Department of Health and Human Services

Part 1. Overview Information

Key Dates

Required Application Instructions

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

Table of Contents

1. Part 1. Overview Information
2. Part 2. Full Text of the Announcement
   1. Section I. Funding Opportunity Description
   2. Section II. Award Information
   3. Section III. Eligibility Information
   4. Section IV. Application and Submission Information
   5. Section V. Application Review Information
   6. Section VI. Award Administration Information
   7. Section VII. Agency Contacts
   8. Section VIII. Other Information

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

This FOA 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.

This FOA provides funding to conduct pharmacodynamics, pharmacokinetics, and in vivo efficacy studies to demonstrate that proposed therapeutic agent(s) have sufficient biological activity to warrant further development to treat neurological disorders. Therapeutic agents may include but are not limited to small molecules, biologics or biotechnology-derived products. It is expected that upon completion, investigators will have strong evidence of target engagement and/or in vivo efficacy for selected therapeutic agent(s) that meet the entry criteria for the NINDS Cooperative Research to Enable or Advance Translational Enterprises program (CREATE) or the Blueprint Neurotherapeutics Network (BPN). Information on these programs can be found on the NINDS Office of Translational Research website.

In preclinical efficacy studies, a combination of in vivo efficacy, pharmacodynamics (PD) and pharmacokinetics (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. For the purpose of this FOA, 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 reflect target engagement.

Pharmacodynamics 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.

This funding opportunity is intended to support projects with a strong biological rationale that includes: 1) evidence that the therapeutic agent(s) has the potential to be therapeutically viable, 2) evidence to support the robustness of the pharmacodynamic measures and/or efficacy models, 3) a description of the unmet need for the therapeutic agent(s), and 4) a clear justification for how the findings from these studies are relevant to treatments for disorders that are within the NINDS mission. Studies proposed must be part of a well-thought out and clearly defined therapeutic development plan.

This FOA uses the R21/R33 Phased Innovation Award mechanism. The R21 phase will support planning and preparation and the R33 phase will support execution of the pharmacodynamics and/or in vivo efficacy studies. Transition from the R21 to the R33 phase is contingent upon the successful completion of one set of proposed milestones. The specific milestones proposed in the application will depend on the entry stage, prior information on the therapeutic agent(s), and the goals of the application. The milestones should be clearly defined, quantifiable, and scientifically justified to allow the investigator and program staff to assess progress in the R21 phase. (For frequently asked questions and milestone examples, please see http://www.ninds.nih.gov/funding/areas/translational_research/ignite.htm )

Examples of activities for the R21 phase include, but are not limited to:

• Preparation of the therapeutic agent(s) to support proposed activities.
• Characterization of therapeutic agent(s). This could include for example, confirmation of purity, stability, 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 proposed PD measures and/or in vivo 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 or cell engraftment.
• Studies to confirm that therapeutic agents reach and engage the target site (directly or indirectly) at a level that exceeds pharmacological potency over the desired period.
• Studies to inform design, refinement, and validation 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, the age, time course and window of disease that are relevant for therapeutic testing, and determination of meaningful clinically relevant measures.

At the end of the R21 phase, investigators must exhibit successful completion of 1) all necessary preparation and characterization (e.g., chemical synthesis and scale up to provide material for proposed project, in vitro or in vivo potency studies, in vitro organ, tissue or cell culture systems) 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 pharmacodynamics 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 detailed in vivo study design (e.g., in an animal model) that meets the NINDS RIGOR guidelines (Landis et. al. Nature 2012, 490:187-91; and NOT-NS-11-023 ) 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:

• Pharmacodynamics and/or in vivo efficacy studies with chemically and biologically characterized therapeutic agent(s).
• Dose (exposure)-response activity with the intended route of administration.
• Studies correlating pharmacokinetic and pharmacodynamics measures (PK/PD)
• Validation and replication studies to confirm observed results.
• Studies to test the agent(s) along with or against positive and negative controls.

Examples of activities that are not appropriate for this FOA include, but are not limited to:

• Development of de novo animal models and pharmacodynamics measures.
• GLP toxicology studies with optimized therapeutic agents.
• Discovery or development of devices, surgical procedures, diagnostics, or rehabilitation strategies.
• Discovery and development of risk, detection, diagnostic, prognostic, predictive, or prevention biomarkers, although use of existing biomarkers is appropriate.
• Studies of disease mechanism.
• Study or use of therapeutic agents to identify targets relevant to a disease.
• Manufacture of therapeutic agents for clinical trials.
• Clinical trials.

The knowledge gained from these studies should meet the entry criteria for the NINDS Cooperative Research to Enable or Advance Translational Enterprises program (CREATE) Bio Discovery Track (PAR-14-286 /PAR-14-287 ) or the Blueprint Neurotherapeutics Network (BPN) (PAR-14-292 /PAR-14-293 ) and facilitate future therapeutic discovery and development for neurological disorders and stroke. Information on these programs can be found on the Office of Translational Research Website at www.ninds.nih.gov/translational research.

Developing therapeutics requires a multidisciplinary approach. Investigators should form collaborations with those knowledgeable in the therapeutic development process (such as those from biotechs or pharma) as well as those familiar with what the desired end product should look like (such as 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 in a timely manner and that commercialization plans are developed and updated over the course of the project.

This FOA utilizes specific milestones that to support transition from the R21 phase to the R33 phase and a project timeline. Milestones are goals that are quantifiable for measuring success that can be used for go/no-go decision making, and should have timelines and quantitative criteria associated with them. NINDS emphasizes the importance of the robustness and reproducibility of experimental results in evaluating progress.

Applicants are strongly encouraged to contact Scientific/Research Staff to discuss potential research projects prior to submitting an application.

For more information about other NINDS Translational Programs visit the website (http://www.ninds.nih.gov/funding/areas/translational_research/index.htm ).

Section II. Award Information

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

Section III. Eligibility Information

1. Eligible Applicants

Eligible Organizations

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)
• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

Other

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

Foreign Institutions

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

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

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

Required Registrations

Applicant Organizations

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

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

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

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

Eligible Individuals (Program Director/Principal Investigator)

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

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

2. Cost Sharing

This FOA 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. This means that the NIH will not accept:

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

In addition, the NIH will not accept a resubmission (A1) application that is submitted later than 37 months after submission of the new (A0) application that it follows. The NIH will accept submission:

• To an RFA of an application that was submitted previously as an investigator-initiated application but not paid;
• Of an investigator-initiated application that was originally submitted to an RFA but not paid; or
• Of an application with a changed grant activity code.

Section IV. Application and Submission Information

1. Requesting an Application Package

Applicants must download the SF424 (R&R) application package associated with this funding opportunity using the "Apply for Grant Electronically" button in this FOA or following the directions provided at Grants.gov.

2. Content and Form of Application Submission

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

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

Page Limitations

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

Instructions for Application Submission

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

SF424(R&R) Cover

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

SF424(R&R) Project/Performance Site Locations

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

SF424(R&R) Other Project Information

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

Other Attachments: Applications should 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 therapeutic agent(s). 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, 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 address any questions of freedom to operate, consistent with achieving the goals of the program.

Applicants should include a letter (see letter of support) from any entity who has ownership of the IP indicating whether they will provide the agent(s), if there are any limitations on the studies that can be performed with that agent(s), agreement about public disclosure of results (including negative results), and whether there is an agreement already in place.

If patents pertinent to the therapeutic agent(s) 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 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.

SF424(R&R) Senior/Key Person Profile

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.

R&R Subaward Budget

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

PHS 398 Cover Page Supplement

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

PHS 398 Research Plan

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

Specific Aims: Within the Specific Aims section, include headers titled R21 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 R21 phase of this FOA is the chemical and pharmacokinetic characterization of the therapeutic compound(s) along with the design, refinement, and validation of the pharmacodynamics and/or in vivo efficacy models, hypothesis testing, per se, may not be the driving force in developing such a application, and therefore, may not be applicable in the R21 phase.

Research Strategy: Within the Research Strategy, applicants should describe both the R21 phase and the R33 phase, including the milestones and timeline. 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 relationship between 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 project status, including information regarding preliminary therapeutic agents to be tested in the current application. A description of the R21 phase should include a well thought-out plan for characterizing proposed preliminary therapeutic agents from a physicochemical, biophysical perspective, and biological perspective. The research strategy for the R21 phase should address the validation status of proposed assays, as well as any validation plans. In addition, there should be evidence of planning for analysis and for a path forward in this R21 phase research strategy section followed by a carefully designed set of milestones, which should allow Go/No Go decisions. The section describing the Research Strategy for the R33 phase should include plans for implementation of the designs described in the R21 phase. An important component of the R33 phase strategy should be a description of the data analysis strategy and an outline of how data obtained in the R33 phase will provide a path for optimization of the preliminary therapeutic agent.

Transition from the R21 to the R33 phase is contingent upon the successful completion of one set of proposed milestones. These milestones are to be included in the Research Strategy section of the application and will be evaluated as part of the scientific and technical merit of the R21/R33 application. The milestones proposed in the application should be well-described, quantifiable, and scientifically justified to allow program staff to assess progress in the R21 phase. A discussion of the milestones relative to the progress of the R21 phase and the implications of successful completion of the milestones for the R33 phase should be included. The clarity and completeness of the R21/R33 application with regard to specific goals and feasibility milestones are critical.

Include 1) evidence that the therapeutic agent(s) has the potential to be therapeutically viable, 2) evidence to support the robustness of the pharmacodynamic measures and/or efficacy models, 3) evidence of the appropriateness of controls and efforts taken to demonstrate dynamic detection range and acceptable variability so the feasibility of conduction the proposed studies can be adequately assessed, 4) a description of the unmet need for the therapeutic agent(s), and 5) a clear justification for how the findings from these studies are relevant to treatments for disorders that are within the NINDS mission. Studies proposed must be part of a well-thought out and clearly defined therapeutic development plan

Innovation: Include headers titled R21 Phase Innovation and R33 Phase Innovation, and address the innovation for the R21 and R33 phases in the appropriate sub-section.

Milestones and Timeline: Provide a timeline with specific milestones for progression from the R21 phase to the R33 phase. The timeline, specific goals and feasibility milestones should be clear and complete. The milestones should be well described, quantifiable, and scientifically justified to allow program staff to assess progress and successful completion in the R21 phase. A discussion of the milestones relative to the progress of the R21 phase and the implications of successful completion of the milestones for the R33 phase should be included.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 set up and validation with positive and negative controls) will be completed. The proposed timeline should be clearly delineated and should appear as the last element of the Research Strategy section.

Rigorous Study Design and Supporting Data: An R21/R33 Phased Innovation Award application in translational research should have a strong biological rationale for the intended approach and supporting data from rigorously designed experiments. NINDS urges applicants to the program to consider the rationale for the chosen animal model(s) and endpoints, adequacy of controls, route and timing of therapeutic dosing, justification of sample size, statistical methods, blinding methods, strategies for randomization, and robustness and reproducibility of results. (See NOT-NS-11-023: Improving the Quality of NINDS-Supported Preclinical and Clinical Research through Rigorous Study Design and Transparent Reporting.)

Overall Plan for Therapy Development: Each NINDS Exploratory/Developmental Project in Translational Research will, if successful, initiate a process for the completion of preclinical development through IND. It is therefore essential for R21/R33 applicants to include, within the Research Strategy, a description of how future preclinical goals will be achieved. Because an NINDS phased innovation award project in translational research can be a preliminary study, the overall plan for therapy development can also be preliminary, and does not have to include details on the resources and processes that will be used. The plan should describe intent to apply the results of the R21/R33 studies to further preclinical development of the most promising candidate, an awareness of the future goals and challenges, and a plan to establish the necessary collaborations and obtain the necessary funding to reach IND. Clearly outline how results from these studies will impact translational research priorities of the NINDS and how they will be used to secure additional funding through BPN or CREATE or other translational programs.

Team Management Plan: NINDS strongly encourages applicants to form multidisciplinary teams that consist of academic/industry experts relevant to the research plan. 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. Describe how the team will work together (e.g., review and report of data across disciplines, decision-making, participate meetings with NINDS, communication etc.) over the course of the project.

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 SF424 (R&R) Application Guide, with the following modification:

• All applications submitted for the January 25, 2015 due date or after are expected to comply with the NIH Genomic Data Sharing Policy as detailed in NOT-OD-14-111, as applicable.

Appendix: Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

Form only available in FORMS-E application packages for use with due dates on or after January 25, 2018.

When involving NIH-defined human subjects research, clinical research, and/or clinical trials 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 a Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information
All instructions in the SF424 (R&R) Application Guide must be followed.

Delayed Onset Study: All instructions in the SF424 (R&R) Application Guide must be followed.

Foreign Institutions

Foreign (non-U.S.) institutions must follow policies described in the NIH Grants Policy Statement, and procedures for foreign institutions described throughout the SF424 (R&R) Application Guide.

3. Submission Dates and Times

Part I. Overview Information contains information about Key Dates. 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.

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. If a Changed/Corrected application is submitted after the deadline, the application will be considered late.

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.

4. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

5. 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.

6. Other Submission Requirements and Information

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

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

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

Important reminders:

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

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

See more tips for avoiding common errors.

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

Post Submission Materials

Applicants are required to follow our Post Submission Application Materials policy.

Section V. Application Review Information

Important Update: See NOT-OD-16-006 and NOT-OD-16-011 for updated review language for applications for due dates on or after January 25, 2016.

1. Criteria

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

For this particular announcement, note the following:

Reviewers will consider whether applications have a strong biological rationale for the intended approach and supporting data from rigorously designed experiments. Reviewers will consider the novel aspects of the application and how their approach is different from what is already known. Finally, reviewers will consider the clarity of the therapeutic development plan and future directions.

Reviewers will consider the milestones when evaluating the approach proposed. The clarity and completeness of the R21/R33 application with regard to timeline, specific goals and feasibility milestones are critical. The milestones proposed in the application will be reviewed based on how well they are described, if they are quantifiable, and if they are justified scientifically, so as to allow assessment of progress and successful completion in the R21 phase.

For the R21/R33 Phased Innovation Award application, the initial review group will evaluate the specific goals for each phase and the feasibility milestones that would justify expansion to the R33 phase. A single overall impact score will be assigned to each discussed application.

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? 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? Is there strong biological rationale based on well-designed experimental data? Is the project relevant for therapeutic development? Will the project, if successful, bring the investigators closer to a therapeutic that will be a significant improvement over existing therapeutics to treat a neurological disorder(s)?

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? Is the investigator team knowledgeable and experienced with the proposed biological target? Do the researchers have sufficient preclinical and therapeutic discovery expertise? Do the researchers have relevant therapy development experience that includes design and implementation of the preclinical studies? Have the researchers formed multi-disciplinary collaborations?

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? Does the project pursue validated targets, mechanisms and pathways, and treatment approaches? Does the project offer significant improvement over existing technologies?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? 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? Is the timeline reasonable for the work proposed?

Is there a sufficiently developed plan for the assessment of therapeutic agent chemical, biophysical, and biological characterization and on target and off-target in vitro profiling within the proposed grant period? Does the proposed study make scientific sense and is it designed rigorously? Are the proposed in vivo efficacy study and/or pharmacodynamics measures relevant to the proposed clinical indication? Are the proposed experiments part of a well-thought out and clearly defined therapeutic development plan? Are the in vivo models and preclinical outcome measures to assess efficacy and/or PD optimal for the proposed clinical indication? Is the project feasible? Will the project, if successful, produce a robust pharmacodynamics measure or in vivo efficacy results that can support future therapeutic development? Will it produce therapeutic agent(s) that meet the entry criteria for BPN or CREATE discovery or other future development mechanisms?

Key entry criteria for BPN and CREATE include: (1) clear and convincing demonstration of proof-of-concept (e.g., clear dose-response relationship); (2) one or more therapeutic leads from, which a candidate can potentially be derived; (3) in vitro and in vivo assays proposed to optimize the leads, applicants must have pre-existing data demonstrating the assays are suitable for the proposed purpose and available in either the applicant's or collaborator's laboratories. Are controls appropriate, and have efforts been made to demonstrate dynamic detection range and acceptable variability, so that the feasibility of the proposed studies can be adequately assessed?

Have the investigators considered the rigor of their experimental design? Does the proposed project use sufficient experimental and statistical rigor? For key experiments, does the application explain assumptions for power analysis, describe statistical analysis methods and criteria for data inclusion or exclusion, and detail the procedures of how blinding and randomization will be conducted?

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

Environment

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

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.

Milestones and Timelines:

Are milestones robust and associated with clear, quantitative criteria for success that allow go/no-go decisions? If a criterion is not to be used for go/no-go decisions, are it justifiable?

Are the timelines proposed for achieving the milestones realistic and inclusive of necessary steps, but also efficient without unnecessary steps? Are there additional key experiments that need to have milestones designated?

Protections for Human Subjects

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

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

Inclusion of Women, Minorities, and Children

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

Vertebrate Animals

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following five points: 1) proposed use of the animals, and species, strains, ages, sex, and numbers to be used; 2) justifications for the use of animals and for the appropriateness of the species and numbers proposed; 3) adequacy of veterinary care; 4) procedures for limiting discomfort, distress, pain and injury to that which is unavoidable in the conduct of scientifically sound research including the use of analgesic, anesthetic, and tranquilizing drugs and/or comfortable restraining devices; and 5) methods of euthanasia and reason for selection if not consistent with the AVMA Guidelines on Euthanasia. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

Biohazards

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

Resubmissions

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

Renewals

Not Applicable

Revisions

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

Additional Review Considerations

As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.

Intellectual Property (IP) Strategy

Are there any intellectual property constraints that potentially could impede the development of the therapeutic and/or commercialization and achievement of the goals of the program?

Are there any constraints of, which they are aware that could impede their use of therapeutic agents, assays, or models for research purposes and/or commercial development (e.g., certain restrictions under transfer or sharing agreements, applicants' previous or present intellectual property filings and publications, compounds with similar structures that are under patent and/or on the market, etc.)? If so how would these issues be addressed? Are the applicants' institution's existing or planned infrastructure for bringing the compounds to practical application (e.g., licensing for further therapeutic development, managing IP, commercializing discoveries) consistent with achieving the program goals? Are the applicants working closely with technology transfer officials at their institution to ensure that royalty agreements, patent filings, and all other necessary IP arrangements are completed in a timely manner and that commercialization plans are developed and updated over the course of the project?

Has information (filing dates, the type of patent, and application status) been included for any pertinent patents?

Applications from Foreign Organizations

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

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 following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: 1) Data Sharing Plan; 2) Sharing Model Organisms; and 3) Genomic Wide Association Studies (GWAS) /Genomic Data Sharing Plan.

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:

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

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 . Following initial peer review, recommended applications will receive a second level of review by the appropriate national Advisory Council or Boardl. The following will be considered in making funding decisions:

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

3. Anticipated Announcement and Award Dates

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons.

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 grantee’s business official.

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

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

NINDS reserves the right to contact the applicant to discuss the proposed milestones and any changes suggested by the review panel as indicated in the Summary Statement prior to funding an application. If necessary, the NINDS Program Officer and the applicant will negotiate and agree on a final set of milestones. These will be the basis for evaluating the success of the R21 work. The release of R33 funds will be based on successful completion of negotiated scientific milestones, program priorities, and the availability of funds. NINDS emphasizes the importance of the robustness and reproducibility of experimental results in evaluating progress.

2. Administrative and National Policy Requirements

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

Cooperative Agreement Terms and Conditions of Award

Not Applicable

3. Reporting

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

A final progress report, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

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

For funded applications, the Project Director/Principal Investigator (PD/PI) will submit a progress report to the Program Officer upon completion of the R21 milestones. To avoid a break in funding, the PD/PI should submit this progress report at least two months before the end of the R21 budget period. Receipt of this progress report will trigger an administrative program review that will determine whether or not the R33 should be awarded.

Section VII. Agency Contacts

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

Application Submission Contacts

eRA Service Desk (Questions regarding ASSIST, eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)
Finding Help Online: https://grants.nih.gov/support/index.html
Email: commons@od.nih.gov

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact CenterTelephone: 800-518-4726
Email: support@grants.gov

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone: 301-945-7573
Email: GrantsInfo@nih.gov

Scientific/Research Contact(s)

Kristopher Bough, PhD
National Institute on Drug Abuse (NIDA)
Telephone: 301-443-9800
Email: boughk@mail.nih.gov

Mary Ann Pelleymounter, PhD
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-1779
Email: mary.pelleymounter@nih.gov

Christina Vert, MS
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-1779
Email: vertc@ninds.nih.gov

Peer Review Contact(s)

Chief, Scientific Review Branch
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-9223
Email: nindsreview.nih.gov@mail.nih.gov

Financial/Grants Management Contact(s)

Pamela Fleming
National Institute on Drug Abuse (NIDA)
Telephone: 301-253-8729
Email: pfleming@nida.nih.gov

Tijuanna DeCoster, PhD
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-9231
Email: decostert@mail.nih.gov

Section VIII. Other Information

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

Authority and Regulations

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Parts 74 and 92.