Part 1. Overview Information

Key Dates

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

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

It is critical that applicants follow the instructions in the Research (R) Instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this NOFO or in a Notice from NIH Guide for Grants and Contracts).

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

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

Part 2. Full Text of Announcement

Section I. Notice of Funding Opportunity Description

Background

Tackling the most ambitious goals and challenges of modern neuroscience research is increasingly dependent on collaborative approaches that leverage expertise and advances across multiple disciplines, an ever-increasing knowledgebase, and a broad armamentarium of technologies. NINDS recognizes the need to support emerging research opportunities of broad scope and complexity that require innovative team science approaches. The COMBINE program, as part of the NINDS Strategic Plan for Research, is designed to support interdisciplinary research teams to achieve transformative goals that could not be met by individual or parallel efforts.

Program Objectives and Scope

A team science approach expands our ability to pursue challenging problems in neuroscience research in a comprehensive, interdisciplinary, rigorous, and mechanistic manner. This Notice of Funding Opportunity (NOFO) encourages ambitious interdisciplinary team efforts to overcome basic, translational, and clinical research challenges within the NINDS mission.

A successful application to the COMBINE program will have a single, focused goal, require team-based integration of distinct disciplines and/or viewpoints, and deliver a transformative outcome within 5 years. This NOFO will support interdisciplinary teams that seek to cross technical and conceptual boundaries through interdisciplinary collaboration to achieve a single, focused, and transformative goal. The research goal must be well-defined and sufficiently focused so that meaningful outcomes can be accomplished within 5 years. It should also be of sufficient scope and complexity that it can only be achieved through an integrative team effort and not by individual, parallel, or series of efforts. All contributions by each team member and pieces of the experimental plan are expected to be synergistic, integrated, and essential to the goal.

The list below includes representative, but not exhaustive, examples of interdisciplinary opportunities:

• A goal that challenges existing paradigms, overcomes long-standing roadblocks to progress, and/or develops new synergies between different scientific fields
• Basic, translational, and/or clinical collaborations with a goal of reaching a significantly higher mechanistic understanding of nervous system function and/or dysfunction
• Challenges in understanding and targeting disease modifying therapies that require collaborations across basic, translational, and/or clinical disciplines
• Scientific efforts requiring integration of previously siloed and/or disparate areas of scientific or technical expertise
• A scientific question that requires leveraging an innovative combination of tools and approaches, or the application of cutting-edge tools, resources, conceptual, or computational frameworks (such as those arising from the BRAIN initiative)
• Challenges that necessitate bridging across species, scales and disciplines (e.g., to reveal shared/generalizable and/or unique neural processes)

Non-Responsiveness Criteria:

Applications deemed to be non-responsive will not proceed to review and will be withdrawn. The following are considered non-responsive to this NOFO:

• Applications with multiple aims or without a single, focused goal 
• Applications in which the goal is not well-defined or has a low likelihood of being completed within 5 years
• Applications in which the primary goal is to create, maintain, expand, and/or disseminate resources or infrastructure
• Applications that lack a minimum of three PD/PIs or that exceed the maximum of six PD/PIs
• Research that is not fully within the NINDS mission 
• Applications that propose to discover and develop a small molecule, biologic therapeutic, or therapeutic device to treat neurological and/or neuromuscular disorders (covered by  NINDS Division of Translational Research Programs ). 
• Development and validation of biomarkers for use in clinical trials or in clinical practice. These types of applications are already covered by the NINDS Biomarker Program funding opportunities (PAR-22-089 and PARs-21-056, 057, 058, and 059), see: NINDS: Focus On Biomarkers Research.
• Clinical trials designed to answer specific questions about safety, tolerability, efficacy and/or effectiveness of pharmacologic, behavioral, biologic, surgical, or device (invasive or non-invasive) interventions (e.g., phase I, phase II, phase III, or pivotal clinical trials). Such designs should be submitted to an NINDS clinical trial-specific funding announcement (see NINDS: Clinical Research). If planning a clinical trial, this NOFO will only accept mechanistic or BESH (Basic Experimental Studies Involving Humans) types of clinical trials.Understanding the distinction between mechanistic, BESH, and efficacy trials can be difficult. PIs are strongly encouraged to discuss any planned clinical trial in consideration for this opportunity with the scientific program contact to avoid errors in interpretation. 
• Clinical research projects with an inherently team science approach (e.g., applications in which the primary goal is multi-site clinical epidemiological or observational studies, genetic studies, or comparative effectiveness research). NINDS will continue to consider these large projects as a separate, unsolicited independent investigator-initiated projects (i.e., R01/U01 applications). For comparative effectiveness research projects, see: PAR-22-076: Prospective Observational Comparative Effectiveness Research in Clinical Neurosciences (UG3/UH3 Clinical Trial Not Allowed) . 

For applications proposing a mechanistic or BESH clinical trial, note the following definitions and restrictions for this funding announcement:

• Clinical trials are research studies in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes. For this funding announcement, only the following types of clinical trials will be supported:
  • Mechanistic trials, defined as studies designed to understand a biological or behavioral process, the pathophysiology of a disease, or the mechanism of action of an intervention (i.e., how an intervention works, but not if it works or is safe).
  • Basic Experimental Studies with Humans (BESH), defined as basic research studies involving humans that seek to understand the fundamental aspects of phenomena.
• The proposed mechanistic or BESH clinical trial must be based on robust and rigorous supporting data (e.g., from non-clinical in vivo and/or in vitro studies or preliminary clinical studies) that demonstrate that there is an adequate scientific foundation to justify the proposed trial. The proposed trial design must also use rigorous and transparent approaches.

Program Organization

This COMBINE program is distinct from the NINDS P01 and parent R01 in that it will support projects with a single, focused goal instead of multiple aims. In addition, this program is distinct from conventional, investigator-initiated R01s in its emphasis on highly transformative and bold research. 

This program also requires a Multiple PD/PI (MPI) structure with three to six PD/PIs who will each bring a distinct scientific viewpoint or expertise necessary to pursue the transformative goal. Each PI is expected to provide a significant, indispensable, and distinct contribution to the project. Teams must not be dominated by a single individual. Applications for smaller projects with one or two PD/PIs should consider submitting a multi-PD/PI application to the "NIH Research Project Grant (Parent R01)" (see the Parent Announcement website for the current issuance of this NOFO).

NINDS recognizes that the success of team science hinges on well-managed team interactions, clear timelines and benchmarks for success, and evidence of commitment to diversity, equity, and inclusion. Therefore, the following three components are required as "Other Project Information" as an attachment (see Section IV for instructions). Applications that fail to include these attachments will be considered incomplete and will be withdrawn.

1. Team Management Plan

Information in the “Multiple PD/PI Leadership Plan” leadership plan is complementary to the Team Management plan; whereas the “Multiple PD/PI Leadership Plan” describes leadership by and interactions across the PD/PIs, the “Team Management Plan” focuses on management of the whole team/key personnel. 

Studies of team science have highlighted the need for effective management to achieve program goals, especially as the team size increases.  Many resources exist to aid in developing effective team-based programs (see e.g., the NCI Collaboration and Team Science Field Guide).  The team management plan will address the following points (see section IV):

• Organizational structure, team composition, and roles
• Shared vision, contributions, and distributed responsibility for decision-making
• Resource sharing and allocation
• Credit assignment
• Knowledge Transfer
• Coordination and communication 
• Intra-team data sharing, archiving, and preservation

Because teams will likely include individuals from widely divergent scientific backgrounds, teams are expected to have a shared vision and a defined plan for communication and management of shared responsibilities, interpersonal interactions, and professional credit. It is highly recommended that a scientific project manager or program coordinator is included in the team. Depending on the specific data needs of the project, data/resource sharing and management systems and/or hiring of professional data science staff should also be considered.

2. Timeline and Benchmarks for Success

The research goal for this team science effort is expected to be feasible, well-defined, and sufficiently focused so that transformative outcomes can be achieved within 5 years. Teams are expected to be intentional about integrating efforts; the extent of integration will be reflected in the presence and types of activities, planned outcomes, and/or framework that will combine and integrate efforts across disciplines and team members.

3. Plan for Enhancing Diverse Perspectives (PEDP)

To support the best science, NINDS encourages inclusivity in research. Examples of structures that promote diverse perspectives include but are not limited to:

• Transdisciplinary research projects and collaborations
• Engagement from different types of institutions and organizations (e.g., research-intensive, undergraduate-focused, minority-serving, community-based)
• Individual applications and partnerships that enhance geographic and regional heterogeneity
• Investigators and teams composed of researchers at different career stages
• Participation of individuals from diverse backgrounds, including groups traditionally underrepresented in the biomedical, behavioral, and clinical research workforce (see NOT-OD-20-031), such as underrepresented racial and ethnic groups, those with disabilities, those from disadvantaged backgrounds, and women
• Project-based opportunities to enhance the research environment to benefit early- and mid-career investigators

Applications are required to include a Plan for Enhancing Diverse Perspectives (PEDP) submitted as Other Project Information as an attachment (see Section IV). The PEDP will be assessed as part of the scientific and technical peer review evaluation, as well as considered among programmatic matters with respect to funding decisions. Applicants are strongly encouraged to read the NOFO instructions carefully and view the COMBINE PEDP webpage.

Here are some important points to consider before applying:

Consultation with NINDS staff

Only applications that are fully within the  NINDS mission will be accepted and considered for funding by NINDS. The COMBINE program has fixed and limited budget commitments, so funding priorities will include considerations where the research might better fit special funding programs like the NIH BRAIN initiative, HEAL Initiative, ADRD, and other active programs. Priority will also be given to integrated teams pursuing a focused transformative goal with defined 5-year outcomes.  It is strongly recommended that potential applicants consult the NINDS COMBINE (RM1) webpage and contact NINDS program staff about mission relevance, research aims, and anticipated budget very early in the planning stage and a minimum of 8 weeks before submission of an application is anticipated. Applicants should provide a draft of the title, planned goal, team composition, and budget. Staff will not evaluate the technical and scientific merit of the proposed project; technical and scientific merit will be determined during peer review using the review criteria indicated in this NOFO. During the consultation phase, if the proposed project does not meet the programmatic needs of this NOFO, applicants will be strongly encouraged to consider other funding opportunities.

Rigor and Transparency

NINDS, as part of NIH, strives for rigor and transparency in all research it funds. For this reason, NINDS explicitly emphasizes the NIH application instructions related to rigor and transparency (https://grants.nih.gov/policy/reproducibility/guidance.htm) and provides additional guidance  to the scientific community (https://www.ninds.nih.gov/funding/preparing-your-application/preparing-research-plan/rigorous-study-design-and-transparent-reporting). For example, the biological rationale for the proposed experiments must be based on rigorous and robust supporting data, which means that data should be collected via methods that minimize the risk of bias and be reported in a transparent manner. If previously published or preliminary studies do not meet these standards, applicants should address how the current study design addresses the deficiencies in rigor and transparency. Proposed experiments should likewise be designed in a manner that minimizes the risk of bias and ensures validity of experimental results.

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

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

Section II. Award Information

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

Section III. Eligibility Information

1. Eligible Applicants

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Local Governments

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

Federal Government

• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations

Eligible Agencies of the Federal Government - Including the NIH Intramural Program.

Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.

Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.

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

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the 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.

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

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

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

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

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

The application is required to be submitted as a multiple PD/PI application, with 3-6 PDs/PIs. We require equivalent efforts from 3-6 investigators with Principal Investigator roles as each PI is expected to provide a significant, indispensable, and distinct contribution to the project. Teams should not be dominated by a single individual. Multiple PDs/PIs on a project share the authority and responsibility for leading and directing the project, intellectually and logistically. Generally, each PD/PI should devote at least 2.4 person months (i.e., the equivalent of 20% effort on a full-year appointment, 26.7% on a 9-month appointment, or 40% on a 6-month appointment) throughout the duration of the award. Visit the multiple PD/PI Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide, and the Grant Policy Statement on Multiple Principal Investigators. Minimum allowed efforts by the PDs/PIs are described in the R&R Budget instructions in Part 2. Section IV.2.

PD(s)/PI(s) who have an active NINDS R35 award can participate as a Collaborator instead of a PD/PI as part of the 50% effort on their current R35 award and may not receive additional funds from this award. 

Multiple PD/PI projects will be subject to the NINDS Special Review Council (SCR) policy if one or more of the PD/PIs has NIH research support that exceeds the SCR threshold.

2. Cost Sharing

This NOFO does not require cost sharing as defined in the NIH Grants Policy Statement.

3. Additional Information on Eligibility

Number of Applications

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

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

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

Section IV. Application and Submission Information

1. Requesting an Application Package

The application forms package specific to this opportunity must be accessed through ASSIST, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace are available in Part 1 of this NOFO. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission

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

Letter of Intent

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

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

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

 The letter of intent should be sent to:

NINDS Team Science Group
Email: [email protected]

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed.

For this specific NOFO, the Research Strategy section is limited to 15 pages.

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this NOFO.

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

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

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions: 

1. Team Management Plan (Required- 3 pages maximum):

As an "Other Attachment" entitled “TeamManagementPlan.pdf”, applicants must address how the entire group will function to accomplish program objectives and vision. Team management approaches raised in the subsections listed below should be described in the Plan. Note that a "Multiple PD/PI Leadership Plan" is also required as a separate attachment, and the information in that plan should not be duplicated here. Whereas the “Multiple PD/PI Leadership Plan” focuses on leadership by and interactions across the PD/PIs, the “Team Management Plan” focuses on management of the whole team/key personnel. Applicants are encouraged to consult resources to aid in developing effective team-based programs (see e.g., the NCI Collaboration and Team Science Field Guide and literature on the Science of Team Science) and/or participate in team-science related training. Applications that exceed the 3-page limit will be withdrawn.

Organizational structure, team composition, and roles: The program management structure must avoid giving any single individual undue authority that prevents contributions from the wider team for setting program priorities, resource distribution, and reward. NINDS recognizes that strong leadership is required for complex team efforts to be successful, while at the same time effective team leadership requires decision-making based on an amalgam of interests, expertise, and roles, guided by recognized project objectives. Applicants should develop a management structure based on project objectives that effectively promote the proposed research. The structure should account for team composition, personnel roles, institutional resources, and policies. NINDS does not specify any particular organizational structure, as this may vary across research questions and groups.

Inclusion of a scientific project manager or coordinator as a Senior/Key Person with adequate authority is strongly recommended. If a project manager or coordinator is included, describe how the qualifications of this individual are appropriate for such a role, for the subject matter, and scale of the proposed project.

Shared vision, contributions, and responsibility for decision making: The Team Management Plan must include a description of how the PD/PIs will establish and sustain an   interdisciplinary team of researchers with an optimal range of backgrounds, expertise, and skills to successfully accomplish the goals of the program. One key consideration is that teams employing complementary approaches and having diverse areas of intellectual and technical expertise are more productive if the process for making decisions incorporates different points of view. The Team Management Plan should describe how major decisions will be made or how conflicts will be resolved. A key characteristic that distinguishes productive teams is the degree that all member contributions are valued. Strategies for building and maintaining group participation to develop collective intelligence are encouraged.

Resource sharing and allocation across the team: Applications must describe management and decision-making processes that promote collective input for allocation of program resources with flexibility when resources may need to be dynamically reallocated to achieve programmatic goals. A plan for how intra-team, institutional, or regional resources that are integral to the team goals will be shared and made accessible to team members should also be included.

Credit assignment: A plan for how credit will be shared, especially with early-career researchers, must be included. Methods for attributing contributions to publications should be described to enable individual professional assessment in joint projects.

Knowledge transfer: Knowledge transfer across   disciplines and career stages is critical to innovative team science. Describe activities that will facilitate bridging of knowledge across disparate disciplines. Regarding bridging knowledge across career stages, an important and meaningful impact of team science may come from shaping the next generation of neuroscientists. Because of the interdisciplinary expertise of the research groups, trainees are exposed to and can learn multiple  scientific languages and methodologies, resulting in multi-faceted, early-career researchers. Plans for how trainees will be immersed in, and benefit from, these  approaches   should be also described. This could include shared mentorship, inter-lab meetings, all-hands tutorials, shared meeting and document space, inter-lab visits, and trainee presentations.

Coordination and Communication plans: Practical aspects must be described, including frequency, logistics, and infrastructure of real time communication across all key personnel, consultants, trainees, and other significant contributors regardless of effort level. If a scientific project manager or coordinator is included, describe his/her role in coordinating team activities and communication.

Intra-team data sharing, archiving, and preservation: A framework for sharing and/or integrating data across team members must be customized to fit the science and the specific data needs of the project. The plan and costs for this are  distinct from the Data Management and Sharing Plan because the intra-team data plan focuses on data sharing and management across the team members rather than on sharing data to the public. Plans for data archiving and long-term preservation for team use should also be described. Depending on the needs and challenges of managing team data, applicants may also include and justify data/resource sharing and management systems and/or hiring of professional data science staff.

2. Timeline and Benchmarks for Success (Required- 2 pages maximum)

As an "Other Attachment" entitled “TimelineBenchmarks.pdf”, applicants should include a project timeline in the form of a Gantt chart/table (or similar) that includes all major tasks to be performed during the project as well as critical benchmarks for success. The chart should also include estimated start and completion dates for those tasks and should identify the contributions expected from each PD/PI toward accomplishing each task. The COMBINE program emphasizes integration. It is expected that pursuit of the research goal will require substantial and integrated contributions across the PD/PIs. Highlight specific activities and/or planned outcomes that act as “glues”, serving to combine and integrate efforts across disciplines and team members. Overall, this chart will aid reviewers in assessing the feasibility and likelihood that the work plan is adequate for achieving project objectives within the funding period. It will also aid in assessing the degree of integration and collaboration, and the availability of appropriate intellectual and technical expertise.

3. Plan for Enhancing Diverse Perspectives (PEDP) (Required- 1 page maximum)

In an "Other Attachment" entitled “PEDP.pdf”, all applicants must include (1) a summary of strategies to advance the scientific and technical merit of the proposed project through expanded inclusivity, (2) timeline and milestones for the PEDP, (3) approaches to assessing progress towards meeting the PEDP defined goals . The PEDP should provide a holistic and integrated view of how enhancing diverse perspectives is viewed and supported throughout the application and can incorporate elements with relevance to any review criteria (significance, investigator(s), innovation, approach, and environment) as appropriate. Where possible, applicant(s) should align their description with these required elements within the research strategy section. The PEDP will vary depending on the scientific aims, expertise required, the environment and performance site(s), as well as how the project aims are structured. The PEDP may be no more than 1-page in length and should include a timeline and milestones for relevant components that will be considered as part of the review. Examples of items that advance inclusivity in research and may be part of the PEDP can include, but are not limited to:

• Discussion of engagement with different types of institutions and organizations (e.g., research-intensive, undergraduate-focused, minority-serving, community-based).
• Description of any planned partnerships that may enhance geographic and regional diversity.
• Plan to enhance recruitment of women and individuals from groups traditionally under-represented in the biomedical, behavioral, and clinical research workforce.
• Proposed monitoring activities to identify and measure PEDP progress benchmarks.
• Plan to utilize the project infrastructure (i.e., research and structure) to support career-enhancing research opportunities for diverse junior, early- and mid-career researchers.
• Description of any training and/or mentoring opportunities available to encourage participation of students, postdoctoral researchers and co-investigators from diverse backgrounds.
• Plan to develop transdisciplinary collaboration(s) that require unique expertise and/or solicit diverse perspectives to address research question(s).
• Publication plan that enumerates planned manuscripts and proposed lead authorship.
• Outreach and planned engagement activities to enhance recruitment of individuals from diverse groups as research participants including those from under-represented backgrounds.

For further information on the Plan for Enhancing Diverse Perspectives (PEDP), see the COMBINE PEDP webpage.

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

R&R Budget

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

Research Budget: To be successful, programs of this level of complexity are expected to require significant effort from all PDs/PIs involved. Generally, each PD/PI should devote at least 2.4 person months (i.e., the equivalent of 20% effort on a full-year appointment, 26.7% on a 9-month appointment, or 40% on a 6-month appointment) throughout the duration of the award.

Certain supporting functions such as equipment, animal research costs, and clinical research costs may be requested if well justified and unique to the institution(s) involved. Within the research budget, equipment, including data sharing and management systems, can be included if well justified. Equipment that duplicates existing institutional or regional shared facilities that are available to investigators must be identified and the proposed duplication should be well justified. Do not request inflationary increases in the overall budget or any of the budget categories. Changes in budget should reflect changes in activities required by the science.

Data sharing costs:

• Applicants may include costs associated with preparing and submitting data to a data archive per NOT-OD-21-015.

PEDP implementation costs:

• Applicants may include allowable costs associated with PEDP implementation (as outlined in the Grants Policy Statement section 7.

R&R Subaward Budget

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

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

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

Applications will be evaluated by review panels that represent a a broad array   of scientific interests. Therefore, jargon must be avoided. Explain the challenge, the transformative outcome, and the approach in language that scientists in other fields can understand.

Specific Aims

In the Specific Aims page, describe the single 5-year scientific goal or aim, why it is transformative and impactful, and why it can only be achieved by a fully integrated and synergistic team effort. Multiple aims are inappropriate as the research plan must be focused on pursuing a single focused goal. Briefly describe how the interdisciplinary team is structured and how the represented areas of expertise will be essential to the approach and outcomes of the project. Provide a schematic of the overall strategy, approach, and experimental design that will enable achievement of the single goal within 5-years. Highlight activities, planned outcomes, and/or frameworks that will integrate and combine efforts across disciplines and team members. Briefly describe why this project is uniquely suited to the COMBINE program.

Research Strategy

Applicants must present a cohesive and impactful program of sufficient scope and complexity that it can only be achieved through an integrative team effort and not by individual, parallel, or series of efforts . To present a truly integrated collaborative effort, applicants must describe how all team member contributions and pieces of the experimental plan are synergistic and essential to the goal. A graphical representation to summarize the integrated team approach should be included.

We expect that the COMBINE program will assume some degree of risk and are in general more ambitious and innovative than traditional NIH applications. Because feasibility will be assessed, applicants should carefully manage any risk in the premise and/or approach. Applicants must provide a strong premise and sound rationale as to how and why the research is tractable and likely to generate an exceptionally high impact if successful. Any new and innovative approaches proposed must be supported by a clear and logical experimental plan.  

Teams should structure the Research Strategy Section using the following subheadings (15 pages max):

I. Importance of the Research and Appropriateness for the COMBINE program 
 A. Importance of the Research

Describe the background and significance of what is being proposed. Highlight the transformative nature of the program by describing  the state-of-the-art or a major challenge in the broad field of the application and how the proposed research will advance knowledge well beyond the current status to transform the field, challenge existing paradigms, overcome long-standing roadblocks to progress, and/or develop new synergies between different scientific fields. Applications should fully describe the goal of the research program, its significance within the relevant scientific field(s), the rigor and status of prior research, current obstacles and challenges, and how a team science approach and expected outcomes will be transformative and/or enable major advances. Clearly describe the anticipated outcomes to be achieved within the 5 years, and how these will be transformative and impactful.

Describe the elements of innovation in your proposed research and why they should be considered innovative compared to current approaches, paradigms, practices, or perspectives. 

B. Appropriateness for the COMBINE program

Applications must describe  why the proposed research is uniquely suited to the stated goals of the COMBINE program, rather than a conventional research grant application. The research strategy should describe how innovative combinations of distinct scientific fields and/or intellectual viewpoints will enable the project goals to be achieved. Applications should justify the need for a larger-scale collaborative approach and explain why the goal of the program could not be accomplished by other means, such as independently funded individual or multiple PD/PI research grants. The diversity of investigator backgrounds and expertise should be justified and sufficient to address the proposed scientific problem. 

II. Approach and experimental design 
Describe the overall strategy, methodology, experimental design, analyses, and the underlying rationale. Although we encourage boldness, and we remind reviewers to not penalize unavoidable risks, feasibility will be assessed. Thus, we recommend that applicants present a thoughtful and logical plan of how risks will be managed and minimized, propose alternative strategies as needed, and discuss what approaches are being undertaken to present a strong likelihood of success. 

Applications must be intentional about integration; describe the activities, planned outcomes, and experimental, quantitative, and/or conceptual frameworks that will serve as “glues” to integrate and combine efforts across disciplines and team members. Applications must describe critical research benchmarks (which can reference the "Timeline and Benchmarks for Success" Other Attachment), definitive 5-year outcomes, and any innovative aspects of the ideas and approach, including those arising from collaborative interactions. 

Although the subheadings are not required, the following points should be addressed: 

Investigator Team . Describe how and why the contribution of each PD/PIs is essential to achieving the goal. The planned effort and expertise by the PDs/PIs must be complementary, appropriate, and sufficient for the work proposed. Teams must not be dominated by a single individual. If the application includes collaborating investigators who will not receive direct support, it should be described how these investigators will participate in the program. If foreign investigators are involved, it should be described how they are uniquely qualified to participate in the team.

Resources and infrastructure . Resources and infrastructure available to accomplish the specific scientific goal  of the research and to support team science. The value of the involvement of multiple expertise, departments, and/or institutions should be described in terms of synergy and diversification of the team, including the backgrounds, expertise, and skills of the researchers. If foreign investigators are involved, it should be described how they will provide unique resources that are not otherwise available.

Note that applications in which the primary goal is to create, maintain, expand, and/or disseminate resources or infrastructure will be considered non-responsive and will not proceed to review. Applications should justify any plans for technology development or new data sharing and archiving resources that are necessary to achieve the program goal. Shared resources that are needed to achieve project objectives should be integrated in the research plan and documented by a letter of agreement. The rationale and use of shared resources should be described within the research plan. Applications requesting resources should include evaluations of the existing resources that are available to the PDs/PIs but that are considered inadequate.

Rigor and Transparency: NINDS urges investigators to follow the NIH guidance for rigor and transparency in grant applications (https://grants.nih.gov/policy/reproducibility/guidance.htm) and additionally recommends the research practices described at https://www.ninds.nih.gov/funding/preparing-your-application/preparing-research-plan/rigorous-study-design-and-transparent-reporting. This will ensure that robust experiments are designed, potential experimenter biases are minimized, results and analyses are transparently reported, and results are interpreted carefully. These recommended research practices include, where applicable, expressing clear rationale for the chosen model(s) and primary/secondary endpoint(s), describing tools and parameters clearly, blinding, randomizing, ensuring adequate sample size, pre-specifying inclusion/exclusion criteria, appropriately handling missing data and outliers, implementing appropriate controls, preplanning analyses, and using appropriate quantitative techniques. It is also strongly recommended to indicate clearly the exploratory vs. confirmatory components of the study, consider study limitations, and plan for transparent reporting of all methods, analyses, and results so that other investigators can evaluate the quality of the work and potentially perform replications.

Investigators should indicate whether data presented or cited in the application as key support for the proposed work were collected, analyzed, and reported in a rigorous and transparent manner as indicated above. A plan to address any ambiguity, weaknesses, or limitations in the prior research should be included in the application. Proposed experiments should similarly adhere to these high standards of rigor and transparency.

If proposing a clinical trial: Applicants must describe the rigor, robustness, and transparency of supporting data that are being used to justify the proposed trial and address any gaps identified. For all clinical trials, the rationale for the trial design, population(s) and hypotheses being tested, and control groups must be described. Potential biases and/or challenges in the study design and protocol should be identified and addressed. For Basic Experimental Studies involving Humans (BESH), the application should describe and address how the expected effect size relates to biologically meaningful differences. Applicants should provide a Statistical Analysis Plan (SAP) for analyses specified in the study protocol. In addition to items requested under Section 4 - Protocol Synopsis of the PHS Human Subjects and Clinical Trials Information form, include the rationale for how missing data will be handled; plans for interim analyses for safety, efficacy, and futility; rationale for recalculation of the sample size midway through the trial (if applicable); and other measures to ensure rigor and transparency of the analysis. Sufficient details should be provided in the SAP about any computer simulations used to investigate the operating characteristics of complex clinical trial designs (such as adaptive designs); to choose between alternative outcome measures; or to determine sample size, accounting for the impact of noncompliance, missing data, subject eligibility criteria, etc. It is particularly important to discuss the range of conditions that were considered in the simulation and why this range was considered appropriate, how robust the findings were across the range of conditions considered, and how the study will adjust for any design deficiencies (e.g., bias, loss of power) the simulations revealed.

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. 

Other Plan(s):

Note: Effective for due dates on or after January 25, 2023, the Data Management and Sharing Plan will be attached in the Other Plan(s) attachment in FORMS-H application forms packages.

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

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

Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

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

When involving human subjects research, clinical research, and/or NIH-defined 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

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start). All instructions in the SF424 (R&R) Application Guide must be followed.

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

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

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.

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.

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

Important reminders:

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

The applicant organization must ensure that the unique entity identifier provided on the application is the same identifier used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the 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 NINDS . Applications that are incomplete, non-compliant, and/or nonresponsive will not be reviewed.

Many NIH ICs encourage the use of common data elements (CDEs) in basic, clinical, and applied research, patient registries, and other human participants research to facilitate broader and more effective use of data and advance research across studies. CDEs are data elements that have been identified and defined for use in multiple data sets across different studies. Investigators are encouraged to consult the NIH CDE Repository and describe in their applications any use they will make of NIH-supported CDEs in their projects, when applicable. Use of CDEs can facilitate data sharing and standardization to improve data quality and enable data integration from multiple studies and sources, including electronic health records. NIH ICs have identified CDEs for many clinical domains (e.g., neurological diseases), types of studies (e.g. genome-wide association studies (GWAS)), types of outcomes (e.g., patient-reported outcomes), and patient registries (e.g., the Global Rare Diseases Patient Registry and Data Repository). NIH has established a “Common Data Element (CDE) Repository Resource Portal" (http://cde.nih.gov/) to assist investigators in identifying NIH-supported CDEs when developing protocols, case report forms, and other instruments for data collection. The Portal provides guidance about and access to NIH-supported CDE initiatives and other tools and resources for the appropriate use of CDEs and data standards in NIH-funded research.

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

Section V. Application Review Information

1. Criteria

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

For this particular announcement, note the following:

The COMBINE program invites applications that have high levels of innovation, which assumes some degree of risk and are in general more ambitious and innovative than traditional NIH applications. Reviewers should evaluate whether a sound rationale has been provided as to how and why the research is tractable and likely to generate an exceptionally high impact if successful. Although reviewers will consider feasibility, unavoidable risks that are intrinsic to new and innovative approaches should not be penalized. 

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.

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.

Significance

Does the project address an important problem or a critical barrier to progress in the field? Is the prior research that serves as the key support for the proposed project rigorous? 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?

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?

Specific to this NOFO:

If successful, to what extent will the proposed program's integrated team research effort be transformative and uniquely advance a scientific area? To what extent does the goal challenge existing paradigms, overcome long-standing roadblocks to progress, and/or develop new synergies between different scientific fields? Is the program of sufficient scope and complexity to warrant a team approach? Does the single scientific goal require an integrated interdisciplinary effort? Can definitive outcomes be accomplished during the 5-year funding period?

Does the application adequately describe whether prior research that serves as the key support for the proposed project employed rigorous practices such as minimization of potential experimenter biases, robust experimental designs, transparent reporting of results and analyses, and careful interpretation? How does the application address ambiguity, weaknesses, or limitations in rigor of the prior research, if applicable?

PEDP (Attachment): To what extent do the efforts described in the Plan for Enhancing Diverse Perspectives further the significance of the project?

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?

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?

Specific to this NOFO:

Is the planned effort by the PDs/PIs complementary, appropriate, and sufficient for the work proposed? Is the diversity of investigator backgrounds and expertise sufficient to address the proposed scientific problem? Is it clear that each investigator is necessary and will contribute to achieving the goals of the program? Teams must not be dominated by a single individual. Is there evidence for synergistic interactions among PDs/PIs beyond the additive benefits of additional investigators? If the application includes collaborating investigators who will not receive direct support, is it clear how these investigators will participate in the program? If foreign investigators are involved, are they uniquely qualified to participate in the team?

Team Management Plan (Attachment): Does the team management plan instill confidence that fair and adequate governance processes will be used for decision-making, conflict resolution, and resource allocation? Does the plan ensure that all investigators will have a voice in decision-making and that no single PD/PI will become overly dominant? Does it provide for effective team leadership and management with shared responsibility and decision-making processes? Is the team plan sufficiently detailed to create a sustainable environment for maintaining integration, productivity, and shared vision? Does the management plan include adequate plans for shared professional credit? Does the management plan include adequate plans for knowledge transfer? To what extent will trainees be involved in and benefit from this team science? If shared research resources will be utilized, are plans adequate to ensure that all team members will have the access they require? Are plans for team coordination and communication adequate? If a scientific program manager or coordinator is proposed, are the qualifications and role of this individual appropriate? Are adequate plans presented to establish and sustain a team of researchers with an optimal range of backgrounds, expertise and skills, and plans to arrive at major decisions, accounting for different points of view? Are adequate plans presented to manage intra-team data sharing, archiving, and preservation?

PEDP (Attachment): To what extent will the efforts described in the Plan for Enhancing Diverse Perspectives strengthen and enhance the expertise required for the project?

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?

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?

Specific to this NOFO:

Does the program involve innovative ideas or approaches that would be very difficult to pursue through independently funded individual or multiple PD/PI research project grants? Does the program involve innovative combinations of distinct scientific fields and/or intellectual viewpoints to address its goals? Is innovation evident in the method by which distinct areas of science are combined?

PEDP (Attachment): To what extent will the efforts described in the Plan for Enhancing Diverse Perspectives meaningfully contribute to innovation?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed 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 individuals of all ages (including children and older adults), 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? Given the methods used to assign participants and deliver interventions, is 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?

Specific to this NOFO:

Is the program presented as a single, focused scientific goal instead of multiple aims? Does the combination of scientific expertise (represented by the PD/PIs) present a compelling case that collaborative, interdisciplinary research will enable scientific advance? To what extent will the strategy, planned outcomes, and activities designed to integrate and combine efforts across fields and team members? Are all contributions by each team member and pieces of the experimental plan synergistic, integrated, and essential to the goal? Does the work plan make adequate use of existing institutional and/or regional resources? If new resources or equipment are requested, are they well justified and not redundant with resources available elsewhere in the institution or region? Although feasibility is considered, unavoidable risks that are intrinsic to new and innovative approaches should not be penalized.

Timeline and Benchmarks for Success (Attachment): Are the timeline and benchmarks proposed appropriate for accomplishing the single scientific goal? Is there sufficient detail on the timing and duration of key project tasks? Are the timelines proposed for achieving project goals realistic and inclusive of necessary steps, but also efficient without adding unnecessary steps? Do the contributions from the PD/PIs suggest a high degree of commitment, integration, and collaboration?

Does the proposed research incorporate adequate methodological rigor where applicable, including, but not limited to, clear rationale for the chosen model(s) and primary/secondary endpoint(s), clear descriptions of tools and parameters, blinding, randomization, adequate sample size, pre-specified inclusion/exclusion criteria, appropriate handling of missing data and outliers, appropriate controls, preplanned analyses, and appropriate quantitative techniques? Do the applicants clearly indicate the exploratory vs. confirmatory components of the study, consider study limitations, and plan for transparent reporting of all methods, analyses, and results so that other investigators can evaluate the quality of the work and potentially perform replications?

PEDP (Attachment): Are the timeline and milestones associated with the Plan for Enhancing Diverse Perspectives well-developed and feasible?

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?

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?

Specific to this NOFO:

Are the resources and infrastructure adequate for accomplishing the single scientific goal and supporting team science? Is there synergy to be gained from the involvement of multiple departments and/or institutions? Will the range of departments and/or institutions involved enhance the diversification of the team in terms of the backgrounds, and expertise and skills of the researchers? If foreign organizations are involved, do they provide unique resources that are not otherwise available?

PEDP (Attachment): To what extent will features of the environment described in the Plan for Enhancing Diverse Perspectives (e.g., collaborative arrangements, geographic diversity, institutional support) contribute to the success of the project?

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.

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)?

Protections for Human Subjects

For research that involves human subjects but does not involve one of the categories of research that are exempt under 45 CFR Part 46, 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 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 Individuals Across the Lifespan

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 individuals of all ages (including children and older adults) 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 Animals 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

Not Applicable

Renewals

Not Applicable

Revisions

Not Applicable

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.

Applications from Foreign Organizations

Not Applicable.

Select Agent Research

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).

Resource Sharing Plans

Reviewers will comment on whether the Resource Sharing Plan(s) (i.e., Sharing Model Organisms) or the rationale for not sharing the resources, is reasonable.

Authentication of Key Biological and/or Chemical 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.

Budget and Period of Support

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

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by NINDS, 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 will receive a written critique.

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

Appeals of initial peer review will not be accepted for applications submitted in response to this NOFO.

Applications will be assigned to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this NOFO. Following initial peer review, recommended applications will receive a second level of review by the National Advisory Neurological Disorders and Stroke Council. 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 including the PEDP.

3. Anticipated Announcement and Award Dates

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

Information regarding the disposition of applications is available in the NIH Grants Policy Statement.

Section VI. Award Administration Information

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 recipient's business official.

Recipients 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 NOFO 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 and results reporting of all trials whether required under the law or not. For more information, see https://grants.nih.gov/policy/clinical-trials/reporting/index.htm

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

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

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

2. Administrative and National Policy Requirements

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, Recipients, and Activities, including of note, but not limited to:

• Federal wide Research Terms and Conditions
• Prohibition on Certain Telecommunications and Video Surveillance Services or Equipment
• Acknowledgment of Federal Funding

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

Should the applicant organization successfully compete for an award, recipients of federal financial assistance (FFA) from HHS will be required to complete an HHS Assurance of Compliance form (HHS 690) in which the recipient agrees, as a condition of receiving the grant, to administer programs in compliance with federal civil rights laws that prohibit discrimination on the basis of race, color, national origin, age, sex and disability, and agreeing to comply with federal conscience laws, where applicable. This includes ensuring that entities take meaningful steps to provide meaningful access to persons with limited English proficiency; and ensuring effective communication with persons with disabilities. Where applicable, Title XI and Section 1557 prohibit discrimination on the basis of sexual orientation, and gender identity, The HHS Office for Civil Rights provides guidance on complying with civil rights laws enforced by HHS. See https://www.hhs.gov/civil-rights/for-providers/provider-obligations/index.html and https://www.hhs.gov/civil-rights/for-individuals/nondiscrimination/index.html.

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. For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this NOFO.

• For guidance on meeting the legal obligation to take reasonable steps to ensure meaningful access to programs or activities by limited English proficient individuals see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/fact-sheet-guidance/index.html and https://www.lep.gov.

• For information on an institution’s specific legal obligations for serving qualified individuals with disabilities, including providing program access, reasonable modifications, and to provide effective communication, see https://www.hhs.gov/civil-rights/for-individuals/disability/index.html.

• HHS funded health and education programs must be administered in an environment free of sexual harassment, see https://www.hhs.gov/civil-rights/for-individuals/sex-discrimination/index.html. For information about NIH's commitment to supporting a safe and respectful work environment, who to contact with questions or concerns, and what NIH's expectations are for institutions and the individuals supported on NIH-funded awards, please see https://grants.nih.gov/grants/policy/harassment.htm.

• For guidance on administering programs in compliance with applicable federal religious nondiscrimination laws and applicable federal conscience protection and associated anti-discrimination laws see https://www.hhs.gov/conscience/conscience-protections/index.html and https://www.hhs.gov/conscience/religious-freedom/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.

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 and 2 CFR Part 200.206 “Federal awarding agency review of risk posed by applicants.” This provision will apply to all NIH grants and cooperative agreements except fellowships.”

Not Applicable

3. Data Management and Sharing

Note: The NIH Policy for Data Management and Sharing is effective for due dates on or after January 25, 2023.

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

4. Reporting

When multiple years are involved, recipients will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

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. NIH NOFOs outline intended research goals and objectives. Post award, NIH will review and measure performance based on the details and outcomes that are shared within the RPPR, as described at 45 CFR Part 75.301 and 2 CFR Part 200.301.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for recipients of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later.  All recipients 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 2 CFR Part 200.113 and Appendix XII to 45 CFR Part 75 and 2 CFR Part 200, 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 and 2 CFR Part 200– Award Term and Conditions for Recipient Integrity and Performance Matters.

Section VII. Agency Contacts

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

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

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

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: [email protected] (preferred method of contact)
Telephone: 301-480-7075

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: [email protected]

For inquiries related to a specific neuroscience topic, contact the relevant NINDS Program Official.

For inquiries related to this NOFO or the COMBINE program, contact the NINDS Team Science Group at: [email protected]

Chief, Scientific Review Branch
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-9223
Email:  [email protected]

Chief Grants Management Officer
National Institute of Neurological Disorders and Stroke (NINDS)
Email: [email protected]

Section VIII. Other Information

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

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75 and 2 CFR Part 200.