Background

The BRAIN Initiative: 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) is 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; and NIH welcomes applications from investigators in these disciplines.

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. While this FOA does not use a cooperative agreement mechanism, it is expected that the awardees will align their research with the BICCN goals, and coordinate their activities by participating in the BRAIN Initiative Cell Census Network (BICCN) meetings and in other BRAIN Initiative activities.

The BRAIN Initiative Cell Census Network (BICCN)

The BRAIN Initiative Cell Census program awarded 9 collaborative projects in 2017 and 5 in 2018 under four companion FOAs (RFA-MH-17-210, -215, -225, and -230), which collectively constitute the BRAIN Cell Census Network (BICCN). The overarching goal of the BICCN is to

generate comprehensive 3D common reference brain cell atlases that will integrate molecular, anatomical, functional, and cell lineage data for describing cell types in mouse, human, and non-human primate brains.

The expected outcomes of the BICCN include:

• fundamental knowledge on diverse cell types and their three dimensional organizational logic in the brain;
• an open-access 3D digital brain cell reference atlas with molecular, anatomical, and physiological annotations of brain cell types in mouse;
• a comprehensive neural circuit diagram in mouse brain;
• reagents for cell-specific targeting;
• validated high throughput and low-cost approaches to characterizing cell diversity in human and/or non-human primate brain samples.

The BICCN operates as a cooperative network to promote collaboration and coordination among the projects within the Network and the BRAIN Initiative, as well as with any external research entities that have similar goals. Currently the BICCN has established close collaboration and coordination relationship with Data Archive projects funded under RFA-MH-17-255. It is expected that the BICCN awardees and their collaborators will work together to achieve the common goals. This will involve regular meetings and other coordinated activities within the BICCN as well as in the BRAIN Initiative and more broadly with the research and education communities. Thus, the BICCN will leverage existing atlases and common coordinate systems to facilitate collaborative efforts for the data annotation and 3D spatial mapping.

Common Coordinate Systems

A large amount of data concerning brain anatomy and physiology exists and continues to grow rapidly. With the advent of single-cell omics technologies, new biomolecular data are expected to flourish, adding to the existing expansion of data sets. Correspondingly, there is an increasing need to enhance data interoperability and harmonization among data producers and data accessibility to the broad research community, and to reduce unnecessary repetition in data generation. Atlases and common coordinate systems play a fundamental role in gathering, analyzing, communicating, and standardizing data. The BICCN embraces the existing effort of the research community (e.g., the International Neuroinformatics Coordination Facility) to collaboratively build up brain atlases with broadly accessible common brain coordinate systems to integrate and disseminate the brain cell census data. Thus, this FOA supports the development and use of common brain coordinate systems to maximize data and resource sharing. Accordingly, the NIH expects that imaging based cell census data will be registered to common coordinate systems, which include in situ hybridization, immunohistochemistry, cell morphology, and neuronal connectivity mapping. When non-imaging-based approaches are used, applicants should spatially assign the data to the brain regions as accurately as possible. For example, microdissection and computational tools may help map single cell sequencing data onto a reference brain atlas spatially.

Much progress has been made to develop and implement common coordinate systems for human brain (e.g., Allen Human Brain Atlas, BigBrain, BrainSpan, Talairach Coordinate System, MNI Coordinate System) and image segmentation and registration tools (e.g, Insight Segmentation and Registration Toolkit (ITK)) that allow individual labs to integrate their data to the common coordinate systems.

This FOA is related to the implementation of the Recommendations in "Section III.1. Discovering Diversity" and "Section III.2. Maps at Multiple Scales"of the Final Report (http://braininitiative.nih.gov/2025/index.htm) of the BRAIN working group.

Research Objectives

The purpose of this FOA is to accelerate the integration and use of scalable technologies and tools to enhance brain cell census research, including the development of technology platforms and/or resources that will enable a swift and comprehensive survey of brain cell types and circuits.

Cell types have been increasingly defined by their location, morphology, connectivity, neurotransmitter type, lineage, function, and most recently, their transcriptomic and epigenomic profiles. Despite a general challenge in defining and distinguishing a cell type from a cell state due to the physiological variability and plasticity of a cell, there is general agreement that cell types can be defined provisionally by stable and generally intrinsic properties of a cell, including (1) molecular signature (e.g., transcriptome, epigenome, proteome, metabolome), (2) anatomy (e.g., location, size, orientation, morphology, and connectivity), (3) function, and (4) development and differentiation. This definition of a cell type can provide a good starting point for a systematic cell census, and a foundation for understanding how brain cells are organized and connected as the source of perceptions, actions, and memories. Recent rapid technological advancements enable the possibility of a large-scale brain cell census in mammalian brains. However, there still exist multiple technology and resource gaps and roadblocks that limit the capability, the breadth, and depth of the current brain cell census research. This FOA solicits applications to overcome these shortcomings and aim for a comprehensive and complete analysis of cell properties and neuronal connectivity in human, non-human primate, and mouse brains. The projects are expected to augment the ongoing systematic collection and integrative analysis of cell census data by the BICCN.

Tools/technologies and studies relevant for this initiative should be scalable and are expected to significantly improve the technical performance including throughput, sensitivity, selectivity, spatiotemporal resolution and robustness. Of interest are those tools/technologies that have potential to enable comprehensive and complete cell census research for human, non-human primate, and mouse brains. In particular, the FOA supports (a) improving technology and resource platforms to remove limitations and bottlenecks in the current pipeline of brain cell census data generation; (b) integrating experimental and computational methods to enhance capabilities of cell census data generation and analysis and to reduce barriers to hypothesis-driven research; (c) generating a substantial amount of spatiotemporal cell census data and/or resources to demonstrate the utility and performance of the improved technology and resource platforms; and (d) conducting comparative studies by using proper criteria to evaluate and benchmark quality of biospecimen, performance of cell census tools/technologies, and effectiveness of computational approaches. Applications are expected to address limitations and gaps of existing technologies/tools and cell census research as a benchmark against which the improvements or competitive advantages of the proposed ones will be measured.

Examples of scalable tools/technologies of interest and studies include but are not limited to:

(1) Molecular profiling

• high-throughput transcriptomics, epigenomics, proteomics, and/or metabolomics to enable large-scale cell census in a comprehensive manner
• highly sensitive and accurate -omics assays to enable detailed analyses of complete molecular signatures
• multiplexed imaging-based spatial profiling of RNAs, DNA methylation and chromatin states, proteins, and/or metabolites in individual cells across whole brain
• simultaneous detection and assay of multiple biomolecule species (e.g., imaging both RNAs and proteins in same cells)
• improved spatial -omics methods to acquire both molecular signatures and 3D cell location and morphology
• generation of cell census tools and reagents including protein capturing reagents (e.g., monoclonal antibodies, recombinant antibodies, nanobodies), genetic and non-genetic cell-specific targeting tools (e.g., viral vectors), labeling reagents (e.g., super bright dyes), molecular markers (e.g., nucleic acid scaffolded sensors)

(2) Neuron morphology

• innovative approaches that will improve the throughput and accuracy of single neuron morphology reconstruction
• efficient approaches to brightly labeling whole neuron morphology including dendritic and axonal terminals presynaptic and postsynaptic structures with adequate sparsity
• generation of improved genetic (e.g. enhancers, promoters) viral reagents to label defined neuronal types
• implementation of high-throughput, high-resolution, and brain-wide imaging
• Efficient computational methods for defining, comparing, and classifying topological and topographic features
• implementation of computational approaches for digital reconstruction, analysis, and 3D brain mapping of neuron morphology

(3) Neuron connectivity and circuit diagram

• comprehensive mapping of connected neurons in local circuits and whole brain at subcellular resolution
• high resolution imaging of circuit structural components including dendritic spines, synaptic junctions, axons, dendrites, and soma
• improved synaptic and trans-synaptic markers, viral and non-viral tracers for antero-, retro-grade, and/or trans-synaptic tracing
• improved labeling tools and technologies to visualize neuron synapses with trackable axons and dendrites for circuit diagram
• comprehensive mapping of chemical and electrical synapses
• implementation of improved computation approaches for the image processing, segmentation, analysis, 3D brain registration, and data annotation
• cross-scale and cross-modality neuron connectivity map and analysis

(4) Cell lineage and development

• implementation of high-throughput methods for a comprehensive characterization of molecular and anatomical signatures of brain cells at different developmental stages
• systematic study of developmental cell types and lineage relationships combining single-cell omics and lineage tracing methods in mouse and non-human primate brains
• establishment of 3D reference brain atlases and common coordinate frameworks for developmental brain maps
• implementation of computation approaches to analyze, integrate, and map the developmental brain cell census data to 3D common coordinate frameworks

Applications funded under this RFA are expected to align their specific aims with the overarching goal of the BICCN to generate comprehensive 3D common reference brain cell atlases that will integrate molecular, anatomical, functional, and cell lineage data for describing cell types in mouse, human, and non-human primate brains. The awardees are expected to generate a substantial amount of cell census data and/or resources during the project period using the proposed technologies or via collaboration with the BICCN and are expected to follow the BICCN's resource and data sharing policy.

Milestones and timelines: The success of the project will be facilitated by the adoption of clear, quantitative milestones with realistic and efficient timelines. Applications are expected to include annual milestones with metrics that will document progress towards the achievement of the specific aims.

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

1. Eligible Applicants

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

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

• 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)

Applicant organizations

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

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

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

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

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.

2. Cost Sharing

3. Additional Information on Eligibility

Number of Applications

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

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

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

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

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

The letter of intent should be sent to:

Email : [email protected]

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

Specific Aims: Describe overall research aims and strategy. Among the proposed specific aims, include one aim to generate a substantial amount of cell census data using the proposed technologies or via collaboration with the BICCN to demonstrate the utility and performance of the technologies.

Research Strategy:

Describe how the project will align with the overarching goals of the BRAIN Initiative Cell Census Network (BICCN) to generate comprehensive 3D common reference brain cell atlases that will integrate molecular, anatomical, functional, and cell lineage data for describing cell types in mouse, human, and non-human primate brains.

Describe limitations and gaps of existing technologies/tools and cell census studies as a benchmark against which the improvements or competitive advantages of the proposed ones will be measured. The improvements include throughput, sensitivity, selectivity, scalability, spatiotemporal resolution and reproducibility in cell census analyses.

For the data generation the applications are expected to :

• describe tissue collection approaches to ensure the high quality of the brain tissue specimens;
• describe research theme(s);
• describe the brain samples and structures/regions to be analyzed;
• describe preliminary data and tool generation effort and the state-of-the art approaches used;
• provide estimates of data quality and plans for how data quality will be evaluated;
• describe how to optimize experimental procedures to reduce technical noise and enhance data quality;
• describe workflow including throughput as well as rate-limiting steps, and provide plans for assessing and improving the pipeline;
• describe quality control/quality assurance measures and decision making process;
• describe anticipated cost reductions with a cost model incorporating a standardized cost structure including a useful unit (e.g., per experiment or per cell characterized) and identify large-cost items that dominate the cost model;
• describe innovative aspects of the project.

Milestones and timelines: Applications to this FOA are expected to define a clear set of overall goals that are aligned with the BICCN’s goals, and include annual milestones with metrics that will document progress towards the achievement of the overall goals. For each approach, clear, quantitative outcomes should be set and described. Annual milestones include plans for critically evaluating and revising these milestones on a regular basis.

The following modifications also apply:

A central goal of this FOA is to build up a comprehensive brain cell census data resource that will be widely used throughout the research community. It will take the combined resources of researchers in the public and private sectors many years to catalog and characterize the biology of brain cells, neuronal connectivity of interest, to understand brain function, and then to use that information to improve public health. The open sharing of the brain census data, research tools, and resources will not only lead more rapidly to their broad use by the research community, but also encourage scientific rigor in data production and analysis, with resulting benefits to public health. In order to reap the maximum value from this program, all molecular, anatomical, and physiological data, experimental protocols, and tools generated are expected to be made publicly available. Applications must include a detailed plan for sharing data and resources and include the following key elements:

• Project management of data and resource sharing;
• Description of what specific data and resources will be shared (e.g., single cell transcriptome data, immunohistochemistry data, cell morphology data, neuronal connectivity data, electrophysiological data, functional connectivity data, software, model organisms, reagents, completed tools or repurposed components);
• Schedule/timeline for availability of data and resources to other users.

Data Sharing. Applicants must provide a specific proposal for data sharing in the application , and address the issues related to the public release of data and data analyses (see the rationale for FAIR (Findability, Accessibility, Interoperability, and Reusability) Data Principles). After the initial review, the BRAIN program staff will be responsible for any additional administrative review of the plan for sharing data and may negotiate modifications of the data sharing plan with the prospective awardee prior to award. The final negotiated version of the data sharing plan will become a term and condition of the award. After all of the awards have been made, the BICCN Steering Committee, of which all awardees will be members, will develop a final, common data release plan as appropriate for the project that will address the interests of the data producers and analysts, as well as the users of the BICCN brain cell census atlases. Applicants should indicate their willingness to participate in the development of such a final plan and to accept it. The NIH expects that verified raw data will be submitted in real time or other agreed-upon timeframe depending on the data types and verification requirements to long-term publicly accessible archives such as GEO or others as appropriate. Applicants should address whether they anticipate any of their data will require controlled access. Agreement to abide by that policy is a requirement for anyone to join the Network.

Resource Sharing. As the BICCN is generating a community resource, in addition to data, resources generated by the BICCN projects should be made rapidly available to the research community. Rapid dissemination of these resources would accelerate scientific exploration and avoid duplicative resource development effort. The applicant should provide specific plans for resource sharing and distribution in the application. After the initial review, the BRAIN program staff will be responsible for any additional administrative review of the plan for sharing resources and may negotiate modifications of the resource sharing plan with the prospective awardee prior to award. The final negotiated version of the resource sharing plan will become a term and condition of the award.

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.

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.

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.

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

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.

Significance

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?

Investigator(s)

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?

Are the PD/PI and other key personnel devoting sufficient time/effort to achieve the goals?

Innovation

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?

Approach

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?

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?

Environment

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?

Protections for Human Subjects

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.

Inclusion of Women, Minorities, and Children

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.

Vertebrate Animals

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.

Biohazards

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.

Resubmissions

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

Renewals

Not Applicable

Revisions

Not Applicable