- Application Guide.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

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

Pre-award costs are allowable only as described in the NIH Grants Policy Statement Section 7.9.1 Selected Items of Cost.

Investigators should provide information regarding the specific regulatory pathway (e.g., will the project require an IDE) and a clear and feasible plan to address all regulatory requirements (e.g., describe the plan for a Q-submission to discuss the regulatory requirements with the FDA and receive their feedback). If an IDE is required, describe the specific plans to submit and obtain the FDA approval.

Applications must be submitted electronically following the instructions described in the How to Apply-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 How to Apply – Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

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

The applicant organization must ensure that the unique entity identifier provided on the application is the same identifier used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the How to Apply-Application Guide.

See more tips for avoiding common errors.

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

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

Send written disclosures to the NIH Chief Grants Management Officer listed on the Notice of Award for the IC that funded the award and to the HHS Office of Inspector Grant Self Disclosure Program at grantdisclosures@oig.hhs.gov.

Post Submission Materials

Applicants are required to follow the instructions for post-submission materials, as described in the policy

Section V. Application Review Information

1. Criteria

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

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). An application does not need to be strong in all categories to be judged likely to have a major scientific impact.

Review Criteria

Reviewers will consider Factors 1, 2 and 3 in the determination of scientific merit, and in providing an overall impact score. In addition, Factors 1 and 2 will each receive a separate factor score. 

Factor 1: Importance of the Research

Significance

• Evaluate the importance of the proposed research in the context of current scientific challenges and opportunities, either for advancing knowledge within the field, or more broadly. Assess whether the application addresses an important gap in knowledge in the field, would solve a critical problem, or create a valuable conceptual or technical advance.
• Evaluate the rationale for undertaking the study, the rigor of the scientific background for the work (e.g. prior literature and/or preliminary data) and whether the scientific background justifies the proposed study.

Innovation

• Evaluate the extent to which innovation influences the importance of undertaking the proposed research. Note that while technical or conceptual innovation can influence the importance of the proposed research, a project that is not applying novel concepts or approaches may be of critical importance for the field.
• Evaluate whether the proposed work applies novel concepts, methods or technologies, or uses existing concepts, methods, technologies in novel ways, to enhance the overall impact of the project.

Specific to this NOFO:

• Evaluate the strength of the design to allow for the validation or rejection of the neural target or device being tested. 
• Evaluate the extent to which the characteristics of the project that make it ready for the proposed phase of testing. 
• Evaluate the extent to which the proposed intervention has a strong, well-supported rationale that is ready for testing.

Factor 2. Rigor and Feasibility

Approach

• Evaluate the scientific quality of the proposed work. Evaluate the likelihood that compelling, reproducible findings will result (rigor) and assess whether the proposed studies can be done well and within the timeframes proposed (feasibility).

Rigor:

• Evaluate the potential to produce unbiased, reproducible, robust data.
• Evaluate the rigor of experimental design and whether appropriate controls are in place.
• Evaluate whether the sample size is sufficient and well-justified.
• Assess the quality of the plans for analysis, interpretation, and reporting of results.
• Evaluate whether the investigators presented adequate plans to address relevant biological variables, such as sex or age, in the design, analysis, and reporting.
• For applications involving human subjects or vertebrate animals, also evaluate:
  • the rigor of the intervention or study manipulation (if applicable to the study design).
  • whether outcome variables are justified.
  • whether the results will be generalizable or, in the case of a rare disease/special group, relevant to the particular subgroup.
  • whether the sample is appropriate and sufficiently diverse to address the proposed question(s).
• For applications involving human subjects, including clinical trials, assess the adequacy of inclusion plans as appropriate for the scientific goals of the research. Considerations of appropriateness may include disease/condition/behavior incidence, prevalence, or population burden, population representation, and/or current state of the science.

Feasibility:

• Evaluate whether the proposed approach is sound and achievable, including plans to address problems or new challenges that emerge in the work. For proposed studies in which feasibility may be less certain, evaluate whether the uncertainty is balanced by the potential for major advances.
• For applications involving human subjects, including clinical trials, evaluate the adequacy and feasibility of the plan to recruit and retain an appropriately diverse population of participants. Additionally, evaluate the likelihood of successfully achieving the proposed enrollment based on age, racial, ethnic, and sex/gender categories.
• For clinical trial applications, evaluate whether the study timeline and milestones are feasible.

Specific to this NOFO:

• Assess whether information is provided regarding the specific regulatory pathway (e.g., will the project require an IDE). 
• Evaluate whether the plan to address all regulatory requirements (e.g., the plan for a Q-submission to discuss the regulatory requirements with the FDA and receive their feedback; if an IDE is required, the specific plans to submit and obtain the FDA approval) are clear and feasible.
• Evaluate whether the plans regarding go/no-go milestones are quantitative and clear. 
• Assess whether the milestones can be achieved in the 2-year period of the UG3 grant. The UG3 phase should provide a design that will move the intervention appropriately forward to the larger UH3 phase. 
• For UG3 studies that are testing target engagement, evaluate whether the study is a rigorous test of target engagement. The research strategy should utilize reliable, objective and valid measures of target engagement to definitively test the intervention's ability to modulate the target.
• Evaluate the extent by which the UH3 phase will provide a more focused study that will move the intervention forward. Evaluate whether sufficient data will be collected in the UH3 phase to determine neuronal target validation, based on relationships between target engagement, measures of brain function and symptom or functional effects.
• Evaluate whether the investigative team has sufficient methodological and statistical expertise 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).

Factor 3. Expertise and Resources

Investigator(s)

• Evaluate whether the investigator(s) have demonstrated background, training, and expertise, as appropriate for their career stage, to conduct the proposed work. For Multiple Principal Investigator (MPI) applications, assess the quality of the leadership plan to facilitate coordination and collaboration.

Environment

• Evaluate whether the institutional resources are appropriate to ensure the successful execution of the proposed work.

Specific to this NOFO:

• Evaluate whether there is sufficient evidence that the investigators can work as a team. 
• Evaluate whether the environment will support timely subject recruitment and completion of both the UG3 and UH3 phases.

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.

Protections for Human Subjects

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

For research that involves human subjects and meets the criteria for one or more of the categories of research that are exempt under 45 CFR Part 46, 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.

Vertebrate Animals

When the proposed research includes Vertebrate Animals, evaluate the involvement of live vertebrate animals according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animals Section.

Biohazards

When the proposed research includes Biohazards, evaluate whether specific materials or procedures that will be used are significantly hazardous to research personnel and/or the environment, and whether adequate protection is proposed.

Resubmissions

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

Renewals

Not Applicable

Revisions

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

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.

Authentication of Key Biological and/or Chemical Resources:

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

Budget and Period of Support

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

2. Review and Selection Process

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

Potential ethical issues should be adequately addressed and the process for obtaining informed consent or assent appropriate. The plans for recruitment outreach, enrollment, retention, handling dropouts, missed visits, and losses to follow-up should be appropriate to ensure robust data collection. Ensure that the planned recruitment timelines are feasible and have an adequate the plan to monitor accrual. 

As part of the scientific peer review, all applications will receive a written critique.

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

Applications will be assigned to NIDA. Applications will compete for available funds with all other recommended applications submitted in response to this NOFO. Following initial peer review, recommended applications will receive a second level of review by the National Advisory Council on Drug Abuse. The following will be considered in making funding decisions:

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

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement Section 2.5.1. Just-in-Time Procedures. This request is not a Notice of Award nor should it be construed to be an indicator of possible funding.

Prior to making an award, NIH reviews an applicant’s federal award history in SAM.gov to ensure sound business practices. An applicant can review and comment on any information in the Responsibility/Qualification records available in SAM.gov.  NIH will consider any comments by the applicant in the Responsibility/Qualification records in SAM.gov to ascertain the applicant’s integrity, business ethics, and performance record of managing Federal awards per 2 CFR Part 200.206 “Federal awarding agency review of risk posed by applicants.”  This provision will apply to all NIH grants and cooperative agreements except fellowships.

3. Anticipated Announcement and Award Dates

After the peer review of the application is completed, the PD/PI will be able to access 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 Section 2.4.4 Disposition of Applications.

Section VI. Award Administration Information

1. Award Notices

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

In accepting the award, the recipient agrees that any activities under the award are subject to all provisions currently in effect or implemented during the period of the award, other Department regulations and policies in effect at the time of the award, and applicable statutory provisions.

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

Individual awards are based on the application submitted to, and as approved by, the NIH and are subject to the IC-specific terms and conditions identified in the NoA.

ClinicalTrials.gov: If an award provides for one or more clinical trials. By law (Title VIII, Section 801 of Public Law 110-85), the "responsible party" must register and submit results information for certain “applicable clinical trials” on the ClinicalTrials.gov Protocol Registration and Results System Information Website (https://register.clinicaltrials.gov). NIH expects registration and results reporting of all trials whether required under the law or not. For more information, see https://grants.nih.gov/policy/clinical-trials/reporting/index.htm

Institutional Review Board or Independent Ethics Committee Approval: Recipient institutions must ensure that all protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the recipient must provide NIH copies of documents related to all major changes in the status of ongoing protocols.

Data and Safety Monitoring Requirements: The NIH policy for data and safety monitoring requires oversight and monitoring of all NIH-conducted or -supported human biomedical and behavioral intervention studies (clinical trials) to ensure the safety of participants and the validity and integrity of the data. Further information concerning these requirements is found at http://grants.nih.gov/grants/policy/hs/data_safety.htm and in the application instructions (SF424 (R&R) and PHS 398).

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

2. Administrative and National Policy Requirements

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

• The rules listed at 2 CFR Part 200, Uniform Administrative Requirements, Cost Principles, and Audit Requirements for Federal Awards.
• All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the terms and conditions in the Notice of Award (NoA). The NoA includes the requirements of this NOFO. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Recipients, and Activities.
• If a recipient receives an award, the recipient must follow all applicable nondiscrimination laws. The recipient agrees to this when registering in SAM.gov. The recipient must also submit an Assurance of Compliance (HHS-690). To learn more, see the Laws and Regulations Enforced by the HHS Office for Civil Rights website.
  • HHS recognizes that NIH research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research. For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this NOFO.

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

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

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (HHS) grant administration regulations at 2 CFR Part 200, and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the recipients is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the recipients for the project as a whole, although specific tasks and activities may be shared among the recipients and NIH as defined below.

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

• Define objectives and approaches, planning, and directing the activities of the proposed plan for digital therapeutics development.
• Conduct of data analyses and publishing results, interpretations, and conclusions of research studies.
• Support the use and guiding the specific development of digital therapeutics and measures.
• All aspects of their study, including any modification of study design, conduct of the study, quality control, data analysis and interpretation, preparation of publications, dissemination of data, tools, and technologies, and collaboration with other investigators.
• Recipients will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies.

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

• Evaluate and provide guidance regarding the specific regulatory pathway (e.g., will the project require an IDE) and a clear and feasible plan to address all regulatory requirements (e.g., describe the plan for a Q-submission to discuss the regulatory requirements with the FDA and receive their feedback). If an IDE is required, describe the specific plans to submit and obtain the FDA approval. Information regarding the regulatory pathway should be included, and where the studies fall along the pathway for submission to FDA for review and regulatory approval.
• Monitor the operational milestones of the UG3/UH3 grant and making recommendations on project execution.
• Periodically review the progress of the UG3/UH3 grant and make recommendations on overall project direction.
• Assist the recipient as a liaison in stimulating their broader interactions with other NIH and federal programs to disseminate results and outcomes and effectively leverage existing NIH and NIDA resources and infrastructures.
• Additionally, a NIDA Program Official will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.

Areas of Joint Responsibility include:

The recipient and members of their scientific team, together with the Project Scientist, will meet at regular intervals to discuss all technical aspects of the project development. These aspects may include re-establishment of objectives during the course of the project as conditions change, and development of research result presentations and publications from the project.

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. It will have three members: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual recipient. This special dispute resolution procedure does not alter the recipient's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16

Consistent with the 2023 NIH Policy for Data Management and Sharing, when data management and sharing is applicable to the award, recipients will be required to adhere to the Data Management and Sharing requirements as outlined in the NIH Grants Policy Statement. Upon the approval of a Data Management and Sharing Plan, it is required for recipients to implement the plan as described.

4. Reporting

When multiple years are involved, recipients will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement Section 8.4.1 Reporting. To learn more about post-award monitoring and reporting, see the NIH Grants & Funding website, see Post-Award Monitoring and Reporting.

A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement Section 8.6 Closeout. NIH NOFOs outline intended research goals and objectives. Post award, NIH will review and measure performance based on the details and outcomes that are shared within the RPPR, as described at 2 CFR Part 200.301.

Section VII. Agency Contacts

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

eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten submission by the due date, and post-submission issues)

Finding Help Online: https://www.era.nih.gov/need-help (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-480-7075

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: support@grants.gov

Will M. Aklin, Ph.D.
National Institute on Drug Abuse (NIDA)
P hone: 301-827-5909
Email: aklinwm@nida.nih.gov

Katrina Foster, Ph.D.
National Institute on Drug Abuse (NIDA)
P hone: 301-827-5815
Email: katrina.foster@nih.gov

Dharmendar Rathore, PhD
National Institute on Drug Abuse (NIDA)
P hone: 301-402-6965
Email: dharmendar.rathore@nih.gov

Amy Connolly 
National Institute on Drug Abuse (NIDA)
P hone: 301 827-4457 
Email: amy.connolly@nih.gov

Section VIII. Other Information

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

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 2 CFR Part 200.