Participating Organization(s)
National Institutes of Health (NIH)
Components of Participating Organizations

National Institute of Mental Health (NIMH)

National Eye Institute (NEI)

National Institute on Aging (NIA)

National Institute on Alcohol Abuse and Alcoholism (NIAAA)

National Institute of Biomedical Imaging and Bioengineering (NIBIB)

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

National Institute on Deafness and Other Communication Disorders (NIDCD)

National Institute on Drug Abuse (NIDA)

National Institute of Neurological Disorders and Stroke (NINDS)

National Center for Complementary and Integrative Health (NCCIH)

Office of Research on Women’s Health (ORWH)

Funding Opportunity Title
BRAIN Initiative: Development of Novel Tools to Probe Cell-Specific and Circuit-Specific Processes in Human and Non-Human Primate Brain (UG3/UH3 Clinical Trial Optional)
Activity Code
UG3/UH3 Exploratory/Developmental Phased Award Cooperative Agreement
Announcement Type
New
Related Notices
None
Funding Opportunity Announcement (FOA) Number
RFA-MH-19-135
Companion Funding Opportunity
None
Catalog of Federal Domestic Assistance (CFDA) Number(s)
93.242, 93.867, 93.866, 93.273, 93.286, 93.865, 93.173, 93.213, 93.279, 93.853, 93.313   
Funding Opportunity Purpose
The purpose of this Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative funding opportunity announcement is to encourage applications that will develop and validate novel tools to facilitate the detailed analysis and manipulation of complex circuits in large brains. Critical advances in the treatment of brain disorders in human populations are hindered by our lack of ability to monitor and manipulate circuitry in safe, minimally-invasive ways. Clinical intervention with novel cell and circuit specific tools will require extensive focused research designed to remove barriers to delivery of gene therapies. In addition to identification and removal of barriers, the need to specifically target dysfunctional circuitry poses additional challenges. Neuroscience has experienced an impressive influx of exciting new research tools in the past decade, especially since the launch of the BRAIN Initiative. However, the majority of these cutting-edge tools have been developed for use in model organisms, primarily rodents, fish and flies. These cutting-edge tools, such as viral delivery of genetic constructs, are increasingly adaptable to larger mammalian brains and more importantly are emerging as potential human therapeutic strategies for brain disorders. A pressing need to develop tools for use in large brains or those that are more directly relevant to the human brain is the focus of this initiative. The initiative will support initial proof of principle studies aimed at demonstrating the feasibility of this approach in humans and other mammalian species (non-human primate [NHP]/sheep/pigs).
Posted Date
August 2, 2018
Open Date (Earliest Submission Date)
September 09, 2018
Letter of Intent Due Date(s)
30 days prior to the application due date.
Application Due Date(s)
October 9, 2018; September 26, 2019 and September 28, 2020 , by 5:00 PM local time of applicant organization. All types of non-AIDS applications allowed for this funding opportunity announcement are due on these dates.

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.

AIDS Application Due Date(s)
Not Applicable
Scientific Merit Review
March 2019, March 2020, March 2021
Advisory Council Review
May 2019, May 2020, May 2021
Earliest Start Date
July 2019, July 2020, July 2021
Expiration Date
September 29, 2020
Due Dates for E.O. 12372
Not Applicable
Required Application Instructions
It is critical that applicants follow the instructions in the Research (R) Instructions in the SF424 (R&R) Application Guide,except where instructed to do otherwise (in this FOA or in a Notice from NIH Guide for Grants and Contracts ).

Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions.

Applications that do not comply with these instructions may be delayed or not accepted for review.

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

  1. Use the NIH ASSIST system to prepare, submit and track your application online.
  2. Use an institutional system-to-system (S2S) solution to prepare and submit your application to Grants.gov and eRA Commons to track your application. Check with your institutional officials regarding availability.

  3. Use Grants.gov Workspace to prepare and submit your application and eRA Commons to track your application.
  4. Table of Contents

Background

The Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative® is aimed at revolutionizing our understanding of the human brain. By accelerating the development and application of innovative technologies, researchers will be able to produce a new dynamic picture of the brain that, for the first time, will show how individual cells and complex neural circuits interact in both time and space. It is expected that the application of these new tools and technologies will ultimately lead to new ways to treat and prevent brain disorders.

NIH is one of several federal agencies involved in the BRAIN Initiative. Planning for the NIH component of the BRAIN initiative is guided by the long-term scientific plan, “BRAIN 2025: A Scientific Vision,” which details seven high-priority research areas and calls for a sustained federal commitment of $4.5 billion over 12 years. This funding opportunity announcement (FOA) and other FOAs issued as part of the BRAIN initiative are based on careful consideration by the NIH of the recommendations of the BRAIN 2025 Report, and input from the NIH BRAIN Multi-Council Working Group. Videocasts of the NIH BRAIN Multi-council Working Group are available at http://www.braininitiative.nih.gov/about/mcwg.htm.

To enable rapid progress in development of new technologies as well as in theory and data analysis, the BRAIN Initiative encourages collaborations between neurobiologists and scientists from statistics, physics, mathematics, engineering, and computer and information sciences; NIH welcomes applications from investigators in these disciplines.

Milestones and success criteria will be established to help determine if the tool/method development effort funded by this award should be continued or discontinued. If justified, future year milestones may be revised based on data and information obtained in the current year. In addition to milestones, the decision regarding continued funding will also be based on the robustness of the entire data package that adequately allows an interpretation of the results, overall progress, NIH BRAIN Initiative portfolio balance, program priorities, competitive landscape, and availability of funds. Therefore, continuation is based upon all available evidence at annual review that there remains a reasonable expectation that the project will achieve the goal initially judged to be meritorious by peer review.

NIH encourages BRAIN Initiative applications from investigators that are underrepresented in the biomedical, behavioral, or clinical research workforce (see data at http://www.nsf.gov/statistics/showpub.cfm?TopID=2&SubID=27 and the most recent report on Women, Minorities, and Persons with Disabilities in Science and Engineering). Such individuals include those from underrepresented racial and ethnic groups, those with disabilities, and those from disadvantaged backgrounds. 

NIH also encourages businesses to participate in the BRAIN Initiative. It is possible for companies to submit applications directly to BRAIN Initiative program announcements or to collaborate with academic researchers in joint submissions. Small businesses should consider applying to one of the BRAIN Initiative small business FOAs (http://braininitiative.nih.gov/funding/index.htm).

In addition to the National BRAIN initiative, the NIH continues to have a substantial annual investment in neuroscience research. The Institutes and Centers contributing to the NIH BRAIN Initiative (http://braininitiative.nih.gov/ ) support those research efforts through investigator-initiated applications as well as through specific FOAs. Potential applicants to this FOA are strongly encouraged to contact Scientific/Program staff if they have any questions about the best FOA for their research.

The BRAIN Initiative will require a high level of coordination and sharing between investigators to achieve its goals.

This FOA is related to the Recommendations in Section III.1 and 2 of the Final Report (http://www.nih.gov/science/brain/2025/index.htm) of the BRAIN working group. Specifically, this FOA solicits applications that will address the recommendations on "Discovering Diversity" and "Maps at Multiple Scales", (Section III).

Research Objectives

This FOA is designed to support development and validation of novel tools to facilitate the detailed analysis and/or manipulation of cells and circuits and provide insights into the neural circuitry and structure underlying complex behaviors in humans and non-human primates and other mammalian brains (e.g., sheep, pig). The human brain consists of an estimated one hundred billion neurons and similar number of supporting glial cells that are uniquely organized to confer the extraordinary computational activities of the brain. Considerable progress has been made in defining the cytology and signal transduction processes in the CNS, but circuit-level function and the neural mechanisms of cognition and behavior remain poorly understood. Cell-type and circuit-specific manipulation strategies are key technical factors in addressing these important areas and represent attractive strategies to treat brain disorders. This initiative is focused on developing tools (or vastly improving existing tools) that will ultimately enable access to individual cells and defined groups of cells within neuronal circuits of the human brain. In order to achieve these goals, it is acknowledged that the use of large brains such as non-human primates, sheep and pig will be instrumental in this process. Development of tools that are applicable to human or non-human primate brains should focus on overcoming barriers to use of such tools (i.e., opto/chemo and magnetogenetic acutators). The tools sought through this FOA can include novel genetic or non-genetic methods for targeted delivery of genes, proteins, and chemicals to specific cells or tightly defined cell types and circuits.

Development of novel tools that will delineate anatomical connections between cells and expand our knowledge of circuit architecture and function is an area well poised for additional investment. Several efforts are currently underway to study large-scale, long-range connections, such as the NIH Human Connectome Project, as well as large scale rodent connectional studies. Recent development of innovative technologies (e.g., CLARITY, expansion microscopy, MERFISH, and several other imaging breakthroughs) allows an unprecedented three-dimensional view into the post-mortem brain. While still at an early stage, these exciting technologies hold promise for mapping short- and long-range connections throughout the brain. Coupled with improved activity monitoring technologies in awake, behaving animals, these new tools promise an understanding of circuitry in action. Further development of these technologies is crucial to push the envelope beyond our current capabilities. To this end, applicants from the biological sciences are encouraged to establish collaborations with engineers, chemists, material scientists, nanobiologists, and colleagues in other disciplines to develop groundbreaking approaches to study brain activity.

This FOA solicits applications to develop next-generation, innovative technologies to define and target specific cell types in the large mammalian and non-human primate brain. Of high importance are first-in-class and/or cross-cutting non-invasive or minimally invasive techniques that permit repeated measurements from and manipulations of cells over time in a non-destructive manner.

Tools/technologies relevant for this initiative are expected to be transformative, either through the development of novel tools that may be high-risk or through major advances in current approaches that break through technical barriers and will significantly improve current capabilities. While an emphasis of the BRAIN initiative is the development of novel tools to study the brain, here we highlight the need for innovative approaches to bridge experimental scales. Studies that can explore molecular and cellular mechanisms of neural activity permitting improved precision and sensitivity in the analysis of micro-and macro-circuits are strongly encouraged. Progress in understanding how the activity of the brain translates to complex behaviors will be facilitated by non-invasive approaches for both monitoring and manipulating neural activity in awake, behaving mammals. The ultimate practical goal of this FOA is to move these tools in to practice. The phased award will be dependent on milestones proposed by applicants and agreed upon at time of award. Validation of methods or tools in other organisms will only be considered responsive during the UG3 phase of the award and should focus on feasibility measures to move into human or non-human primate models during the UH3 phase. Milestones must be proposed that will demonstrate feasibility for moving into large brains during Year 3 of the award. The new tools and technologies should inform and/or exploit cell-type and/or circuit-level specificity. Plans for validating the utility of the tool/technology will be an essential feature of a successful application and applicants are expected to address issues related to safety, stability, reliability etc. The development of new genetic and non-genetic tools for delivering genes, proteins and chemicals to cells of interest or approaches that are expected to target specific cell types and/or circuits in the nervous system with greater precision and sensitivity than currently established methods are encouraged. Methods to track and monitor exogenously delivered constructs for brain targeting and circuit manipulation are also desired goals. Applications that provide approaches that break through existing technical barriers to substantially improve current capabilities are highly encouraged.

Applications using invasive devices for recording or stimulating neural activity in the human brain should consider one of the following BRAIN Initiative FOAs, and should contact the listed research contact to discuss the appropriateness of the project:

RFA-NS-18-021: BRAIN Initiative:  Next-Generation Invasive Devices for Recording and Modulation in the Human Central Nervous System (UG3/UH3 Clinical Trial Required)

RFA-NS-18-023: BRAIN Initiative:  Clinical Studies to Advance Next-Generation Invasive Devices for Recording and Modulation in the Human Central Nervous System (UH3 Clinical Trial Required)

RFA-NS-18-022, BRAIN Initiative: Next-Generation Invasive Devices for Recording and Modulation in the Human Central Nervous System (U44 Clinical Trial Required)

Research Scope

This FOA will support the phased development and validation of novel tools to facilitate the detailed analysis and/or manipulation of cells and circuits and provide insights into the neural circuitry and structure underlying complex behaviors in humans and non-human primates. Support will be provided for the initial development phase and can be continued through the validation and application phase if a rigorous set of milestones are achieved. For all tools and methods proposed, applicants should address issues related to safety stability, reliability and/or other relevant topics that may be barriers to adaptation in human or non-human primate brains.   

This FOA seeks applications in areas including, but not limited to:

  • Improving the stability, reliability, or safety of circuit therapeutic tools for use in large animal brains (including sheep, pig, and primate models).
  • Novel methods with high safety profiles to deliver actuators (non-genetic and genetic) that are cell- and circuit-specific in human and non-human primates.
  • Novel conditional intersectional tools that are both activity- and cell-specific.
  • Novel methods for tagging individual neurons such that cellular components of a functional circuit can be explored.
  • Adaptation, refinement and validation of gene delivery systems for targets in large brains (e.g., human and non-human primate).
  • Chemical or genetic engineering of blood brain barrier-crossing carrier agents (such as tagged antibodies or other tools) to allow delivery of specific cargoes (e.g., neuronal actuators, effectors, tracers or sensors) to specific cells or circuits.
  • Novel methods for non-invasive targeted access to, or manipulation of, distinct cell types in defined circuits with spatio-temporal control.
  • Novel trans-synaptic tracers that can work in retrograde and anterograde direction or deliver cargoes to cells in the nervous system.
  • New methods to trace cell lineage to understand how circuits develop.
  • Enhanced temporal and spatial resolution techniques for noninvasive molecular imaging of neuronal cells for in situ brain studies.
  • Unique combinations of tools for multiplex analysis and/or manipulation of single cells in situ to maximize data content over many parameters (e.g., RNAs, proteins, metabolites, organelles, electrochemical dynamics, signal secretion/reception/transduction, cytoarchitecture or migratory changes).
  • Innovative tools that provide significant advances in sensitivity, selectivity or spatiotemporal resolution of molecules/structures/activities within single cells in the brain and between ostensibly similar cells in situ (e.g., high resolution imaging of molecular interactions within single cells).
  • Novel automated and scalable assays for high-throughput analysis of single cells in situ in the brain, including scalability of measured parameters in parallel, cell numbers and/or speed of processing.
  • New tools and approaches that minimize tissue and cell perturbations so that cell viability is maintained, allowing for multiple repeated measures in the same cell over time.
  • Novel methods for visualizing or manipulating epigenomic marks or gene expression in neural cells.
  • Innovative approaches to bridge scales of experimental approach. Studies that can explore molecular and cellular mechanisms of neural activity in broader contexts are encouraged.
  • Innovative molecular complementation methods to identify synaptic connections and determine their phenotypes.
  • Development of cell type-specific molecular sensors and additional tools and approaches to address circuit-specific manipulation and monitoring. Validation could include behavioral measures.
  • Generation of genetic modifications that express cell type-specific labels such as fluorescent indicators or other markers.

Applications will be considered non-responsive and will not be reviewed if they propose:

  • To develop tools or approaches that use organisms other than large brain mammals or non-human primates, except in the UG3 phase where some feasibility studies may be warranted.
  • Studies to develop transgenic models of disease.
  • Projects whose main goal is to address a scientific question(s).

The UG3/UH3 is a two-phased award. The UG3 phase should be focused on the development of the tool, method, or approach, including demonstrating feasibility for use in humans. Each phase will be milestone driven and only those projects attaining the UG3 milestones have potential to progress to the UH3 phase. The UG3 phase supports feasibility, safety, biocompatibility testing and optimization of tools in large brains (e.g., sheep, pig) as well as non-human primates and humans if possible. The initial UG3 phase could support non-clinical testing toward filing of an IND/IDE for a significant risk (SR) study or to obtain IRB approval for a non-significant risk (NSR) clinical trial. Only those UG3 projects that have met specific criteria (see below) will transition to the subsequent UH3 phase after NIH administrative review. The UH3 phase could support a small clinical trial. The UH3 phase supports testing/validation of the tools in efforts to evaluate the performance, sensitivity, and selectivity of the tool(s) in humans or non-human primates.

1.   UG3 Tool Development Phase

The UG3 Phase of this FOA supports milestone-driven tool development. The applicant should describe the specific tool, its potential, and what developments are required to translate the tool to larger animal or human brains. Tools that meet the scientific milestones and feasibility requirements will be eligible for transition to the second UH3 stage pending NIH administrative review, availability of funds, and programmatic balance as described below. For applications wishing to perform human studies in the UH3 phase, a detailed regulatory pathway pre-clinical testing plan with commensurate milestones must be included. Regulatory milestones include pre-submission meetings where pre-clinical testing is discussed with the FDA as well as further pre-IND/IDE meetings. Relationships with industry partners that may be necessary for clinical testing should be described. An IND/IDE will be required for the UH3 transition prior to the start of any clinical trials.

2.  UH3 Tool Evaluation and Validation Phase

The UH3 Phase of the FOA will support milestone-driven evaluation and validation of tool performance. This phase should evaluate the tool's capability as well as performance in the context of large brains. Capability can be demonstrated by the ability to target, manipulate, record, or otherwise impact brain circuitry in a measurable fashion. Performance should be evaluated by the tool's stability, safety, reliability, or other similar metrics tested within a large brain construct. Validation should extend the tool's use outside of the primary investigators' lab to assess performance across multiple constructs. Different variants within a species and trans-species testing may be used to demonstrate generalizability. While not required for this FOA, applications that propose independent evaluation of the tool by outside laboratories will be prioritized. For applications proposing clinical studies, detailed milestones focusing on patient recruitment, retention, safety, and performance metrics should be included.

Applicants are strongly encouraged to consult the appropriate Scientific/Research Contact, listed below, to discuss the alignment of their proposed work with BRAIN Initiative Program goals.

Milestones and Go/No-Go Criteria

Because tool/technology development in the UG3 phase is likely to be high risk, it is anticipated that there will be attrition of some projects after the development phase (UG3). Objective milestones of success and go/no-go rules for tool optimization/validation will be required and both should have quantitative criteria associated with them (see Section IV.2 for details). Milestones are defined as annual goals while the Go/No-Go criteria are defined as the major goals to be met to inform the UG3 to UH3 transition.

Specific Go/No-Go criteria should be detailed at the UG3 to UH3 phase transition. Projects that seek to test first-in-human during the UH3 phase should have regulatory approval as their major Go/No-Go criteria. Projects that will focus on animal-model validation in the UH3 should detail specific performance metrics to be obtained in the UG3 phase prior to transition.

NIH program staff will contact the applicant to discuss and negotiate the proposed milestones and any changes recommended prior to funding the application. The final agreed upon and approved milestones will be specified in the Notice of Award (NoA). Progress towards achievement of the final set of milestones will be evaluated by NIH program staff. Program staff may involve independent consultants with relevant expertise. If justified, future milestones may be revised based on data and information obtained during the previous project period. If, based on the progress report, a funded project does not meet the milestones, funding for the project will be discontinued. In addition to milestones, the decision regarding continued funding will also be based on the overall robustness of the entire data package that adequately allows an interpretation of the results (regardless if they have been captured in the milestones), overall progress, portfolio balance and program priorities, competitive landscape, and availability of funds.

NIH encourages increasing the rigor and reproducibility of observed results. In some cases, conducting additional critical experiments will be important for NIH to have confidence in making a funding decision. Therefore, program staff may suggest modification or additional experiments that need to be conducted prior to or during the award as an additional milestone(s). In most cases, these studies will be supported by additional funds.

UG3 phase to UH3 phase transition:

An administrative review will be conducted by program staff, with potential input by independent consultants, to decide whether a UG3 phase project will be transitioned into the UH3 phase based on the:

  • successful achievement of the defined milestones for the UG3 phase of the project;
  • likelihood of success in further pre-clinical/clinical validation testing;
  • competitive landscape;
  • program balance;
  • availability of funds;
  • for significant risk studies, submission of an IND/IDE for the clinical trial with documentation of final or conditional approval of the IDE from the FDA;
  • IRB approval(s), if necessary;
  • for clinical studies, submission of the final clinical protocol and supporting documents to NIH for administrative review, and notification of approval by NIH;
  • feedback on activities involving human subjects obtained from relevant NIH human subject protection bodies;
  • agreement on updated timeline, milestones and budget for the UH3 phase

Appeals of the transition decision will not be accepted.

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

Appeals of the transition decision will not be accepted.
See Section VIII. Other Information for award authorities and regulations.
Funding Instrument
Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, NIH scientific or program staff will assist, guide, coordinate, or participate in project activities. See Section VI.2 for additional information about the substantial involvement for this FOA.
Application Types Allowed
New
Resubmission
Revision

The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.

Clinical Trial?
Optional: Accepting applications that either propose or do not propose clinical trial(s)

Need help determining whether you are doing a clinical trial?

Funds Available and Anticipated Number of Awards
Issuing IC and partner components intend to commit an estimated total of $10,000,000 to fund 6-9 awards.
Award Budget
Application budgets are not limited but need to reflect the actual needs of the proposed project.
Award Project Period
The duration of the UG3 phase cannot exceed 3 years and the total duration of the UG3/UH3 phases combined may not exceed 5 years.
NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from this FOA.

1. Eligible Applicants

Eligible Organizations

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)

Governments

  • State Governments
  • County Governments
  • City or Township Governments
  • Special District Governments
  • Indian/Native American Tribal Governments (Federally Recognized)
  • Indian/Native American Tribal Governments (Other than Federally Recognized)
  • Eligible Agencies of the Federal Government -including the NIH Intramural Program
  • U.S. Territory or Possession
Other
  • Independent School Districts
  • Public Housing Authorities/Indian Housing Authorities
  • Native American Tribal Organizations (other than Federally recognized tribal governments)
  • Faith-based or Community-based Organizations
  • Regional Organizations
  • Non-domestic (non-U.S.) Entities (Foreign Institutions)
Foreign Institutions

Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply

Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement, are allowed. 
Required Registrations

Applicant organizations

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

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

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

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

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 his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

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

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.  This means that the NIH will not accept:

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

1. Requesting an Application Package

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

2. Content and Form of Application Submission

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

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

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:
 
Michelle Freund, Ph.D.
National Institute of Mental Health
Telephone: 301-443-1815
Email: BRAIN-info-NIMH@mail.nih.gov

Page Limitations
All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed
Instructions for Application Submission
The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.
SF424(R&R) Cover
All instructions in the SF424 (R&R) Application Guide must be followed.
SF424(R&R) Project/Performance Site Locations
All instructions in the SF424 (R&R) Application Guide must be followed.
SF424(R&R) Other Project Information
All instructions in the SF424 (R&R) Application Guide must be followed.
SF424(R&R) Senior/Key Person Profile
All instructions in the SF424 (R&R) Application Guide must be followed.
 

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

Budget Justification: For each budget year, indicate if the requested budget is for the UG3 phase or the UH3 phase. The UG3 and UH3 cannot be funded in the same fiscal year.

The UG3/UH3 budget may include travel costs for one or two trips per year to attend meetings of the BRAIN Initiative.

It is expected that the PD/PI or each PD/PI on a multiple PD/PI application will dedicate at least 15% level of effort (1.8 person months) to managing the project.

R&R Subaward Budget
All instructions in the SF424 (R&R) Application Guide must be followed.
PHS 398 Cover Page Supplement
All instructions in the SF424 (R&R) Application Guide must be followed.
PHS 398 Research Plan
All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions: Specific Aims: 

Provide the overall goals for the entire application. The Specific Aims section should include distinct Aims for the UG3 and UH3 phases. All applications are required to include both UG3 and UH3 phases.

Research Strategy: Organize the Research Strategy in the subsections identified below, addressing all specific points below.

UG3 Tool Development Phase

The specific improvements to be made, such as stability, reliability, safety, should be described in detail. Applicants should provide a detailed plan that includes critical steps required for successful development of their tool. UG3 projects are milestone driven and include milestones' criteria for each proposed tool, or stage of development if appropriate that will be used to determine whether there is likelihood for successful translation to larger brain.

Applicants should describe both the UG3 phase and the UH3 phase within these subsections as described, including milestones.

Significance:  

  • Discuss the need for the tool to further research in human and non-human primate brain
  • Describe ways in which the tool(s) will advance the field
  • Does the tool or technology confer a high degree of cell or circuit-specificity? Has the current state of the art been accurately described? Would the proposed tool significantly advance current capabilities? Does the tool have the potential to be applied in humans? Will the proposed study be significant to developing and validating novel tools to analyze cell-specific and circuit-specific processes in the human brain? 

Innovation: 

  • Explain how the project offers a novel approach to monitor and manipulate brain activity in human and non-human primate brain
  • Discuss feasibility to overcome current obstacles
  • Does the proposed work address existing barriers?
  • Will the proposed tool enable discovery related to brain circuitry underlying complex behaviors?
  • Are the proposed tools/technologies potentially transformative either through the development of novel tools that may be high-risk or through major advances in current approaches that break through technical barriers and will significantly improve current capabilities? 

Approach:  This section should cover the application, as a whole, as well as the UG3/UH3 phases with the appropriate headers within the text.

  • Are the appropriate studies included to validate the technology?
  • Is a sound rationale provided as to why the approach proposed is the most appropriate and is likely to generate an exceptionally high impact if successful?
  • Does the application address issues related to safety, stability, reliability and/or other relevant topics that may be barriers to adaptation in human or non-human primate brains?

Current State-of-the-Art Statement: Investigators should specifically define the current state of technology as a benchmark against which their proposed groundbreaking technology or improvements will be measured. Preliminary/feasibility data are not required or expected for early-stage, high-risk projects. However, a sound rationale should be provided as to why the approach proposed is the most appropriate and likely to generate an exceptionally high impact if successful. In these cases, more emphasis should also be placed in details of the approach, particularly feasibility-testing. Applicants are expected to explain the specific biological assay(s) to be utilized in the application to validate the new tool in proof-of-concept testing. Applicants are expected to address if proposed tool(s) have the potential to be applied in multiple model species. The tools should enable analysis of brain circuitry underlying complex behaviors.

Project Timeline (Gantt chart): A project timeline should be included as part of the Research Strategy and should include a distinct final section, entitled “Milestones”, that briefly proposes indicators of progress at critical junctures. These should be tailored to the unique scope of each project and written concretely enough to evaluate what exactly will have been achieved (e.g., crucial steps in tool making) over the duration the project. Given that projects are likely to be early stage and high-risk in nature, this should include the specific proof-of-concept test(s) that will indicate whether/how a proposed tool actually “works”, along with alternative strategies should that effort fail to perform as expected. Tests should include a comparison against existing benchmark technologies; if a tool is truly first-in-class, comparisons may be done against a nearest neighbor technology. Investigators should briefly note how results will be used to inform future phases of tool development such as testing in other model systems or in non-human primate or human brain.  Note:  This timeline is distinct from the Clinical Trials Study Timeline (if applicable).

Milestones:  As part of the application, projects should include quantitative milestones and go/no-go decision points. Applicants must describe milestones to be used for measuring success in achieving each of the research plan's objectives. One or more milestones should be used for each objective. Details on methods, assumptions, experimental designs, and data analysis plans (if the results are quantitatively measured) should be included for each milestone. Applicants are expected to include quantitative criteria for measuring success and the rationale for the quantitative criteria. Quantitative criteria should be robust and consistent with the state-of-the-art in the field. Each milestone must have a timeline, and be incorporated into the overall project timeline, which should also be reflected in a Gantt chart. There should be at least one milestone proposed for completion at the end of each year. Strategies for alternative approaches should be discussed in detail. Technology development is inherently risky, but probability of success is greatest when potential hurdles are anticipated and contingency plans are in place. A Milestone report from the Principal Investigator will be submitted to the NIMH Grants Management Branch 60 days before the Budget End date. The Milestone report will be included in the non-competing year progress report via RPPR. Please note that milestone/progress reports should include an executive summary of progress and milestone achievement, followed by a more detailed description of progress which explains and justifies the use of all selected study parameters or objectives, including but not limited to, number of animals used per study (stratified by gender if applicable), statistical analysis used and assumptions, rules for inclusion/exclusion of animals or data, randomization/blinding details, before demonstrating how study results conform or corroborate each parameter or objective. This information will be used by NIH program staff to evaluate the overall robustness of the data package and path forward.

Applications lacking clearly described timelines for the UG3 and the UH3 phase, as well as Milestones will be considered incomplete and will not be reviewed.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide.

The following modifications also apply:

While it is understood that many tools will be at an early proof-of-concept stage, a central goal of this FOA is to generate transformative tools that will be widely used throughout the research community. Applications that propose to generate such tools are expected to include a detailed plan for sharing these resources and expected to include the following key elements:

  • Project management of resource sharing;
  • Description of what specific resources will be shared (e.g., model organisms, reagents, completed tools or repurposed components);
  • Schedule/timeline for availability of resources to other users;
  • Persons who will have access to the resources (written as broadly as possible to the extent consistent with applicable laws, regulations, rules, and policies);
  • Plan for post award disposition of resources.
  • Investigators are strongly encouraged to obtain a research resource ID from the Resource Identification Initiative (http://scicrunch.com/resources/info/add) and to use Resource IDs in their publications if available. (http://scicrunch.com/resources ).
Appendix:
Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.
PHS Human Subjects and Clinical Trials Information
When involving NIH-defined human subjects research, clinical research, and/or clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

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

Study Record: PHS Human Subjects and Clinical Trials Information

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

Delayed Onset Study

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

PHS Assignment Request Form
All instructions in the SF424 (R&R) Application Guide must be followed.
 
Foreign (non-U.S.) institutions must follow policies described in the NIH Grants Policy Statement, and procedures for foreign institutions described throughout the SF424 (R&R) Application Guide.
 

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

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

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 Policy on Late Application Submission.

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

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

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.

7. Other Submission Requirements and Information

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

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

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

Important reminders:

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

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

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.
In order to expedite review, applicants are requested to notify the NIMH Referral Office by email at nimhpeerreview@mail.nih.gov when the application has been submitted. Please include the FOA number and title, PD/PI name, and title of the application.

Applications Involving the NIH Intramural Research Program

The requests by NIH intramural scientists will be limited to the incremental costs required for participation. As such, these requests will not include any salary and related fringe benefits for career, career conditional or other Federal employees (civilian or uniformed service) with permanent appointments under existing position ceilings or any costs related to administrative or facilities support (equivalent to Facilities and Administrative or F&A costs). These costs may include salary for staff to be specifically hired under a temporary appointment for the project, consultant costs, equipment, supplies, travel, and other items typically listed under Other Expenses. Applicants should indicate the number of person-months devoted to the project, even if no funds are requested for salary and fringe benefits.

If selected, appropriate funding will be provided by the NIH Intramural Program. NIH intramural scientists will participate in this program as PDs/PIs in accord with the Terms and Conditions provided in this FOA. Intellectual property will be managed in accord with established policy of the NIH in compliance with Executive Order 10096, as amended, 45 CFR Part 7; patent rights for inventions developed in NIH facilities are NIH property unless NIH waives its rights.

Should an extramural application include the collaboration with an intramural scientist, no funds for the support of the intramural scientist may be requested in the application. The intramural scientist may submit a separate request for intramural funding as described above.
Post Submission Materials
Applicants are required to follow the instructions for post-submission materials, as described in the policy. Any instructions provided here are in addition to the instructions in the policy.

1. Criteria

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

In addition, for applications involving clinical trials:

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

For this particular announcement, note the following:

The UG3/UH3 is a two phased mechanism. Each phase is milestone driven and only those projects attaining the UG3 milestones have potential to progress to the UH3 phase. The UG3 phase supports feasibility testing and optimization of measures in animals and humans.  The UG3 phase need not have extensive preliminary data. Accordingly, reviewers will focus their evaluation on the conceptual framework, the level of innovation, the potential for addressing the challenges of moving technologies developed in small model organisms into humans and the adequacy of the approach for demonstrating feasibility into large, mammalian brain (e.g, pig, non-human primate and human). The novel technology sought in this FOA is expected to be at the earliest stage of development, prior to empirical studies of proof-of-concept or preliminary data. Transition to the second phase will be dependent on attaining milestones defined for the UG3 phase.

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

 

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

Does the tool or technology confer a high degree of cell or circuit-specificity? Has the current state of the art been accurately described? Would the proposed tool significantly advance current capabilities? Does the tool have the potential to be applied in humans? Will the proposed study be significant to developing and validating novel tools to analyze cell-specific and circuit-specific processes in the human brain? 

In addition, for applications involving clinical trials

Are the scientific rationale and need for a clinical trial to test the proposed hypothesis or intervention well supported by preliminary data, clinical and/or preclinical studies, or information in the literature or knowledge of biological mechanisms? For trials focusing on clinical or public health endpoints, is this clinical trial necessary for testing the safety, efficacy or effectiveness of an intervention that could lead to a change in clinical practice, community behaviors or health care policy? For trials focusing on mechanistic, behavioral, physiological, biochemical, or other biomedical endpoints, is this trial needed to advance scientific understanding?

 

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or those in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

In addition, for applications involving clinical trials

With regard to the proposed leadership for the project, do the PD/PI(s) and key personnel have the expertise, experience, and ability to organize, manage and implement the proposed clinical trial and meet milestones and timelines? Do they have appropriate expertise in study coordination, data management and statistics? For a multicenter trial, is the organizational structure appropriate and does the application identify a core of potential center investigators and staffing for a coordinating center?   

 

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

Does the proposed work address existing barriers? Will the proposed tool enable discovery related to brain circuitry underlying complex behaviors? Are the proposed tools/technologies potentially transformative either through the development of novel tools that may be high-risk or through major advances in current approaches that break through technical barriers and will significantly improve current capabilities?  

In addition, for applications involving clinical trials

Does the design/research plan include innovative elements, as appropriate, that enhance its sensitivity, potential for information or potential to advance scientific knowledge or clinical practice?

 

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

Are the appropriate studies included to validate the technology? Is a sound rationale provided as to why the approach proposed is the most appropriate and is likely to generate an exceptionally high impact if successful? Does the application address issues related to safety, stability, reliability and/or other relevant topics that may be barriers to adaptation in human or non-human primate brains

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

 In addition, for applications involving clinical trials

Does the application adequately address the following, if applicable

Study Design

Is the study design justified and appropriate to address primary and secondary outcome variable(s)/endpoints that will be clear, informative and relevant to the hypothesis being tested? Is the scientific rationale/premise of the study based on previously well-designed preclinical and/or clinical research? the study design adequately powered to answer the research question(s), test the proposed hypothesis/hypotheses, and provide interpretable results? Is the trial appropriately designed to conduct the research efficiently? Are the study populations (size, gender, age, demographic group), proposed intervention arms/dose, and duration of the trial, appropriate and well justified?

Are potential ethical issues adequately addressed? Is the process for obtaining informed consent or assent appropriate? Is the eligible population available? Are the plans for recruitment outreach, enrollment, retention, handling dropouts, missed visits, and losses to follow-up appropriate to ensure robust data collection? Are the planned recruitment timelines feasible and is the plan to monitor accrual adequate? Has the need for randomization (or not), masking (if appropriate), controls, and inclusion/exclusion criteria been addressed? Are differences addressed, if applicable, in the intervention effect due to sex/gender and race/ethnicity?

Are the plans to standardize, assure quality of, and monitor adherence to, the trial protocol and data collection or distribution guidelines appropriate? Is there a plan to obtain required study agent(s)? Does the application propose to use existing available resources, as applicable?

Data Management and Statistical Analysis

Are planned analyses and statistical approach appropriate for the proposed study design and methods used to assign participants and deliver interventions? Are the procedures for data management and quality control of data adequate at clinical site(s) or at center laboratories, as applicable? Have the methods for standardization of procedures for data management to assess the effect of the intervention and quality control been addressed? Is there a plan to complete data analysis within the proposed period of the award?

 

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

In addition, for applications involving clinical trials

If proposed, are the administrative, data coordinating, enrollment and laboratory/testing centers, appropriate for the trial proposed?

Does the application adequately address the capability and ability to conduct the trial at the proposed site(s) or centers? Are the plans to add or drop enrollment centers, as needed, appropriate?

If international site(s) is/are proposed, does the application adequately address the complexity of executing the clinical trial?

If multi-sites/centers, is there evidence of the ability of the individual site or center to: (1) enroll the proposed numbers; (2) adhere to the protocol; (3) collect and transmit data in an accurate and timely fashion; and, (4) operate within the proposed organizational structure? 
Additional Review Criteria
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.

Project Timeline and Milestones

Are the Proposed Milestones and Project Timeline described in sufficient detail and are they appropriate for the project? Is the timeline reasonable? Are the milestones feasible, well developed, and quantifiable with regard to the specific aims?

 Study Timeline

 Specific to applications involving clinical trials

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

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

 

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

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

 

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

 

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment 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. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

 

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

 

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

 

Not Applicable

 

For Revisions, the committee will consider the appropriateness of the proposed expansion of the scope of the project. If the Revision application relates to a specific line of investigation presented in the original application that was not recommended for approval by the committee, then the committee will consider whether the responses to comments from the previous scientific review group are adequate and whether substantial changes are clearly evident.
Additional Review Considerations
As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.

 

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

 

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

 

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

While it is understood that many tools will be at an early proof-of-concept stage, a central goal of this FOA is to generate transformative tools that will be widely used throughout the research community. For applications that propose to generate such tools, does the application include an adequate and detailed plan for sharing these resources as appropriate and consistent with achieving the goals of the program? Does the plan provide a strong rationale for each of the following key elements as appropriate and consistent with achieving the goals of the program?

  • Project management of resource sharing;
  • Description of what specific resources will be shared (e.g., model organisms, reagents, completed tools or repurposed components);
  • Schedule/timeline for availability of resources to other users;
  • Persons who will have access to the resources (written as broadly as possible to the extent consistent with applicable laws, regulations, rules, and policies);
  • Plan for post award disposition of resources.

 

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

 

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

2. Review and Selection Process

2. Review and Selection Process 

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

As part of the scientific peer review, all applications:
  • May undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score. 
  • Will receive a written critique.
Appeals of initial peer review will not be accepted for applications submitted in response to this FOA.
Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the appropriate national Advisory Council or Board. The following will be considered in making funding decisions:
  • Scientific and technical merit of the proposed project as determined by scientific peer review.
  • Availability of funds.
  • Relevance of the proposed project to program priorities.

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.

1. Award Notices

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

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

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

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

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

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

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

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

2. Administrative and National Policy Requirements

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

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

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

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

Cooperative Agreement Terms and Conditions of Award

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 (DHHS) grant administration regulations at 45 CFR Parts 74 and 92 (Part 92 is applicable when State and local Governments are eligible to apply), 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 awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

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

  • Overseeing all aspects of the award including management of resource sharing, preparing comprehensive progress reports, scheduling meetings with NIH program staff, and other duties as necessary.
  • Defining objectives and approaches, and for planning, conducting, analyzing, interpreting, drawing conclusions on their studies, publishing and sharing the results.
  • Developing and proposing rigorous milestones that will be achieved during the project period.
  • Retaining custody of and having all rights to the data and technology developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.
  • Pursuing patent protection, as appropriate and consistent with the terms and conditions of the award and goals of the program.
  • Providing quarterly progress reports with completeness that include experimental design with rigor, including assumptions for the design of the experiments, the results of the investigations, interpretations of the results, and for concluding whether milestones have been met or not.
  • In cases when NIH program staff request raw data, awardees agree to provide the data.
  • Participating at least twice a year in progress meetings (teleconferences) that are organized by NIH staff.
  • Communicating regulatory meeting dates and agenda to the NIH program staff and invite their participation.
  • Communicating study reports from Clinical Research Organizations (CROs), meeting minutes (and associated data packages if applicable), letters and other forms of communications with FDA, Recombinant DNA Advisory Committee (RAC), and other authorities, and to provide IND number and registration numbers in clinical trial.gov, if applicable.
  • Providing regulatory and clinical documents that are required for administrative review.
  • Verifying that the clinical trial (if applicable) is performed in accordance with Good Clinical Practices (GCP) and all IC specific guidelines for data and safety monitoring in clinical trials (e.g. NINDS Guidelines for Data and Safety Monitoring in Clinical Trials: http://www.ninds.nih.gov/research/clinical_research/policies/data_safety_monitoring.htm, and must provide data and regular updates to NIH.

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

  • The NIH Project Scientist(s) will have substantial scientific/programmatic involvement during the conduct of this activity, through technical assistance, advice, and coordination above and beyond normal program stewardship for grants.
  • NIH Project Scientist(s) provides input on the milestones and makes recommendations regarding their finalization.
  • NIH Project Scientist(s) will be responsible for assessing the progress of the project towards the specified milestones, and for advising the Program Officer about whether further funds should be released to the project.
  • NIH Project Scientist(s), in consultation with the PIs, may suggest modification or additional experiments to be conducted prior to or during the award as an additional milestone(s). In most cases, these studies will be supported by additional funds from NIH.
  • NIH Project Scientist(s) participates in meetings together with PIs with regulatory agencies related to the funded project.
  • Additionally, an NIH Program Officer will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.
  • The Program Officer, with advice from others managing the BRAIN Initiative, will make decisions on project continuation based on staff recommendations, programmatic prioritizations and budget considerations. NIH program staff may consult as necessary with independent consultants with relevant expertise. If justified, future year milestones may be revised based on data and information obtained during the previous year. If, based on the progress report, a funded project does not meet the milestones, funding for the project may be discontinued.  In addition to milestones, the decision regarding continued funding will also be based on the overall robustness of the entire data package that adequately allows an interpretation of the results (regardless if they have been captured in the milestones), overall progress, NIH portfolio balance and program priorities, competitive landscape, and availability of funds.

Areas of Joint Responsibility include:

Clarifying and negotiating the milestones and timelines. Creation of a steering committee if warranted.

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 for the investigators 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 disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardee'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. Final decisions made by NIH regarding a discontinuation are not appealable.

3. Reporting

When multiple years are involved, awardees will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.
A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

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

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

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.
Application Submission Contacts
eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten on-time submission, and post-submission issues)

Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

General Grants Information (Questions regarding application processes and NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-945-7573

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

Scientific/Research Contact(s)

Michelle Freund, Ph.D
National Institute of Mental Health (NIMH)
Telephone: 301-443-1815
Email: BRAIN-info-NIMH@mail.nih.gov

Peer Review Contact(s)

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

Financial/Grants Management Contact(s)

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

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.
Authority and Regulations
Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75.


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