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.

Part 1. Overview Information
Part 2. Full Text of the Announcement

Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

Optimization of novel therapeutics is usually dependent upon preclinical evaluation in animal models or ex vivo model systems. In addition, it is widely recognized that the ability to monitor the direct effects of potential therapeutic agents on the intended biological target using pharmacodynamic (PD) markers is essential for accurate interpretation of clinical data. Unfortunately, many drug discovery programs focused on neurological disease lack both PD markers and validated models of disease and are therefore unable to adequately inform or predict translational outcomes. This FOA is intended to support the development of validated and clinically relevant model systems, testing paradigms, and/or PD markers focused on neurological disorders. These model systems and PD markers should translate to the clinical setting to the degree that they can inform the decision to advance a therapeutic candidate to clinical testing and can inform clinical study design.

Model systems should represent a significant advance over those that currently exist for a defined neurological disease. They can include genetic, chemical, and/or physiological manipulations in animals or ex vivo systems that recapitulate a significant component (clinical manifestations and underlying physiology) of the disease condition in humans. Model systems should be compatible with endpoints that are measureable and relevant to the disease process in both preclinical and clinical settings.

Development of model systems or testing paradigms that translate to a human disorder or disease requires rigorous internal and external validation. In order to demonstrate internal validation, it is important to evaluate and understand the precision, reliability, sensitivity, accuracy, and dynamic range characteristics of the endpoints used to assess the effect of therapeutic or physiological intervention in the model system. In addition, it is essential that the general experimental design procedures utilized in characterizing the model are conducted in a rigorous manner, utilizing randomization, blinding and the appropriate power analysis.

It is also important to address external validation, showing that the model system or testing paradigm can recapitulate aspects of the disease phenotype and etiology, where endpoints or biomarkers of disease are similar and measureable in both the model system and in human disease. One component of external validity is the similarity between the model and the clinical manifestation of the disease (as measured by overt clinical symptoms, patterns of activation using fMRI or EEG, functional or behavioral read-outs, disease progression, etc). Another component of external validity is the similarity between the physiological or biological basis of the model and the actual human disorder (i.e., genetic, proteomic, metabolomic markers). Although components of both forms of external validity are certainly desirable in a model system, predictive validity provides the most confidence in the ability of the model system or testing paradigm to translate to human disease. Predictive validity refers to the probability that a known therapeutic agent (biologic or small molecule) will have the same effects in the model or testing paradigm as it will in the intended clinical population. By definition, the evaluation of predictive validity requires a molecular tool that has been shown to alter disease progression in humans. Since these tools do not necessarily exist for many neurological diseases, it is not always possible to obtain true evidence of predictive validity until the candidate therapeutic is actually tested in humans. Therefore, it may not always be possible to evaluate the predictive validity of a new model system. However, it is important to include evaluations of both internal and external validity (to the extent possible), to provide evidence that the proposed model system represents a significant advance over existing model systems or testing paradigms.

This FOA will also support the development of PD markers that indicate the biologic effect of therapeutics administered to treat neurological disease. PD markers typically represent a component of the molecular pathway mediating the biological effects of therapeutic target modulation. Some examples of PD markers include receptor occupancy, phosphorylation of proteins in the target signaling pathway, changes in substrate or product levels as a result of target enzyme modulation, gene transcription, physiological changes, etc. These PD markers are intended to: 1) represent endpoints that can be measured in both preclinical and clinical settings, and 2) represent a significant advance over PD measurements that may already exist for the therapeutic agent and targeted neurological disorder. Since PD markers must represent meaningful and quantitative indices of a therapeutic agent's effects in humans, these indices typically have demonstrated external validity, in that the PD marker represents a component of disease etiology and/or therapeutic target mechanism of action. For example, manipulation of the therapeutic target (i.e., knockdown, silencing, activation) should result in a quantitative change in the PD marker that is consistent with knowledge of the target pathway. In addition, manipulation of the target with a therapeutic agent that has been in clinical testing (if any are available) should have the same effects on the PD marker in preclinical and clinical settings.

The FOA will fund applications to develop animal models of neurological disease that recapitulate aspects of the disease pathophysiology as well as its etiology, where endpoints or markers of disease are similar and measureable in the animal model and human disease (i.e., neurological deficits, patterns of activation using functional Magnetic Resonance Imaging (fMRI) or electroencephalography (EEG), measureable genetic markers, functional or behavioral read-out, disease progression, etc). The FOA will also support the development of testing paradigms and non-genetic models (i.e., motor function, physiological manipulations such as artificial vessel obstruction or diet) that expose disease symptoms in animals and humans. In addition, it will support the development and validation of ex vivo testing systems that utilize existing human cell systems (i.e., induced Pluripotent Stem Cells (IPSC). Finally, the FOA supports the development and validation of PD markers (receptor occupancy, gene transcription, protein synthesis/secretion, etc.) that can be used to follow the biological effects of the therapeutic test agent in the context of a defined neurological disease. Since this FOA does not support the development of model systems for the purpose of testing hypotheses about disease etiology, it is assumed that model development will be based upon widely accepted hypotheses or knowledge regarding disease etiology.

The knowledge gained from these studies should lead to the development of "next generation" translational models of neurological disease and/or PD markers of target engagement for therapeutics designed to treat a defined neurological disease. Taken together, the new translational model systems and PD markers developed as a result of applications to this FOA should provide an improved translational toolkit that will better predict the efficacy and safety of new therapeutic entities, thereby facilitating future drug discovery and development in the field of neurological disorders and stroke.

Out-of-scope activities include:

• Development of animal and ex vivo cellular models for the purpose of understanding disease etiology
• Cell line development; please see the published NINDS notice: https://grants.nih.gov/grants/guide/notice-files/NOT-NS-14-032.html
• Identification of CNS drug targets
• Development of disease initiation, remission, relapse, or progression biomarkers
• Human clinical validation of model systems or pharmacodynamic markers
• In vitro primary assay development and test agent screening (covered by PAR-15-070)
• Studies aimed at testing a potential therapeutic agent for efficacy or safety in an existing and validated model system (covered by PAR-15-071)
• Studies aimed at identifying, optimizing or developing a potential therapeutic agent in an existing and validated model system (covered by PAR-15-070 and PAR-15-071)
• Pharmacokinetic studies of a potential therapeutic agent (covered by PAR-15-071)
• Device discovery and/or development (covered by PAR-14-300)

Applications focused on any of the above will be deemed unresponsive and will not be reviewed.

Phased Award Activities

The identification and characterization of clinically relevant preclinical models and testing paradigms typically require a multi-step process that includes initial feasibility testing of the model system followed by internal and external validation. Therefore, this funding opportunity will use a phased R21/R33 mechanism. The R21 phase will support initial development and optimization of the model, testing paradigm or PD marker and will include a set of clear and quantitative milestones as indicators of feasibility. After completion of this phase, the project may advance to the R33 phase for any required scaling, along with completion of internal and external validation studies. The final outcome should be a fully validated model system, testing paradigm or PD marker that can be utilized in both preclinical and clinical settings to test the biological effects of candidate therapeutic test agents designed to treat neurological disease.

Activities in the R21 Phase

• Initial development of the model, testing paradigm, ex vivo system or PD measure
• Any optimization of the above related to feasibility, endpoint range and sensitivity, potential to scale up for validation studies (breeding, aging, etc.), specificity of the model system/PD measure as it relates to the disease or endpoint measures, identification of confounding variables, etc.
• Activities in the R33 Phase Complete internal validation for endpoints used in the model system or PD measure
• Scale-up for external validation studies
• All external validation studies, including comparisons of phenotype to human disease, comparisons of disease etiology in preclinical species to what is known about the human disease and efficacy of clinically tested therapeutic agents (if available) in the new model system

Demonstration of collaborative relationships between applicants with preclinical and clinical drug development expertise is highly encouraged. A letter of support from the contributing or advising clinician would be considered an excellent example of a demonstrated collaborative relationship between an applicant and his/her clinical colleague. The clinician should have demonstrated experience in the development of therapeutic entities to treat neurological disease.

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.

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

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.

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)

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.

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.

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.

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

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).

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.

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.

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

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.

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

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

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

Other Attachments:

Intellectual Property (IP): Applications should include an Intellectual property (IP) strategy, if appropriate. 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 model system or PD marker. Applicants should describe any known constraints that could impede their model system/PD marker discovery and development (e.g., certain restrictions under transfer or sharing agreements, applicants' previous or present IP filings and publications, similar model systems/PD markers 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 a technology or agent(s) for validation purposes 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 technology or validating agent(s), if there are any limitations on the studies that can be performed with that technology or validating 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 technology or validating 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.

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

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

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

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

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

Specific Aims: Briefly provide the context and overall rationale for the proposed set of studies, with an emphasis on the reason that the proposed model system, testing paradigm, or PD marker will significantly improve the translational quality of existing tools in the specified neurological disease area. In addition, the major objectives of the proposed set of studies should be stated, including the technical questions to be answered to determine the feasibility and the validity of the proposed model systems, testing schemes, or PD markers relative to the end goal of a clinical setting.

Research Strategy: The Research Strategy section should include the following sections:

• Rationale and Unmet Need
  • Translational rationale for the proposed model system or PD marker, which includes any existing clinical evidence that the model system could be relevant in human neurological disease ( how well will the model system recapitulate the neurological deficits, pathology, disease progression, and genetic basis of the human disease compared to current models)
  • Biological rationale for the proposed model system or PD marker as it relates to the current knowledge of disease etiology or targeted pathway for a potential therapeutic
  • Novelty of the model system, testing paradigm or PD marker, along with the potential advantages of the proposed model over alternatives available in the neurological disease of interest
  • Description of the unmet need for the proposed model system, testing paradigm or PD marker
• Value for Future Drug Discovery/Development
  • Brief discussion of the value of the proposed model system or PD marker to the drug discovery and development process
  • Address how the model system, testing paradigm, or PD marker would be utilized in the drug discovery/development process (i.e., preliminary efficacy testing, proof of concept, as a surrogate for efficacy, as a marker of target engagement, for eventual hypothesis testing, etc.).
• Approach
  • Description of how the model system, testing paradigm or PD marker will be produced, including a plan to confirm the feasibility and applicability of the model system, testing paradigm or PD marker
    1) Is there evidence that the endpoints for the model system would be feasible in a clinical setting?
    2) If the model requires breeding or aging, will sufficient animals be available to conduct validation studies within the 3-year limit of the funding period?
    3) What are the plans to optimize (if necessary) the model system or PD marker in order to conduct the studies required to provide external validation of the model system or PD marker?
• Include a detailed plan for internal and external validation of the model system, testing paradigm or PD marker
  • o Provide a clear outline of the studies designed to evaluate internal and external validity
  • o Examples of points to address for the evaluation of internal and external validity in the development of animal or ex vivo model systems are provided in Part 2, Section I of this announcement
  • o In the case of PD marker development, evaluation of external validity could include the following:
    • Plans to address the consistency of the PD marker with the expected effects of target modulation (i.e., does an activator increase the amplitude of the PD marker and does an inhibitor or genetic silencing reduce the amplitude of effect?)
    • Plans to address the role of the PD marker in the specified disease etiology
    • Plans to demonstrate the feasibility and utility of the PD marker in preclinical and clinical settings
    • Plans for studies of the correlation between the pharmacokinetics of a reference drug (if one exists) and the PD endpoint
• Timeline and Proposed Milestones
  • The proposed timeline should be clearly delineated relative to the proposed quantitative milestones and should appear as the last element of the Research Strategy.
  • One set of milestones is required to transition between the R21 phase to the R33 phase of the grant. The specific milestone(s) proposed in the application will depend on the goals of the application and the accomplishments necessary in the R21 phase for advancement into the scaling and validation studies proposed for the R33 phase. The set of milestone(s) should be clearly defined, quantifiable, and scientifically justified to allow the investigator and 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 those milestones for the execution of the R33 phase should be included.
    (For frequently asked questions and milestone examples, please see http://www.ninds.nih.gov/funding/areas/translational_research/ignite.htm).

Letters of Support: Applicants should include a letter of support from a clinical collaborator, as described in Part 2, Section I. The letter of support should outline a collaboration plan between the preclinical and clinical applicants. The collaboration plan should include the roles and responsibilities of the preclinical and clinical scientists in developing the model system or PD marker as it relates to the pathophysiology and/or disease etiology of clinical populations typically recruited in drug development programs focused on a specific neurological disease. The plan should also address the feasibility of endpoint measures in preclinical and clinical settings, along with the strategy for external validation.

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, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.

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 (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.

See Part I. Section III.1 for information regarding the requirements for obtaining a Dun and Bradstreet Universal Numbering System (DUNS) Number and for completing and maintaining an active System for Award Management (SAM) registration. 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.

This initiative is not subject to intergovernmental review.

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

Pre-award costs are allowable only as described in the NIH Grants Policy Statement.

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

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

For assistance with your electronic application or for more information on the electronic submission process, visit 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 and responsiveness by components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

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

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.

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:

The R21/R33 phased innovation grant supports investigation of novel scientific ideas or new interventions, model systems, tools, or technologies that have the potential for significant impact on biomedical or behavioral and social sciences research. Appropriate justification for the proposed work can be provided through literature citations, data from other sources, or, when available, from investigator-generated data. It is important to critically evaluate the evidence supporting the biological and translational rationale for the project. Accordingly, reviewers will focus their evaluation on the conceptual framework, (including the biological and translational premise), the level of innovation, and the potential to significantly advance the discovery of neurotherapeutic agents. Reviewers will assign a single impact score for the entire application, which includes both the R21 and R33 phases.

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).

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

Does the project address an important problem or a critical barrier to progress in the field? 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?

Further criteria specific to this opportunity: 1) What is the potential of the model system, testing paradigm or PD marker to translate to human disease? 2) How carefully have the investigators considered the phenotype, physiology, and feasibility of measurement of the targeted clinical population in the design and validation of their preclinical model system? 3) What are the feasibility and utility of the model system or PD marker from both preclinical and clinical perspectives? 4) How strong is the rationale of unmet need for the model system or PD marker in the defined neurological disease area? 5) Has the investigator carefully considered the role of the model system or PD marker in the drug discovery and development process? 6) What is the overall potential for the proposed studies to significantly advance translational medicine and drug development in the disease area described?

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?

Further criteria specific to this opportunity: Are the investigators knowledgeable and experienced about the biological target and/or disease biology? Do the investigators have sufficient expertise in the areas of in vivo or ex vivo pharmacology, experimental design, statistical analysis, systems analysis, etc (as appropriate) for the project? Have they formed collaborations with clinicians who have drug development experience? Are the roles of each collaborator carefully defined in the research plan?

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?

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?

Further criteria specific to this opportunity: Has the application included plans to optimize the model system, testing paradigm, or PD marker (if necessary)? Are there plans to estimate the feasibility of the model system, testing paradigm, or PD marker for validity testing? Does the application include a carefully detailed plan for assay validation (both internal and external validation)? In the case of endpoint measures (PD markers, model systems, or testing paradigms), have methods for addressing internal validity characteristics such as dynamic range, precision, accuracy, etc., been addressed? Is the proposed statistical analysis appropriate for the experimental design and the quantitative characteristics of the endpoints? Have methods for evaluating external validity characteristics (how well the model system recapitulates human clinical symptoms, pathology, physiology and genetic basis for disease) been systematically outlined in the application for animal model systems and PD marker characterization? Has the applicant thoughtfully considered the potential to produce an animal model system or PD marker that will be feasible to implement and will meaningfully translate to human biology?

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?

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?

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, is 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? Does the set of milestones allow the evaluation of progress in the R21 phase and will successful completion of these milestones provide confidence that the investigator will be able to successfully implement the R33 phase?

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

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

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

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following 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.

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

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

Not Applicable

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.

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

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

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

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

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.

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

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

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

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.

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.

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

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.

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

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

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)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-945-7573

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

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

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

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

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

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

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