It is critical that applicants follow the Research (R) 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

This Funding Opportunity Announcement (FOA) is part of a suite of complementary programs to encourage the translation of research discoveries into new treatments for disorders that fall under the NINDS mission.

The NINDS Cooperative Research to Enable and Advance Translational Enterprises for Biologics (CREATE Bio) program is dedicated to biotechnology products and biologics-based therapies, which broadly include modalities such as peptides, proteins, oligonucleotides, gene therapies, cell therapies, and novel emerging therapies. The CREATE Bio program includes two tracks: The Optimization Track (PAR-17-456) supports lead optimization to obtain a clinical candidate eligible for entry into the Development Track. This Development Track supports IND-enabling studies for the candidate with the possibility to include an optional small delayed-onset first in human Phase I clinical trial at the end of the funding period.

At entry, for this NINDS CREATE Bio Development Track FOA, a project should have an identified clinical candidate that has undergone rigorous nonclinical testing and has demonstrated bioactivity, stability, manufacturability, bioavailability, in vivo efficacy and/or target engagement, and is considered state-of-the-art for the disease (see entry criteria for details). At a minimum, projects are expected to achieve filing of an Investigational New Drug (IND) application to the U.S. Food and Drug Administration (FDA), at the end of the funding period. For more advanced projects, a small delayed-onset first in human Phase I clinical trial may also be proposed, but is not required (see 'Scope' for more details). A typical project will include some preparatory activities for IND-enabling studies (e.g. preliminary pharmacology and/or dose-range finding toxicology, conducting a pre-IND meeting with FDA, manufacturing and release testing of enough material needed for IND-enabling studies), followed by IND-enabling studies (e.g., GLP toxicology, biodistribution, immunogenicity evaluations), and submission of an IND package. A small delayed-onset Phase I first in human clinical trial at the end of the funding period is optional.

Projects are funded via a U01 cooperative agreement mechanism that is milestone-driven and involves NINDS Scientific/Research staff's participation in developing the project plan, monitoring research progress, and setting appropriate go/no-go decision-making criteria.

For more information about earlier stage translational funding opportunities and programs, visit the NINDS Division of Translational Research website and, for more information specifically about the CREATE Bio Program, visit the website. Applicants are strongly advised to read through the CREATE Program FAQs.

Projects must focus on a single disorder that falls within the NINDS mission.

The CREATE Bio FOAs focus on development of biotechnology products and biologic therapeutics, which broadly include modalities such as peptides, proteins, antibodies, oligonucleotides, gene therapies, cell therapies and novel emerging therapies. Applicants are encouraged to contact NINDS Scientific/Research staff regarding small peptide derivatives, natural products, molecules with complex structures, or combination products, to determine the fit for this FOA.

Applicants are expected to develop a Target Product Profile (TPP) based on the FDA guidance (see CREATE Bio Example: Target Product Profile (TPP)) that shows the ultimate goals of the proposed therapy development effort, such as disease indication and stage, patient population, delivery mode and dosing regimen, treatment duration, and standards for clinical efficacy.

Entry Criteria:

Applicants are not required to have received and completed a prior NINDS CREATE Bio Optimization Track award to be eligible to apply to the NINDS CREATE Bio Development Track. Applicants are encouraged to talk to Scientific/Research staff about the stage of their activity and receive advice as to which program is the best fit.

Only the most promising agents that have undergone rigorous nonclinical testing and are considered state-of-the-art for the disease of interest will be considered for advancement to IND-enabling studies. To be supported for this Development Track FOA, applicants must have a candidate with the final structure for human testing that minimally satisfies all the following:

(1) Optimization is finished and final characterization of the candidate, such as structure/identity, selectivity, stability, manufacturability, and other modality-specific characteristics are complete.

(2) For a candidate with sufficient purity, its minimal effective dose, optimal effective dose, time and duration of treatment, have been determined for example in relevant in vivo assays using clinically relevant functional and/or anatomical outcome measures, and/or in vivo target engagement assays. This normally should have been done using the clinically intended route of administration and special formulations if proposed (such as slow release, liposomes, nanoparticles, etc.), unless justified to use other routes of administration in which case the dose-response must have been reliably bridged by pharmacokinetics measurements. The in vivo study results should also include assessment of pharmacokinetics, bioavailability at the relevant site of action, and pharmacokinetics-pharmacodynamics relationship. Particularly, for CNS disorders, there needs to be rigorous evidence that the agent is blood-brain-barrier penetrant (unless the agent is proposed to be delivered directly to the CNS) and available at an effective dose or evidence that the agent can act in the periphery. Key studies should be sufficiently powered and controlled with experimental and statistical rigor to lend a high degree of confidence in the results, with sufficient information available about study design, execution, analysis, and interpretation.

(3) Demonstrated feasibility for reproducible production of the clinical candidate.

(4) An established and engaged multi-disciplinary project team to execute the proposed project plan that will submit at least an IND application to the FDA at the end of the funding period.

Examples of within scope and progressive activities leading towards an IND-submission that may be proposed include, but are not limited to:

• Preliminary pharmacokinetic and/or safety evaluations in species relevant for toxicology or human dose-prediction
• Dose-range finding toxicology studies
• Pre-IND meeting with FDA (if not done before)
• Chemistry, Manufacturing, and Control (CMC) related activities (e.g., master and working banks development, purification development, CMC analytical development, final formulation development, scale-up manufacturing or cGMP manufacturing) for IND-enabling pharmacology/toxicology testing
• If needed for certain therapeutic modalities, final and definitive verification of in vitro and in vivo activities such as nonclinical target engagement and/or efficacy studies, using the final manufactured material (using final cGMP process depending on regulatory requirement) intended for IND-enabling toxicology studies
• Validation of existing assays for pharmacokinetics, target engagement markers or other assays to monitor safety and/or efficacy outcomes to enable human use.
• IND-enabling safety pharmacology and toxicology, with toxicokinetics if applicable, in relevant animal model(s)
• Preparation and submission of an IND package to FDA

Optional: conduct a small, delayed-onset, first in human Phase I clinical trial:

Note: This CREATE Bio Development Track FOA supports an optional small, delayed-onset first in human Phase I clinical trial only for projects where the nonclinical activities are conducted under this same funding mechanism and the proposed clinical trial has transitioned from these nonclinical studies.

• Population: patients with indicated disease or healthy volunteers
• Total number of subjects not exceeding 50
• Design is single dose or single ascending dose treatment, and may be placebo-controlled or open-label studies; multiple ascending dose may be requested only if agent has a short half-life
• Clinical trial outcomes may include safety, tolerability, pharmacokinetics and pharmacodynamics/target engagement/target modulation endpoints.

Note: clinical efficacy outcome data may be collected to prepare for Phase 2 studies, but efficacy cannot be the primary objective of this delayed-onset clinical study

• The duration of the delayed-onset clinical trial, from initiation at first informed consent signature to the completion of data analysis, should rarely exceed 2 years

In-scope activities for optional small delayed-onset first in human clinical trial preparatory activities (only if clinical trials are proposed), which may be performed concurrently with IND-enabling nonclinical studies include, but are not limited to:

• Manufacturing of cGMP (current Good Manufacturing Practices) material for the small, early-Phase clinical trial if not done earlier.
• Development and validation of biochemical assays required for clinical trials if not already completed (e.g., pharmacokinetic, pharmacodynamic, and/or immunogenicity assays)
• Preparation of documents such as a clinical trial protocol, investigator's brochure etc.
• Preparation of documents required to support a clinical trial (e.g., case report forms, pharmacy manual, study coordinator manual, monitoring plan)

Within scope clinical trial activities, include but are not limited to:

• Patient/subject recruitment and enrollment
• Site monitoring
• Data collection and quality assurance
• Statistical analysis
• Safety reviews

Examples of activities inappropriate for this FOA include:

• Animal model development
• Basic research and studies of disease mechanisms
• Early research such as identifying and validating targets and generation of preliminary agents that are not suitable for human testing
• Activities to optimize an agent or lead that are covered under CREATE Bio Optimization Track, except for activities to transition to IND-enabling studies
• Activities already performed utilizing other private or public funds to advance the agent
• Inclusion of a clinical trial with the objective of demonstrating clinical efficacy or clinical proof-of-concept
• Clinical trial activities that require more than 2 years to complete and/or are beyond the funding period of the FOA.
• Stand-alone clinical trials. Applicants proposing clinical trials or biomarker studies that fall outside of the scope of this FOA may wish to consider applying to the NINDS NeuroNEXT clinical trials program, the NINDS Exploratory Clinical Trials program (PAR-17-122), and NIH StrokeNet programs.

Milestones are quantifiable goals that are used to monitor project progress and facilitate dialogue and go/no-go decision making between program staff and the project team to effectively manage the project (see Section IV.2 for details). NINDS recognizes time sensitivity in developing therapeutics for patients who urgently need new or better treatment. If the research contains parallel activities from an independently funded, ongoing study prior or during the funding period, its impact should be noted in the milestone section of the U01.

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

Progress towards achievement of the final set of milestones will be evaluated by NINDS Program staff. NINDS Program staff may seek advice from independent consultants with relevant expertise as necessary. If justified, future year milestones may be revised based on data and information obtained during the previous year. Funding for the project may be discontinued if milestones are not met. In addition to milestones, the decision regarding continued funding will also be based on the overall robustness of the entire data package that adequately allows an interpretation of the results (regardless if they have been captured in the milestones), overall progress, NINDS portfolio balance and program priorities, competitive landscape, and availability of funds.

Since the primary focus of this Development Track is to determine the safety and toxicology of the product that will move into human testing, applicants should keep in mind that the efficacious dose levels should, ideally, be non-overlapping with a dose(s) resulting in significant toxicity and reflect the fact that one must carefully assess toxicity in relationship to efficacy. NINDS intends to only support candidates that are both efficacious and safe. Although the primary goals of this Development Track are to assess safety and toxicology, lack of evidence of robust efficacy in the dose range where the candidate is safe can also be a consideration for discontinuation.

NINDS emphasizes the importance of the robustness and reproducibility of experimental results. In some cases, conducting additional critical experiments will be important for NINDS to have confidence in making a funding decision. Therefore, NINDS Program staff, in consultation with the PD/PI, may add experiments that need to be conducted prior to, or during, the award as an additional milestone(s). In most cases, these studies will be supported by additional funds from NINDS.

Applicants are encouraged to read examples of milestones (CREATE Bio Example Milestones), and see a summary chart of a milestone timeline (CREATE Bio Milestone Summary and Timeline).

Transition to an optional small delayed-onset, first in human Phase I clinical trial:

Some clinical trial preparatory activities may be performed concurrently with IND-enabling nonclinical activities with approval by NINDS staff. General criteria for starting clinical preparatory activities, if applicable, will be based on:

• Meeting previous project milestone criteria
• Progress with IND-enabling studies
• Assessment that submission of an IND appears feasible on a timeline allowable within the grant

Prior to commencement of the small delayed-onset first in human clinical trial (defined as first subject signature on an informed consent form), the grantee must provide required documentation to NINDS for evaluation by a clinical trial working group. After the clinical protocol is fully developed, but before submitting the IND package to FDA, a NINDS convened working group must review the proposed small delayed-onset first in human clinical trial. This working group may require inclusion of additional specifications before the IND package is submitted and reviewed by FDA. Subsequently, if the submitted IND package is not on clinical hold, the working group will make a recommendation to the NINDS council. Therefore, NINDS council funding approval must be obtained for the proposed small delayed-onset first in human clinical trial prior to release of NINDS funds and commencement of clinical trial activities.

General requirements before initiating a small delayed-onset, first in human Phase I clinical trial:

• Successful completion of the established project milestones for the preceding nonclinical studies
• Successful completion of any clinical trial preparatory activities
• Submission of clinical protocol, clinical team members with their qualifications, and supporting documents to NINDS Clinical Trial Working Group for review prior to filing IND package to FDA
• NINDS Clinical Trial Working Group recommendation and NINDS Council approval of clinical protocol, safety monitoring plan and feasibility of proposed clinical trial
• If applicable, obtained Recombinant DNA Advisory Committee (RAC) approval
• Submission of an IND package to FDA and IND not on clinical hold for any reason
• Agreement with NINDS staff on updated timeline, milestones and budget for clinical trial

Since the goal of this program is to develop therapeutics that may be eligible for FDA approval, the use of Good Laboratory Practices (GLP) and current Good Manufacturing Practices (cGMP) for investigational products and IND enabling nonclinical studies should be performed in compliance with FDA regulations.

Since the ultimate goal of the CREATE Bio program is to bring new therapies to the market/patients, the program strongly encourages the awardees and/or their collaborators to obtain and retain any IP developed around the therapy during the project period (see instructions on attachment of letters to address IP issues in Section IV). In compliance with the Bayh-Dole Act, this program is structured so that the awardee institution can elect to retain title to inventions; not withstanding the rights reserved by the U.S. Government if title is elected by awardee institution, NINDS/NIH does not intend to hold any additional IP rights for therapies developed in this program. NIH policy requires invention reporting in iEdison. Patents should also include a reference to NIH funding support by including the grant/cooperative agreement number in the patent. The awardee institution will take responsibility for patent filings, prosecution, and maintenance as well as licensing efforts toward eventual commercialization. PDs/PIs are expected to work closely with their institutional technology transfer/business development officials to ensure that appropriate technology transfer 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. Award recipients are encouraged to identify and foster relationships with potential licensing and commercialization partners early in the therapy development process. For rare or ultra-rare diseases, where commercialization may be challenging, applicants are encouraged to discuss alternative strategies with NINDS Scientific/Research staff to get further guidance.

As an U01 cooperative agreement, implementation will involve the participation of NINDS Program staff in the planning and execution of the therapy-directed projects. Applicants are strongly encouraged to consult with NINDS Scientific/Research staff when planning an application. Early contact provides an opportunity for NINDS Scientific/Research staff to provide further guidance on program scope, goals, developing appropriate milestones, and budget. Applicants should contact NINDS Scientific/Research staff at least 12 weeks before a receipt date.

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

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from 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 cannot simultaneously submit both an Optimization and Development Track application on the same agent and disease.

Buttons to access the online ASSIST system or to download application forms are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

It is critical that applicants follow the Research (R) Instructions in the SF424 (R&R) Application Guide, 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 For this specific FOA, the Research Strategy section is limited to 30 pages.

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

Applications should include an Intellectual property (IP) strategy that is no more than 1 page. Applicants are encouraged to prepare this section of the application in consultation with their institution's technology transfer officials.

Applicants should describe the IP landscape surrounding their therapy. 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.

If the applicant proposes using an agent(s) whose IP is not owned by the applicant's institution, e.g. either an investigational therapeutic, FDA-approved therapeutic, or other licensed product, the applicantmust ensure that all IP issues are considered and will not block achieving the goals of the program . Applicants should include a letter (see letter of support) from the entity who owns 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 therapy being developed under this application have been filed, the applicant should indicate the details of filing dates, what type of patents were filed, 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.

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: A scientific hypothesis is not required.

Research Strategy:

The Research Strategy section should include the following sections:

A. Significance

Clinical Impact and Feasibility

Each application should focus on only one disorder or disease, even if the therapeutics proposed for development shows activity in models for more than one disorder. This is because the target patient population and intended use guide the design of the therapy and the path for an IND, and the nonclinical IND-enabling studies. Levels of tolerated toxicities may also differ between different disorders especially if the proposed treatment is chronic versus acute.

• Describe the current state of knowledge of the etiology, clinical characteristics, and prevalence of the proposed disease indication.
• Briefly discuss available treatments (if any), their limitations, and how the proposed project would provide an advantage over all existing therapies, regardless of therapeutic class (i.e., discussion only on within class comparisons is not sufficient).
• If the therapy is an improvement over an earlier generation agent(s) that has not been marketed, discuss what advantages the proposed new agent will have. Include results from previous clinical trials with related agents.
• Discuss how the proposed project relates to therapy development efforts underway in academia and industry, regardless of therapeutic class. What are the distinct advantages to the new, proposed therapy considering other investigational agents that might be entering the clinical pipeline soon?
• Provide a Target Product Profile (TPP) that shows the ultimate goals of the proposed therapy development effort, such as disease indication and stage, patient population, delivery mode and dosing regimen, treatment duration, and standards for clinical efficacy. Explain the rationale behind the minimally acceptable and ideal parameters for the clinical population.
• In addition to a TPP, outline the plans for the first clinical proof-of-concept study that aligns with the proposed TPP and comment on feasibility of conducting the trial(s). Details may include but are not limited to: How you would have access to the planned population (e.g., adult, pediatric, newly diagnosed, advanced disease, subtype and/or screened for molecular/cellular target); route of administration; what clinical endpoints are meaningful; correlative or surrogate analyses designed to assess target engagement (e.g., using blood, urine, saliva, cerebral spinal fluid (CSF), or imaging measures); etc.

Supporting Data for Entry

The Supporting Data for Entry section contains, but is not limited to, comprehensive data that support the scientific premise, that justify that the application meets the entry criteria, as well as data that demonstrate the feasibility of conducting studies to address the specific aims, for example:

1. Scientific Rationale

• Make a strong case for the choice of target (can be molecular, cellular, or system). Indicate whether evidence from multiple groups supports this is a compelling target for the disease. It is not absolutely necessary to know the precise molecular target, but knowledge of the mechanism of action is helpful to anticipate potential toxicities and essential to assess target engagement.
• Provide data and justify your selection of the candidate. Describe what is known about the candidate such as structure/identity, selectivity/specificity, bioactivity, stability, bioavailability, and other modality- specific characteristics. Show structure/identity such as cell identity for cell therapies, purity, aggregation, epitope mapping, glycosylation, or other post-translational modification for proteins
• Describe bioactivities of the candidate in vitro (e.g., binding affinities, IC50 in relevant in vitro model). Show evidence that the candidate modulates the targets or pathway in vitro.

2. Present data showing the minimal effective dose, optimal effective dose, time and duration of treatment. These should have been determined in relevant in vivo assays using clinically relevant functional and/or anatomical outcome measures, and/or in vivo target engagement assays, using a candidate that is sufficiently pure. [This normally should have been done using the clinically intended route of administration and special formulations if proposed (such as slow release, liposomes, nanoparticles, etc.), unless justified to use other routes of administration in which case the dose-response must have been reliably bridged by pharmacokinetics measurements]. Present data on pharmacokinetics, CNS penetration, and pharmacokinetics-pharmacodynamics relationship. NINDS encourages discussion of robustness and reproducibility of the observed results (see guidance on Rigor and Reproducibility).

• Explain the choice of models or assays, primary, secondary and exploratory endpoints for nonclinical studies, and how they are clinically relevant. If multiple models have been employed, outline the pros and cons of each model and why one model may be more robust than another. Explain which model(s) is the one most frequently employed in IND-enabling studies to seek approval from the FDA.
• For nonclinical studies, describe power analyses and associated assumptions for the determination of sample size, effect size, statistical handling of the data such as criteria for data inclusion or exclusion, and describe the procedures of how blinding and randomization were conducted, and whether independent replication was employed in these studies.
• Describe bioavailability; include data and analyses performed to demonstrate the candidate can penetrate the blood-brain-barrier, if required for efficacy.
• When interpreting the results, consider alternative interpretations of the experimental data, relevant literature in support of or in disagreement with the results, and include a detailed discussion of effect size in relation to potential therapeutic or clinical impact.
• Applicants should explain what key data, if any, has been reproduced, by the applicants or by independent investigators.

3. Discuss feasibility of production and reproducibility of production of the candidate.

B. Approach

Detailed Plans for Research Strategy (Including Milestones and Timelines)

In this section applicants should elaborate on their strategy for therapy development. This section should contain detailed milestones for nonclinical studies and if proposed only anticipated start and end date milestones for clinical trials in relation to project years. Detailed clinical trial milestones would be established and assessed just prior to commencement of the delayed-onset clinical trial if proposed. One or more milestones should be used for measuring success of each objective. For each milestone provide details on methods, assumptions, experimental designs, and data analysis plans (if the results are quantitatively measured). Specify the quantitative criteria for measuring success and the rationale for the quantitative criteria. Quantitative criteria should be robust and be consistent with the state-of-the-art in the field. The quantitative criteria for success in the milestones will also be used for making go/no-go decisions and this should be specified. Specify the timeline for each milestone. There should be at least one milestone proposed for completion at the end of each year for the duration of the entire project. If the research contains parallel activities from an independently funded, ongoing study prior or during the funding period, it should be noted with appropriate milestones.

Plans could include but are not limited to:

• Describe detailed experimental designs including if the studies proposed are planned to be done using a Contract Research Organization (CRO) or Contract Manufacturing Organizations (CMO). If applicable, list the name(s) of the CRO/CMO(s) for these activities and how oversight will be managed.
• If applicable, present a plan for all preparatory work for IND-enabling studies such as CMC activities, preliminary safety studies, validation of target engagement assays to support future human clinical trials, final characterization of the manufactured material intended for nonclinical IND-enabling toxicology studies, etc.
• Present a plan for how nonclinical studies that are consistent with or per regulatory guidance will be achieved. These include IND-enabling toxicology, tumorigenicity evaluations as needed, immunogenicity evaluations as needed, biodistribution studies as needed, large animal study to assess biocompatibility of means of clinical delivery of the candidate, validation of appropriate assays for target engagement markers to enable human use, etc.
• For critical nonclinical studies, like definitive verification of the activities of the candidate (if needed) in nonclinical efficacy studies, and/or pharmacokinetics-pharmacodynamics studies, provide the following:
• The choice of models, assays, and clinically-relevant endpoints (primary, secondary, and exploratory when applicable) for these studies;
• Information on study design, power analyses and associated assumptions for sample size estimation (e.g., what is considered a minimal change predictive of clinically meaningful change, variance known in the in vivo assay described in supporting data, expected treatment effect size), and detailed procedures of how blinding and randomization will be done;
• Data handling rules such as criteria for inclusion and exclusion of data;
• Plans for data analysis and interpretation;
• Outline any differences between how these analyses will be performed and those used to develop the Entry Criteria (outlined above) for the candidate. Provide a rationale for any changes.

At the end of the Research Strategy summarize milestones and timelines. See an example at CREATE Bio Milestone Summary and Timeline.

C. Nonclinical Team Management Plan

Therapy development is a complex and time-consuming undertaking, and NINDS expects applicants to form multidisciplinary teams that consist of nonclinical and clinical scientists, PK experts, CMC experts, regulatory experts, statisticians, project manager, and other academic/industry experts relevant to the therapeutic modality and disorder. This multidisciplinary team should establish a desired TPP , define the attributes of a successful therapeutic for the intended clinical indication, identify gaps that need to be filled during this funding period, and design the details of the plans and experiments to execute the research strategy. Engaging a team that includes members experienced in the IND process will help identify issues, strategize solutions and options, plan details of studies and set a realistic timeline. Describe how the team, including consultants, has already been engaged and a plan as to how they will continue working together over the course of the project (e.g., recurring team meetings, review and report of data across disciplines, decision-making, participate in meetings with NINDS, communication, etc.). Letters of support should be included and should not be generic, but instead indicate what has been contributed so far and what they expect to provide during the project to allow an evaluation of team engagement (see below). Indicate the willingness of the PD/PI(s) and key personnel to operate under the cooperative agreement terms and conditions outlined in section VI.2. Of the FOA. Note: Team management plans should not duplicate information from the multi-PI plan.

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 senior official 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. If patent protection is being sought, investigators should explain how data will be shared after patent protection is secured.

Appendix:

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

Use only for applications with due dates on or after January 25, 2018. 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:

Delayed-onset Study

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

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.

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

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

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

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

Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.

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. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile 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 or non-compliant will not be reviewed.

Applicants requesting $500,000 or more in direct costs in any year (excluding consortium F&A) must contact a Scientific/ Research Contact at least 6 weeks before submitting the application and follow the Policy on the Acceptance for Review of Unsolicited Applications that Request $500,000 or More in Direct Costs as described in the SF424 (R&R) Application Guide.

Applicants are required to follow the instructions for post-submission materials, as described in the policy. In addition, the NINDS Scientific Review Officer (SRO) will accept regulatory meeting minutes and transcripts, patents, and late-breaking data not later than 30 calendar days prior to the peer review meeting. Any instructions provided here are in addition to the instructions in the policy.

Important Update: See NOT-OD-18-228 for updated review language for due dates on or after January 25, 2019.

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 market size for the proposed therapy will not be considered in assessing the significance of a project. NINDS is supportive of research for both rare and high incidence disorders.

In addition, for applications involving clinical trials:

A proposed Clinical Trial application may include study design, methods, and intervention that are not by themselves innovative but address important questions or unmet needs. Additionally, the results of the clinical trial may indicate that further clinical development of the intervention is unwarranted or lead to new avenues of scientific investigation.

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?

Specific to this announcement:

Regarding the Section on Clinical Impact and Feasibility:

If the project is successful according to the proposed Target Product Profile, how does it affect clinical practice with consideration to existing treatments and therapeutic development efforts underway in academia and industry, including all therapeutic classes?

Regarding the Section on Supporting Data for Entry:

Scientific Premise: what is the robustness of the data provided in support of the target (can be molecular, cellular or system) for the intended disease? Does the clinical candidate show efficacy and target engagement in relevant animal model(s) using sufficient experimental and statistical rigor? Were the models and assays used clinically relevant? Were the efficacy endpoints used clinically relevant? For key supporting data, did 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 were conducted? What key data, if any, have been reproduced, by the applicants or independently?

Is there a complete description of the candidate such as structure/identity, selectivity/specificity, stability, bioactivity that shows modulation of the target or pathway in vitro, manufacturability, and other modality-specific characteristics? Does this candidate represent a competitive, state of the art agent that should be advanced to IND-enabling studies?

Have the minimal effective dose, optimal effective dose, time and duration of treatment been determined using in vivo assays? Were these conducted using clinically intended route of administration and special formulations, clinically relevant functional and/or anatomical outcome measures, and/or in vivo target engagement assays, using a candidate that is sufficiently pure? Did the application address bioavailability, blood-brain-barrier penetration issues if it is a CNS target, and pharmacokinetics-pharmacodynamics relationship?

Does the application discuss feasibility of production and reproducibility of production of the candidate?

In addition, for applications proposing clinical trials

Are the scientific rationale and need for a clinical trial to test the proposed hypothesis or intervention well supported by preliminary data, clinical and/or preclinical studies, or information in the literature or knowledge of biological mechanisms? For trials focusing on clinical or public health endpoints, is this clinical trial necessary for testing the safety, efficacy or effectiveness of an intervention that could lead to a change in clinical practice, community behaviors or health care policy? For trials focusing on mechanistic, behavioral, physiological, biochemical, or other biomedical endpoints, is this trial needed to advance scientific understanding?

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?

Specific to this announcement:

Has a multidisciplinary team been engaged, including expertise in nonclinical, clinical, PK, CMC, regulatory, statistics, and any other experts relevant to the therapeutic modality and disorder? Is any expertise lacking? Based on the team management plan and letters of support descriptions of how the members have already contributed to the design and proposed implementation of the project and how they will continue working together over the course of the project, does the team seem capable and sufficiently engaged to successfully complete the activities needed to develop the therapeutic candidate?

In addition, for applications proposing clinical trials

With regard to the proposed leadership for the project, do the PD/PI(s) and key personnel have the expertise, experience, and ability to organize, manage and implement the proposed clinical trial and meet milestones and timelines? Do they have appropriate expertise in study coordination, data management and statistics? For a multicenter trial, is the organizational structure appropriate and does the application identify a core of potential center investigators and staffing for a coordinating center?

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?

In addition, for applications proposing clinical trials

Does the design/research plan include innovative elements, as appropriate, that enhance its sensitivity, potential for information or potential to advance scientific knowledge or clinical practice?

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

Specific to this announcement:

Regarding the Section on Detailed Plans for Research Strategy

(Including Milestones and Timelines):

Are the plans necessary and sufficient to achieve the Specific Aims?

How rigorous are the experimental design and methodological approaches for key proposed nonclinical experiments, and do the proposed analyses include the following?

• Appropriate models and/or assays, that are clinically relevant
• A primary endpoint and/or other endpoints and an explanation as to why they were chosen
• Appropriate controls
• An explanation of assumptions and reference to supporting data for statistical power analyses
• A description of planned data analyses and data handling rules such as criteria for data inclusion or exclusion
• A detailed description of the procedures of how blinding and randomization will be implemented
• Are the proposed therapy development plans and activities appropriate for enabling final toxicology and safety studies, and, if applicable, early-Phase I clinical development, consistent with the desired TPP?

Does the application adequately address the following, if applicable to delayed-onset clinical trials

Study Design

Is the study design justified and appropriate to address primary and secondary outcome variable(s)/endpoints that will be clear, informative and relevant to the hypothesis being tested? Is the scientific rationale/premise of the study based on previously well-designed nonclinical and/or clinical research? Given the methods used to assign participants and deliver interventions, is the study design adequately powered to answer the research question(s), test the proposed hypothesis/hypotheses, and provide interpretable results? Is the trial appropriately designed to conduct the research efficiently? Are the study populations (size, gender, age, demographic group), proposed intervention arms/dose, and duration of the trial, appropriate and well justified?

Are potential ethical issues adequately addressed? Is the process for obtaining informed consent or assent appropriate? Is the eligible population available? Are the plans for recruitment outreach, enrollment, retention, handling dropouts, missed visits, and losses to follow-up appropriate to ensure robust data collection? Are the planned recruitment timelines feasible and is the plan to monitor accrual adequate? Has the need for randomization (or not), masking (if appropriate), controls, and inclusion/exclusion criteria been addressed? Are differences addressed, if applicable, in the intervention effect due to sex/gender and race/ethnicity?

Are the plans to standardize, assure quality of, and monitor adherence to, the trial protocol and data collection or distribution guidelines appropriate? Is there a plan to obtain required study agent(s)? Does the application propose to use existing available resources, as applicable?

Data Management and Statistical Analysis

Are planned analyses and statistical approach appropriate for the proposed study design and methods used to assign participants and deliver interventions? Are the procedures for data management and quality control of data adequate at clinical site(s) or at center laboratories, as applicable? Have the methods for standardization of procedures for data management to assess the effect of the intervention and quality control been addressed? Is there a plan to complete data analysis within the proposed period of the award?

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?

In addition, for applications proposing clinical trials,

If proposed, are the administrative, data coordinating, enrollment and laboratory/testing centers, appropriate for the trial proposed?

Does the application adequately address the capability and ability to conduct the trial at the proposed site(s) or centers? Are the plans to add or drop enrollment centers, as needed, appropriate?

If international site(s) is/are proposed, does the application adequately address the complexity of executing the clinical trial?

If multi-sites/centers, is there evidence of the ability of the individual site or center to: (1) enroll the proposed numbers; (2) adhere to the protocol; (3) collect and transmit data in an accurate and timely fashion; and, (4) operate within the proposed organizational structure?

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 the milestones robust and associated with clear, quantitative criteria for success that allows go/no-go decisions? If a criterion is not to be used for go/no-go decisions, is it justifiable? Is a rationale provided for each milestone?

Are the timelines proposed for achieving the milestones realistic and inclusive of necessary steps, but also efficient without adding unnecessary steps? Will the proposed timeline allow completion of all the activities within the grant period?

Are there any gaps in the proposed milestones?

Would achieving all milestones in the application allow the project to achieve the end goals?

Study Timeline

Specific to applications proposing clinical trials

Is the study timeline described in detail, taking into account start-up activities, the anticipated rate of enrollment, and planned follow-up assessment? Is the projected timeline feasible and well justified? Does the project incorporate efficiencies and utilize existing resources (e.g., CTSAs, practice-based research networks, electronic medical records, administrative database, or patient registries) to increase the efficiency of participant enrollment and data collection, as appropriate?

Are potential challenges and corresponding solutions discussed (e.g., strategies that can be implemented in the event of enrollment shortfalls)?

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 criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate 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

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.

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 potential issues regarding the IP landscape for the therapeutic being developed and the freedom to operate addressed?

Do the IP Strategy attachment and related letters of support address potential concerns?

Are there any known current or future constraints that could impede the development of the therapeutic?

Are IP filing plans described and appropriate?

If multiple institutions are involved, is IP sharing addressed?

Reviewers will assess whether the project presents special opportunities for furthering research programs using 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 (GDS).

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

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.

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 Board. The following will be considered in making funding decisions:

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

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

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

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.

Additionally, ICs may specify any special reporting requirements for the proposed clinical trial to be included under IC-specific terms and conditions in the NoA. For example: If the proposed clinical trial has elevated risks, ICs may require closer programmatic monitoring and it may be necessary to require the awardee to provide more frequent information and data as a term of the award (e.g., to clarify issues, address and evaluate concerns, provide documentation). All additional communications and information related to programmatic monitoring must be documented and incorporated into the official project file. Individual awards are based on the application submitted to, and as approved by, the NIH and are subject to the IC-specific terms and conditions identified in the NoA. ClinicalTrials.gov: If an award provides for one or more clinical trials. By law (Title VIII, Section 801 of Public Law 110-85), the "responsible party" must register and submit results information for certain applicable clinical trials on the ClinicalTrials.gov Protocol Registration and Results System Information Website (https://register.clinicaltrials.gov). NIH expects registration of all trials whether required under the law or not. For more information, see http://grants.nih.gov/ClinicalTrials_fdaaa/

Institutional Review Board or Independent Ethics Committee Approval: Grantee institutions must ensure that the application as well as all protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the awardee must provide NIH copies of documents related to all major changes in the status of ongoing protocols. Data and Safety Monitoring Requirements: The NIH policy for data and safety monitoring requires oversight and monitoring of all NIH-conducted or -supported human biomedical and behavioral intervention studies (clinical trials) to ensure the safety of participants and the validity and integrity of the data. Further information concerning these requirements is found at http://grants.nih.gov/grants/policy/hs/data_safety.htm and in the application instructions (SF424 (R&R) and PHS 398). Investigational New Drug or Investigational Device Exemption Requirements: Consistent with federal regulations, clinical research projects involving the use of investigational therapeutics, vaccines, or other medical interventions (including licensed products and devices for a purpose other than that for which they were licensed) in humans under a research protocol must be performed under a Food and Drug Administration (FDA) investigational new drug (IND) or investigational device exemption (IDE).

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.

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person’s race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency. HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research.

For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/index.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html; and https://www.hhs.gov/civil-rights/for-providers/laws-regulations-guidance/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 Federal awarding agency review of risk posed by applicants. This provision will apply to all NIH grants and cooperative agreements except fellowships.

Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Parts 74 and 92 (Part 92 is applicable when State and local Governments are eligible to apply), and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the U01 cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the purpose of NIH is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

The PD(s)/PI(s) will have primary responsibility for:

• The PD(s)/PI(s) will have primary responsibility for defining objectives and approaches, and for planning, conducting, analyzing, interpreting, drawing conclusions on their studies, publishing and sharing the results.
• Awardees are responsible for developing and proposing rigorous milestones that will be achieved during the project period.
• Awardees will retain custody of and have all rights to the data and therapy developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.
• Awardees are responsible for pursuing patent protection.
• Awardees are responsible for providing progress reports with completeness that include experimental design with rigor, including assumptions for the design of the experiments, the results of the investigations, interpretations of the results, and for concluding whether milestones have been met or not. In cases when NINDS Program staff request raw data, awardees agree to provide the data.
• Awardees agree to participate at least once a year in progress meetings (teleconferences) that are organized by NINDS staff.
• Regarding meetings and interactions with regulatory agencies, awardees agree to communicate meeting dates and agenda to the NINDS Program staff and invite their participation.
• Awardees agree to communicate study reports from CROs, meeting minutes (and associated data packages if applicable), letters and other forms of communications with FDA, Recombinant DNA Advisory Committee (RAC), and other authorities, and to provide IND# and registration numbers in clinical trial.gov, if applicable.
• If performing a clinical trial, awardees are responsible for providing regulatory and clinical documents that are required for administrative review.
• If a clinical trial is performed, awardees must verify that it is performed in accord with Good Clinical Practices (GCP) and in accord with NINDS Guidelines for Monitoring in Clinical Trials, and must provide data and regular updates to NINDs.

NIH staff have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:

• Each project will have the support of one or more Project Scientists from NINDS Program staff who are assigned an administrative role for the neurological disorder being studied and have expertise in the implementation of the NINDS CREATE Bio Program in Translational Research.
• The NINDS Project Scientists will have substantial scientific/programmatic involvement during the conduct of this activity, through technical assistance, advice, and coordination above and beyond normal program stewardship for grants.
• NINDS Project Scientist(s) provides input on the milestones and makes decisions regarding their finalization.
• NINDS Project Scientist(s) will be responsible for assessing the progress of the project towards the specified milestones, and for recommending if further funds should be released to the project.
• NINDS Project Scientist(s), in consultation with the PD/PIs, may add critical experiments that need to be conducted prior to or during the award as an additional milestone(s). In most cases, these studies will be supported by additional funds from NINDS.
• NINDS Program Scientist(s) participates in meetings together with PD/PIs with regulatory agencies related to the funded project.
• An important part of the NINDS CREATE Bio program is the coordination of research efforts across different funding mechanisms and research capabilities, and the coordination among efforts aimed at different neurological disorders. NINDS Project Scientists will have the primary responsibility for this overall coordination.
• Additionally, an agency program official or IC program director will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice. The assigned program director may also serve as an NIH Project Scientist.
• NINDS leadership will make decisions on project continuation based on Program staff recommendations, programmatic prioritizations and budget considerations. NINDS Program staff may consult as necessary with independent consultants with relevant expertise. If justified, future year milestones may be revised based on data and information obtained during the previous year. If, based on the progress report, a funded project does not meet the milestones, funding for the project may be discontinued. In addition to milestones, the decision regarding continued funding will also be based on the overall robustness of the entire data package that adequately allows an interpretation of the results (regardless if they have been captured in the milestones), overall progress, NINDS portfolio balance and program priorities, competitive landscape, and availability of funds.

Areas of Joint Responsibility include:

Clarifying, negotiating and finalizing the milestones and timelines.

Dispute Resolution

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. It will have three members: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16. Final decisions made by NINDS regarding a discontinuation are not appealable.

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

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.

In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period. The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 Award Term and Conditions for Recipient Integrity and Performance Matters.

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

eRA Service Desk (Questions regarding ASSIST, eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Finding Help Online: http://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 Center Telephone: 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

Chris Boshoff, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-1779
Email: chris.boshoff@nih.gov

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

Chief Grants Management Officer
National Institute of Neurological Disorders and Stroke (NINDS)
Email: ChiefGrantsManagementOfficer@ninds.nih.gov NINDS)

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.