Part 1. Overview Information

Key Dates

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

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

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

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

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

Part 2. Full Text of Announcement

Section I. Notice of Funding Opportunity Description

This notice of funding opportunity (NOFO) is part of a suite of Innovation Grants to Nurture Initial Translational Efforts (IGNITE) to encourage the translation of research discoveries into new treatments for disorders that fall under the NINDS mission. Supported therapeutic agents include small molecules and biologics (modalities such as peptides, proteins, oligonucleotides, gene therapies, cell therapies, and novel emerging modalities).

R61/R33 Mechanism

This NOFO uses the R61/R33 Phased Innovation Award mechanism in which the R61 phase is generally utilized to support preparatory or prerequisite activities that establish feasibility for execution of the R33 phase. The R61 and R33 phases cannot overlap in time. By design, this R61/R33 supports dependent aims; the R33 depends on the R61. The risk of dependent aims is mitigated by milestones between the R61 and R33 (discussed in detail below). Only if the milestones are met does the project progress from the R61 to the R33. 

NOFO Scope

This NOFO provides support to conduct therapeutic agent characterization and pharmacokinetic studies in the R61, and pharmacodynamic and in vivo efficacy studies in the R33 to demonstrate that proposed therapeutic agent(s) have sufficient biological activity to warrant further development to treat neurological or neuromuscular disorders. This NOFO does not support optimization of potential therapeutic agents. For this NOFO, optimization is defined as the rational, iterative design of new agents based on data obtained in the prior iteration. Testing of a few pre-defined potential therapeutics to determine the best option is supported. (For example, testing 2 different pre-defined promotors in a gene therapy could be supported.)

In preclinical efficacy studies, a combination of in vivo efficacy, pharmacodynamic (PD) and pharmacokinetic (PK) measures are warranted to determine the feasibility of candidate therapeutic agent(s) to serve as a starting point for further therapy development. Combined measures of PK and PD greatly increase the understanding of the in vivo efficacy of the therapeutic agent(s) by exploring the relationship between the concentration of the agent(s) at the site of action and the resulting efficacy measures. PK measurements reflect the body’s effect on the absorption, metabolism, distribution and excretion of the therapeutic agent. For some biologic modalities, traditional PK might not apply; such applicants should still aim to measure the kinetics and distribution as needed for therapeutic development. For the purposes of this NOFO, in vivo efficacy measures reflect the effects of the therapeutic agent on endpoints that are closely tied to the desired clinical endpoints, but do not necessarily reflect target engagement. While PD measures may also reflect the effects of the therapeutic agent on endpoints closely tied to the desired clinical endpoint, they must also reflect target engagement.

Pharmacodynamic studies may include but are not limited to determination of 1) target occupancy (e.g., binding) and 2) proximal target activation (i.e., signal transduction, neurotransmission, protein synthesis, and gene regulation and transcription). Examples of target occupancy studies may include but are not limited to Positron Emission Tomography (PET) and Single-Proton Emission Computed Tomography (SPECT). In addition to the examples of proximal target activation listed above, more remote measures of target activation may also be considered, for example (but not limited to): ex vivo studies of ion channel function, EEG modulation, or changes in cerebral blood flow or metabolism as measured by fMRI.

Further development of potential therapeutic agents identified in IGNITE-supported efforts can be supported in later-stage programs such as the NIH Blueprint Neurotherapeutics Program (BPN) for Small Molecules, NIH BPN-Biologics, NIH SBIR/STTR, or other private or public sources.

Phased Award Milestones

This NOFO uses the R61/R33 Phased Innovation Award mechanism. Transition from the R61 to the R33 phase is contingent upon the successful completion of proposed milestones. Milestones are success criteria that are quantifiable and can be used for go/no-go decision-making at the R61/R33 transition point and must have timelines and quantitative criteria associated with them. The R61 and R33 must be distinct phases that do not overlap in time. NINDS emphasizes the importance of the robustness and reproducibility of experimental results in evaluating progress (see https://www.ninds.nih.gov/funding/preparing-your-application/preparing-research-plan/rigorous-study-design-and-transparent-reporting). Specific Aims or a list of activities are not considered milestones because they do not provide decision-making criteria for success. Section IV includes additional information regarding project milestones. For frequently asked questions and milestone examples, please see https://www.ninds.nih.gov/Current-Research/Research-Funded-NINDS/Translational-Research/Funding-Programs-Researchers/IGNITE.

Rigor of Experimental Data

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 and provides additional guidance to the scientific community. 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.

Rigor is particularly important for translational work, which forms a foundation for further development of potential therapeutic agents. Rigorous efficacy studies are studies done with multiple doses that are supported by the pharmacokinetics data and done with clinically relevant routes of administration. Rigorous studies are also done using timings of treatments that reflect what is planned for in the patient population in models that reflect the relevant aspects of human disease as much as possible. 

Entry Criteria:

• Novelty: This NOFO seeks to apply new knowledge around targets, mechanisms, pathways or therapeutic indications. Projects should aim to develop or “re-purpose” therapeutics that are significant improvements over existing therapeutics for neurological or neuromuscular disorders.
• Biological rationale and preliminary data: Projects funded through this opportunity must have a strong biological rationale for the intended approach, along with preliminary data or literature-based evidence supporting the feasibility and importance of the approach. Preliminary data should be rigorous from well-designed experiments and can include outcomes analysis or validation studies. Examples of the most critical elements for a well-designed study are summarized on the NINDS website (https://www.ninds.nih.gov/funding/preparing-your-application/preparing-research-plan/rigorous-study-design-and-transparent-reporting).
• Relevance for therapy development: Projects should utilize early-stage therapeutic agents that have potential to be further developed for a neurological or neuromuscular disorder. Applications should illustrate how the early-stage therapeutic(s) will be advanced toward later stages of discovery/development once the R33 phase is complete. Applicants should describe which patients would ultimately benefit from a successful therapeutic and how/when an eventual successful therapy would be delivered.

Examples of activities for the R61 phase include, but are not limited to:

• Preparation (such as synthesis of a pre-defined small molecule or small-scale manufacture of a biologic) of the therapeutic agent to support proposed activities. This is not intended to support manufacture of material for IND-enabling or clinical studies 
• For use and development of iPSC line therapeutics, please see NOT-NS-24-019
• Confirm the identity and characterization of therapeutic agent(s). This could include for example, confirmation of purity, stability, biophysical properties, in vitro absorption, distribution, metabolism, and excretion, in vitro potency and selectivity, degradation products, and process impurities
• Studies to develop dosage form(s) to support the proposed studies
• Pharmacokinetics studies to determine direct or indirect therapeutic agent levels. For gene and cell therapy, these include characterization of gene copy numbers or tropism in tissues
• Studies to confirm that therapeutic agent reaches and engages the target site/tissue (directly or indirectly) at a concentration that exceeds in vitro pharmacological potency over the desired time period
• Studies to confirm selectivity of the therapeutic agent
• Limited studies to identify potential pharmacodynamic biomarkers specific for the purposes of developing the therapeutic agent(s) to be tested in the application
• Studies to inform design and refinement of the PD measure and/or in vivo efficacy models and testing procedures, including examination of model variability to estimate sample size, calibration of the model according to positive and negative controls, along with the age, time course and window of disease that are relevant for therapeutic testing. For complete model validation, see PAR-25-060.

At the end of the R61 phase, investigators must exhibit successful completion of 1) all necessary preparation and characterization of proposed therapeutic agent(s), 2) pharmacokinetic studies (for gene and cell therapy, this can be the level of tropism by copy numbers and engraftment in various tissue or cells), 3) design, refinement, and validation of pharmacodynamic and/or in vivo efficacy animal studies using the appropriate positive and negative controls and demonstrating feasibility of conducting therapeutic agent testing and 4) a further refined in vivo study design (e.g., in an animal model) that meets the NIH guidance for rigor and transparency in grant applications  and the NINDS NIH and NINDS Rigorous Study Design and Transparent Reporting guidelines and will allow for correlation of dose, therapeutic agent exposure in the target tissue, and pharmacological effect (i.e., demonstration of dose response and exposure response), thereby addressing subsequent feasibility.

Examples of activities for R33 phase include, but are not limited to:

• Pharmacodynamic and/or in vivo efficacy studies with chemically and biologically characterized therapeutic agent(s) including positive and negative controls, as appropriate
• Dose (exposure)-response activity with a route of administration relevant to future clinical use
• Studies correlating pharmacokinetic and pharmacodynamics measures (PK/PD)
• Preliminary studies to assess early safety or off-target effects (not including IND-enabling toxicity)
• Validation and replication studies to confirm observed results

Collaborations

Developing therapeutics requires a multidisciplinary approach. Investigators should form collaborations with those familiar with successful drug/biologic development (such as those from industry) as well as those familiar with what the desired end-product should look like (such as biostatisticians, technical experts and clinicians). Applicants should consider how they will identify and foster relationships with potential licensing and commercialization partners early in the therapy development process once an award is made. PDs/PIs are expected to work closely with their institutional technology transfer officials to ensure that royalty agreements, patent filings, and all other necessary IP arrangements are completed at an appropriate time and that commercialization plans are developed and updated over the course of the project.

Additional Considerations:

1. Applicants are strongly encouraged to contact NINDS Scientific/Research Staff to discuss potential research projects prior to submitting an application. This is to ensure this is the right NOFO and institute for your project and to help make sure critical elements (such as milestones and phases) are included.

2. Small Business applicants who are eligible for the Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) programs are strongly encouraged to submit through either the SBIR or STTR Omnibus Solicitations or other appropriate SBIR or STTR funding opportunity to take advantage of the congressionally mandated set-aside specifically for small businesses. Please see https://www.ninds.nih.gov/Funding/Small-Business-Grants for more information about the programs.

3. Prior to funding an application, NINDS Program staff may contact the applicant to discuss the proposed milestones and any changes suggested by the NINDS review panel or Program staff. A final set of approved milestones will be specified in the Notice of Award.

Applications Not Responsive to this NOFO:

Non-responsive studies include those that involve any of the following activities:

• Applications containing the following later-stage activities: 
  • Medicinal chemistry optimization or Structure-Activity-Relationship (SAR) studies for small molecules (for support for this work, please consider PAR-24-043)
  • Optimization for biologics (for support for this work, please consider PAR-24-293)
  • Investigational New Drug (IND)-enabling studies
  • Manufacture of therapeutic agents for IND-enabling studies or clinical use
• Applications containing the following basic science activities:
  • Studies designed to establish proof of concept for a biological target or use of therapeutic agents to identify targets relevant to a disease
  • Studies of disease mechanism
  • Development of assays or probes to support basic understanding of disease or other basic research
• Applications containing the following activities covered in companion IGNITE NOFOs:
  • Extensive development and validation of animal or ex vivo models (for support for this work, please consider PAR-25-060)
  • Screening/identification of novel therapeutic agents (for support for this work, please consider PAR-25-059)
• Applications with a significant focus (e.g. an entire aim) on developing pharmacodynamic biomarkers
• Discovery and development of diagnostic, monitoring, predictive or prognostic biomarkers (for support for this wok, please consider the NINDS Biomarker Program).
• Development of devices (for support for this work, please consider the NINDS Translational Devices Program) device/drug combinations, surgical procedures, diagnostics, and rehabilitation strategies
• Projects that are entirely in silico

Applications that are missing any of the following will be deemed to be incomplete and will be withdrawn and not reviewed:

• Activities for both the R61 and R33 phases with a clear demarcation of which activities are in the R61 phase and which are in the R33 phase, as described in Section IV.2. The R61 and R33 phases cannot overlap in time; they are separate, sequential phases.
• Quantitative go/no-go milestones as an attachment, as described in Section IV.2.
• PEDP attachment, as described in Section IV.2

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

Section II. Award Information

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

Section III. Eligibility Information

1. Eligible Applicants

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Local Governments

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

Federal Government

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

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations
• Non-domestic (non-U.S.) Entities (Foreign Organizations).

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

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

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

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the How to Apply-Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. Failure to complete registrations in advance of  a due date is not a valid reason for a late submission, please reference the NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications.

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

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

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

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with their organization to develop an application for support. Individuals from diverse backgrounds, including underrepresented racial and ethnic groups, individuals with disabilities, and women are always encouraged to apply for NIH support. See, Reminder: Notice of NIH's Encouragement of Applications Supporting Individuals from Underrepresented Ethnic and Racial Groups as well as Individuals with Disabilities, NOT-OD-22-019 and Notice of NIH's Interest in Diversity, NOT-OD-20-031.

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

2. Cost Sharing

This NOFO does not require cost sharing as defined in the NIH Grants Policy Statement Section 1.2 Definition of Terms.

3. Additional Information on Eligibility

Number of Applications

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

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

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

Section IV. Application and Submission Information

1. Requesting an Application Package

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

2. Content and Form of Application Submission

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

Page Limitations

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

The following section supplements the instructions found in the How to Apply- Application Guide and should be used for preparing an application to this NOFO.

SF424(R&R) Cover

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

SF424(R&R) Project/Performance Site Locations

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

SF424(R&R) Other Project Information

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

Other Attachment #1: Milestones (required, 1-page limit)

Transition from the R61 to the R33 phase is contingent upon the successful completion of one set of proposed milestones. These milestones will be evaluated as part of the scientific and technical merit of the R61/R33 application. The milestones proposed in the application must be well-described, quantifiable, and scientifically justified to allow program staff to assess progress in the R61 phase. In addition, milestones should reflect the objectives of the application and be appropriate for the therapeutic approach, stage of development, and indication. Rationale should be provided for the choice of measures and values proposed for the milestones. Specific aims or a list of activities are not considered milestones because they would not provide decision-making goals. A discussion of the milestones relative to the progress of the R61 phase and the implications of successful completion of the milestones for the R33 phase should be included. The clarity and completeness of the R61/R33 application with regard to specific goals and feasibility milestones are critical. Milestones should provide clear indicators of a project's continued success or emergent difficulties and will be used to evaluate the application as part of the consideration of the awarded project for further funding of non-competing award years by the Program Director(s)/Principal Investigator(s), and Program Official(s). For example, for a therapeutic where brain exposure is necessary, one milestone might be to show brain exposure of free drug or distribution of a biologic at a specified level for a specified time in an animal model. Applicants should propose milestones based on their particular project and should measure success of all essential R61 activities. More example milestones can be found at https://www.ninds.nih.gov/Funding/Apply-Funding/Application-Support-Library/IGNITE-Milestone-Examples. The existence of clear, quantitative, go/no-go milestones for transition from the R61 to the R33 phase is a requirement for this NOFO. Applications lacking an attached milestone document will be administratively withdrawn without review. 

Other Attachment #2: Intellectual Property (required, 1-page limit)

Applications must include an Intellectual property (IP) strategy. Applicants are encouraged to prepare this section of the application in consultation with their institution's technology transfer officials.

Applicants should describe the IP landscape surrounding their therapy and assay. Applicants should describe any known constraints that could impede their therapeutic discovery and development (e.g., certain restrictions under transfer or sharing agreements, applicants' previous or present IP filings and publications, applicant's out-licensing agreements, similar therapies that are under patent protection and/or on the market, etc.) and how these issues could be addressed with achieving the goals of this program. If the applicant proposes using an agent(s) whose IP is not owned by the applicant's institution, either an investigational therapeutic, FDA-approved therapeutic, or other licensed product, the applicant should include a letter (see letter of support) from any entities owning the IP indicating there will not be any limitations imposed on the studies or the product which would impede achieving the goals of the funding program.

If patents pertinent to the therapy being developed under this application have been filed, the applicant should indicate the details of filing dates, what type of patents are filed, and application status, and associated USPTO links, if applicable.

Applicants should also discuss future IP filing plans. For a multiple-PD/PI, multiple-institution application, applicants should describe the infrastructure of each institution for bringing the technologies to practical application and for coordinating these efforts (e.g., licensing, managing IP) among the institutions. Applicants should clarify how IP will be shared or otherwise managed if multiple PD/PIs and institutions are involved, consistent with achieving the goals of the program.

For information on exceptions to the NIH data sharing policy due to intellectual property considerations, please see here: https://sharing.nih.gov/faqs#/data-management-and-sharing-policy.htm?anchor=56972. Applicants are encouraged to contact Scientific/Research Staff if they have any questions or concerns.

Other Attachments:

SF424(R&R) Senior/Key Person Profile

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

R&R Budget

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

R&R Subaward Budget

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

PHS 398 Cover Page Supplement

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

PHS 398 Research Plan

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

Specific Aims: Within the Specific Aims section, include headers titled “R61 Phase Specific Aims” and “R33 Phase Specific Aims”. Under each header, state the specific objectives of the efforts, including the technical questions you will try to answer to determine the feasibility of the proposed approach. Since the goal of the R61 phase of this NOFO is the characterization of the therapeutic agent(s) (such as physio-chemical characteristics or pharmacokinetics of a small molecule, biological characteristics or distribution/tropism of a biologic agent(s)) along with the design and refinement of the pharmacodynamic and/or in vivo efficacy models or tests, hypothesis testing, per se, may not be the driving force in developing such an application, and therefore, may not be applicable in the R61 phase.

Research Strategy: Within the Research Strategy, applicants must describe both the R61 phase and the R33 phase, including the R61 transitional milestones and timeline. The R61 and R33 must be distinct phases that do not overlap in time. The Research Strategy section should include a background section that clearly outlines the biological and therapeutic rationale for the application, including: 1) a description of the biological rationale linking the proposed therapeutic target and the disease of interest, 2) evidence for unmet medical need in the therapeutic disease area, 3) a brief description of any pertinent history for therapeutic development in the disease area, 4) evidence supporting the novelty of the therapeutic approach, and 5) a summary of the project status, including information regarding therapeutic agents to be tested in the current application. The applicant should discuss the strengths and weaknesses of the prior research used to support the application and describe how the proposed research will address weaknesses or gaps identified by the applicant. This may include the applicant’s own preliminary data, data published by the applicant, or data published by others. NINDS urges investigators to follow the NIH guidance for rigor and transparency in grant applications and additionally recommends the research practices described at 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. 

Description of the R61 phase should include a carefully designed plan for characterizing the proposed preliminary therapeutic agents from a physicochemical, biophysical, and biological perspective, as appropriate. Characterization of selectivity and early safety are also appropriate at this stage. An important component of the R33 phase strategy should be a carefully developed rationale for the experimental design and a description of the data analysis strategy. Efficacy studies should be done in multiple doses that are supported by the pharmacokinetics data and done with clinically relevant routes of administration. Models should be chosen based on the planned indication and timings of treatments should reflect what is planned for the patient population. As this is an R61/R33 mechanism, clear demarcation of which activities are in the R61 and which are in the R33 is required; the two phases must not overlap in time. Applications that do not propose both an R61 and R33 phase will be administratively withdrawn without review.

Innovation: Novelty of therapeutic strategy/target over what is currently available in the clinic or under therapeutic development by the field should be emphasized. A description of the therapeutic agent proposed in relation to the state of the field should be included.

Timeline: Provide a timeline. Indicate when it is anticipated that essential components of the project (e.g., optimization of protocols, generation and characterization of therapeutic agents, pharmacokinetics studies, in vivo animal model adaptation and validation with positive and negative controls) will be completed. The proposed timeline with specific milestones should be clearly delineated and should appear as the last element of the Research Strategy section. Timelines must be feasible.

Therapeutic Discovery Plan: At the completion of this project, it is expected that applicants have a promising small molecule or biologic starting point for later-stage development. It is essential for applicants to include, within the Research Strategy, a description of how knowledge gained from this work will support future therapeutic discovery efforts beyond the project period through to early clinical trials. As part of this consideration, attention should be paid to the intended patient population such that appropriate experiments (animal models, end point measures, routes of administration, treatment timelines, etc.) are used in the current application.

Collaboration: NINDS strongly encourages applicants to form multidisciplinary teams that consist of academic/industry experts relevant to the research plan (i.e., biostatisticians, clinicians, drug development experts, technical experts). This multidisciplinary team should be able to define the goals of the research, outline specific gaps that need to be addressed during this funding period, outline detailed plans and experiments, and execute the research strategy.

Letters of Support: Applicants should include letters of support from consultants, contractors, and collaborators.

If applying from an academic institution, include a letter of support from the technology transfer official who will be managing intellectual property associated with this project.

If research will be performed at more than one institution, include a letter of support from each institution clarifying how intellectual property will be shared or otherwise managed across the institutions.

If collaborating with a private entity, include a letter of support that addresses any agreement to provide agent(s), any limits on the studies that can be performed with said agent(s), any limitations on sharing of data (including negative results), and whether a licensing agreement(s) is in place. This letter should come from a high official within the private entity who has authority to speak on these issues.

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

Other Plan(s): 

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

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

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

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

PHS Human Subjects and Clinical Trials Information

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

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

Study Record: PHS Human Subjects and Clinical Trials Information

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

Delayed Onset Study

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

PHS Assignment Request Form

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

Foreign Organizations

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

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

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

4. Submission Dates and Times

Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time.  If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications.

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

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

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

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

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

Applications must be submitted electronically following the instructions described in the How to Apply-Application Guide.  Paper applications will not be accepted.

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

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

Important reminders:

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

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

See more tips for avoiding common errors.

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

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

Send written disclosures to the NIH Chief Grants Management Officer listed on the Notice of Award for the IC that funded the award and to the HHS Office of Inspector Grant Self Disclosure Program at [email protected].

Post Submission Materials

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

Section V. Application Review Information

1. Criteria

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

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed). An application does not need to be strong in all categories to be judged likely to have a major scientific impact.

Review Criteria

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

Factor 1: Importance of the Research

Significance

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

Innovation

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

Specific to this NOFO:

• Evaluate the relevance for therapy development and whether a successful project will bring the field closer to a therapeutic that is substantially better than current approaches
• Evaluate the target; it should be novel but validated for the proposed disorder. Evaluate the applicant's understanding of the state of the field 

Factor 2. Rigor and Feasibility

Approach

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

Rigor:

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

Feasibility:

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

Specific to this NOFO:

• Evaluate the therapeutic agent chemical, biophysical, and biological characterization plans
• Evaluate the clinical relevance of the chosen in vivo efficacy plans and pharmacodynamic measures. Evaluate whether efficacy plans include multiple doses using clinically relevant routes of administration. Evaluate whether the timings of treatment (before versus after diseases onset) are appropriate given the therapeutic goals and whether models chosen reflect the relevant aspects of the human disease as much as possible  
• Evaluate the overall therapy development plan and whether the proposed project activities logically integrate into the larger plan
• Milestones and timeline:
  • Evaluate the robustness and clarity of the milestones; they should be quantitative enough to allow for go/no-go decisions
  • Evaluate whether the milestones reflect success of the R61 and that the R33 is feasible and worthwhile
  • Evaluate the feasibility of completing the therapeutic agent characterization before the R61/R33 transition point
  • Evaluate whether the overall timeline is realistic and includes the necessary steps but is also efficient without unnecessary steps

Factor 3. Expertise and Resources

Investigator(s)

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

Environment

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

Specific to this NOFO:

• Evaluate whether the investigator team is knowledgeable and experienced with the proposed biological target as well as the therapy development process. Evaluate whether the team has the expertise to not only do the proposed experiments but also to anticipate and mitigate issues that might arise in future therapy development. Evaluate whether adequate effort is being dedicated to the project. 

As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.

Protections for Human Subjects

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

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

Vertebrate Animals

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

Biohazards

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

Resubmissions

Renewals

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.

Specific for this NOFO: 

• Intellectual Property (IP) Strategy
  • Evaluate whether the application outlines any known constraints that could impede the therapeutic from being developed (e.g., certain restrictions under transfer or sharing agreements, applicants' previous or present IP filings and publications, applicant's out-licensing agreements, similar therapies that are under patent protection and/or on the market, etc) and how these issues could be addressed while achieving the goals of the program
  • If applicable, evaluate how strong the applicant's IP portfolio/position (pertinent to the proposed project) is, and to what extent the applicant has a reasonable strategy to protect its IP going forward. If the applicant has filed patents pertinent to the therapeutic, do they provide details about those patents? If IP will be shared among co-investigators, evaluate whether the applicant provide details about the plans for IP sharing

Authentication of Key Biological and/or Chemical Resources:

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

Budget and Period of Support

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

2. Review and Selection Process

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

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this NOFO. Following initial peer review, recommended applications will receive a second level of review by the appropriate national Advisory Council or Board. The following will be considered in making funding decisions:

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

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

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

3. Anticipated Announcement and Award Dates

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

Information regarding the disposition of applications is available in the NIH Grants Policy Statement Section 2.4.4 Disposition of Applications.

Section VI. Award Administration Information

1. Award Notices

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

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

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

Institutional Review Board or Independent Ethics Committee Approval: Recipient institutions must ensure that 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.

2. Administrative and National Policy Requirements

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

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

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

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

Not Applicable

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

4. Reporting

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

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

Section VII. Agency Contacts

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

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

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

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: [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]

Becky Roof, PhD
National Institute of Neurological Disorders and Stroke (NINDS)
Email: [email protected]
 

Chief, Scientific Review Branch
National Institute of Neurological Disorders and Stroke (NINDS)
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 2 CFR Part 200.