Background

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 animal models, model systems, 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.

Animal Models and Model Systems
Animal models and 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. Animal models should be compatible with endpoints that are measurable and relevant to the disease process in both preclinical and clinical settings.

Development of animal models or model systems 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 animal model or 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 animal model or model system can recapitulate aspects of the disease phenotype and etiology, where endpoints or biomarkers of disease are similar and measurable in both the model system and in human disease. One component of external validity is face validity-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 construct validity--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 face and construct external validity are certainly desirable in an animal model or model system, predictive validity provides the most confidence in the ability of the animal model or model system to translate to human disease. Predictive validity refers to the probability that a clinically validated therapeutic agent (biologic or small molecule) will have the same effects in the animal model or model system as it will in the intended clinical population. By definition, the evaluation of predictive validity requires a validated 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 animal model or model system. However, it is important to include evaluations of internal validity, and face, construct, and predictive validity (to the extent possible), to provide evidence that the proposed animal model or model system represents a significant advance over existing animal models or model systems.

Pharmcodynamic (PD) Markers
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 should represent meaningful and quantitative indices of a therapeutic agent's effects in humans, evidence of robust internal and external validation must be demonstrated. Internal validation includes evaluation of the precision, reliability, sensitivity, accuracy and dynamic range characteristics of the PD measurement. External validation typically verifies that the PD marker represents a component of disease etiology and/or therapeutic target mechanism of action that can be demonstrated in both preclinical and clinical settings. 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.

FOA Scope

The FOA will support 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 measurable in the animal model and human disease (i.e., neurological deficits, patterns of activation using functional Magnetic Resonance Imaging (fMRI) or electroencephalography (EEG), measurable genetic markers, functional or behavioral read-out, disease progression, etc). The FOA will also support the development of 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 animal models or 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
• Discovery of disease initiation, remission, relapse, or progression biomarkers
• In vitro primary assay development and test agent screening (covered by PAR-18-762 )
• Test agent screening and optimization (covered by PAR-18-762 )
• Studies aimed at testing a potential therapeutic agent for efficacy or safety in an existing and validated model system (covered by PAR-18-761)
• Studies aimed at identifying, optimizing or developing a potential therapeutic agent in an existing and validated model system (covered by PAR-18-761 and PAR-18-761)
• Pharmacokinetic studies of a potential therapeutic agent (covered by PAR-18-761)
• Device discovery and/or development
• Clinical Research or Clinical Studies with the exception of research that meets the E4 human subjects exemption criteria:https://humansubjects.nih.gov/sites/hs/public_files/exemption_infographic_v4_hs_internet.pdf

Applications focused on any of the above will be deemed inappropriate .

Phased Award Activities

The identification and characterization of clinically relevant preclinical models 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 R61/R33 mechanism. The R61 phase will support initial development, internal validation and optimization of the animal model, model system, or PD marker.

The R33 phase will support any required scaling along with external validation studies. The final outcome should be a fully validated model system, or PD marker that can be utilized in both preclinical and clinical settings to test the biological effects of candidate therapeutics designed to treat neurological disease. Transition from the R61 to the R33 phase is contingent upon the successful completion of proposed milestones. Milestones are goals that are quantifiable for measuring success that can be used for go/no-go decision making at the R61/R33 transition point, and should have timelines and quantitative criteria associated with them. All milestones should be useful as a measure of progress toward the overall goal of the project. Specific Aims or a list of activities planned for each year are not considered milestones because they do not provide decision-making goals. NINDS emphasizes the importance of the robustness and reproducibility of experimental results in evaluating progress.


Examples of activities in the R61 Phase include, but are not limited to:

• Initial development of the model, 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.
• Complete internal validation for endpoints used in the model system or PD measure
• Scale-up for external validation studies

Examples of activities in the R33 Phase include, but are not limited to:

• 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 validated therapeutic agents (if available) in the new model system

Additional Considerations

Demonstration of collaborative relationships between applicants with preclinical and clinical drug development expertise (such as biostatisticians and clinicians) is highly encouraged. It is preferred that the collaborating clinician is listed as a co-investigator or a formal member of the investigative team. Alternatively, a letter of support from the collaborating clinician can be used to demonstrate involvement in the project, but should include a plan for collaboration with the principal investigator. The clinician should have demonstrated experience in the development of therapeutic entities to treat neurological disease.

Applicants are strongly encouraged to contact Scientific/Research staff to discuss potential research projects prior to submitting an application.
Small Business applicants who are eligible for the Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) programs are strongly encouraged to submit through either the SBIR or STTR Omnibus Solicitations (https://sbir.nih.gov/funding#omni-sbir) to take advantage of the congressionally mandated set-aside specifically for small businesses. Please see https://www.ninds.nih.gov/Funding/Small-Business-Grants for more information about the programs.

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
https://www.ninds.nih.gov/Current-Research/Research-Funded-NINDS/Translational-Research.

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)

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.

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.

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: Within the Specific Aims section, include headers titled R61 Phase Specific Aims and R33 Phase Specific Aims. Under each header, state the specific objectives of the efforts. Briefly provide the context and overall rationale for the proposed set of studies, with an emphasis on the reason that the proposed animal model, model system, 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 animal model, model system, or PD marker, which includes any existing clinical evidence that the animal model, model system, or PD marker could be relevant in human neurological disease (how well the model system will recapitulate the neurological deficits, pathology, disease progression, and genetic basis of the human disease compared to current models)
  • Biological rationale for the proposed animal model, 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 animal model, model system, 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 animal model, model system, or PD marker
• Value for Future Drug Discovery/Development
  • Brief discussion of the value of the proposed animal model, model system, or PD marker to the drug discovery and development process
  • Address how the animal model, model system, 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 animal model, model system, 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 animal model, model system, or PD marker
  • Provide a clear outline of the studies designed to evaluate internal and external validity
  • 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
  • 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

Milestones Transition from the R61 to the R33 phase is contingent upon the successful completion of one set of proposed milestones. The specific milestone(s) proposed in the application will depend on the goals of the application and the accomplishments necessary in the R61 phase for advancement into the scaling and validation studies proposed for the R33 phase. These milestones are to be included as the last element of the Research Strategy section of the application and will be evaluated as part of the scientific and technical merit of the R61/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 R61 phase. Specific aims or a list of activities are not considered milestones because they would not provide decision-making goals. A discussion of the milestones relative to the progress of the R61 phase and the implications of successful completion of the milestones for the R33 phase should be included. The clarity and completeness of the R61/R33 application with regard to specific goals and feasibility milestones are critical. Milestones should provide clear indicators of a project's continued success or emergent difficulties and will be used to evaluate the application as part of the consideration of the awarded project for further funding of non-competing award years by the Program Director(s)/Principal Investigator(s), and Program Official For frequently asked questions and milestone examples, please see https://www.ninds.nih.gov/Current-Research/Research-Funded-NINDS/Translational-Research/Funding-Programs-Researchers/IGNITE.

Timeline Provide a timeline with specific milestones for progression from the R61 phase to the R33 phase. The timeline, specific goals and feasibility milestones should be clear and complete. Indicate when it is anticipated that essential components of the project will be completed. The proposed timeline with specific milestones should be clearly delineated and should appear as the last element of the Research Strategy section.

Rigorous Study Design and Supporting Data
An R61/R33 Phased Innovation Award application in translational research should have a strong biological rationale for the intended approach, supporting data from rigorously designed experiments, and proposed studies that exhibit methodological rigor. NINDS urges applicants to the program to consider the rationale for the chosen animal model(s) and endpoints, adequacy of controls, justification of sample size, statistical methods, blinding methods, strategies for randomization, and robustness and reproducibility of results. (See https://grants.nih.gov/reproducibility/index.htm and NOT-NS-11-023: Improving the Quality of NINDS-Supported Preclinical and Clinical Research through Rigorous Study Design and Transparent Reporting.)

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

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

When involving NIH-defined human subjects research, clinical research, and/or clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

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

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

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

Applicants are required to follow the instructions for post-submission materials, as described in the policy. Any instructions provided here are in addition to the instructions in the policy.

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? Is there a strong scientific premise for the project? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?