Required Application Instructions

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

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

A. Overview

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 Biotechnology Products and Biologics (CREATE Bio) program is dedicated to biotechnology product- and biologics- based therapies, which broadly include modalities such as peptides, proteins, oligonucleotides, gene therapies, and cell therapies. The program includes two tracks: the Discovery Track (link to PAR-14-286) supports lead optimization in order to obtain a candidate appropriate for entering the Development Track, and the Development Track supports IND-enabling studies for the candidate, as well as early-phase clinical trials.

For the NINDS CREATE Bio Development Track FOA, at entry, the project should have an identified candidate that has undergone rigorous preclinical testing and has sufficient 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). Projects are expected to achieve filing of an Investigational New Drug (IND) application to the U.S. Food and Drug Administration (FDA), at a minimum, by the end of the funding period. For more advanced projects, a small, early-phase clinical study may also be proposed when feasible, but is not required (see 'Scope' for more details). The Development Track has two phases, UH2 and UH3. While the UH2 phase supports the preparatory activities needed before launching IND-enabling studies (such as manufacturing for IND-enabling toxicology and verification of such manufactured material for its activities), the UH3 phase supports the IND-enabling studies (e.g., GLP toxicology, biodistribution, immunogenicity evaluations), and early-phase clinical trials.

Projects are funded via a UH2/UH3 cooperative agreement mechanism, which is milestone-driven and involves NINDS Scientific/Research staff's participation in developing the project plan, monitoring research progress, and appropriate go/no-go decision-making. NINDS staff will also provide assistance to academic investigators in helping them to distinguish activities that fall under the UH2 versus UH3 phases of a Development project. The expectations of the program are in line with those of industry in regards to advancing therapeutic agents through the developmental pipeline.

For more information about other NINDS Translational Programs visit the website http://www.ninds.nih.gov/funding/areas/translational_research/index.htm and for more information specifically about the CREATE Bio Program visit the website (http://www.ninds.nih.gov/funding/areas/translational_research/CREATE-Bio.htm). Applicants are strongly advised to read through the CREATE Program Announcement Frequently Asked Questions (FAQs) and examples at the website (http://www.ninds.nih.gov/funding/areas/translational_research/CREATE-FAQ.htm).

B. Scope

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

The CREATE Bio FOAs focus on biotechnology products and biologics, which broadly include modalities such as peptides, proteins, oligonucleotides, gene therapies, and cell therapies. Applicants should contact NINDS Scientific/Research staff regarding small peptide derivatives, natural products, molecules with complex structures, or combination products, to determine the fit for the FOA.

Entry Criteria:

Applicants are not required to have received and completed a prior NINDS CREATE Bio Discovery 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. Applicants cannot simultaneously submit both a Discovery and Development Track application on the same agent and disease.

Only the most promising agents that have undergone rigorous preclinical testing and are considered state-of-the-art for the disease of interest will be considered for advancement to IND-enabling studies. To be eligible for this Development Track FOA, applicants must have a candidate with the final structure for human testing that minimally satisfies all of 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 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. In particular 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) Feasibility for production and reproducible production of the candidate.

UH2 Scope

Examples of studies that can be proposed during this preparatory phase include, but are not limited to:

• Chemistry, Manufacturing, and Control (CMC) activities (e.g., master and working banks development, purification development, CMC analytical development, formulation development, scale-up manufacturing or cGMP manufacturing) for IND-enabling pharmacology/toxicology tests
• Pharmacokinetic evaluations in species relevant for toxicology or human dose-prediction
• If needed for certain therapeutic modalities, final characterization and definitive verification of in vitro and in vivo activities such as preclinical 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
• Preliminary safety such as safety pharmacology and/or dose-range finding toxicology
• Optimizing and/or validation of appropriate assays for pharamcokinetics, target engagement markers or other assays to monitor safety to be used in human trials
• Pre-IND meeting (if not done already)

The length of the UH2 phase can be brief depending on the maturity of the project at entry. Funding for the UH2 phase cannot exceed two years.

UH3 Scope

The UH3 phase will support IND-enabling development activities. For more advanced projects, a small, early-phase clinical trial (see definitions below) can also be supported when feasible during the UH3 phase. It should be noted that in this FOA clinical trials are only supported for projects where the preclinical activities are conducted under this funding mechanism and have transitioned from the UH2 phase. Applicants seeking support only to conduct early stage clinical trials should consider applying for an NINDS Exploratory Clinical Trials R01, through PAR-13-281, which provides additional flexibility in budget and time, as well as the option of including a phase II trial.

In-scope preclinical development activities for UH3 include, but are not limited to:

• IND-enabling toxicology, with toxicokinetics, if applicable
• Tumorigenicity evaluations particularly for gene therapies and cell therapies, if applicable
• Immunogenicity evaluations, if applicable
• Biodistribution studies, if applicable
• Large animal study to assess biocompatibility of means of clinical delivery of the candidate, if applicable
• Validation of appropriate assays such as for target engagement markers to enable human use
• IND and other regulatory submissions

In-scope small, early-phase clinical trials include:

• Population: patients with indicated disease, or healthy volunteers
• Total subjects =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
• Outcomes are safety, pharmacokinetics and pharmacodynamics/target engagement/target modulation. Note that clinical efficacy outcome data may be collected to prepare for Phase 2 studies, but efficacy cannot be the primary objective of the study
• The duration of the clinical trial, from initiation at first informed consent signature to the completion of data analysis, should rarely exceed 2 years

In-scope activities for clinical trial preparatory activities (only if clinical trials are proposed), which may be performed concurrently with IND-enabling preclinical studies during UH3 include, but are not limited to:

• Manufacturing of cGMP (current Good Manufacturing Practices) material for the small, early-phase clinical trial if not done already in UH2 phase
• Development and validation of biochemical assays required for clinical trials if not already complete (e.g., pharmacokinetic, pharmacodynamic, and/or immunogenicity assays)
• Preparation of clinical trial protocol, Investigator's brochure
• Preparation of documents required to support a clinical trial (e.g., case report Fforms, pharmacy manual, study coordinator manual, monitoring plan)

Within scope clinical trial activities during UH3 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
• Development of risk, detection, diagnostic, prognostic, efficacy prediction biomarkers. (NINDS recognizes that target engagement markers developed under the UH2 phase may evolve into predictive markers for treatment trials, but it is not the intent of this FOA to develop predictive biomarkers.)
• Activities to obtain a candidate that are covered under CREATE Bio Discovery Track
• Activities already performed utilizing other private or public funds to advance the agent
• Performance 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. 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 (http://www.ninds.nih.gov/news_and_events/proceedings/20101217-NEXT.htm), the NINDS Exploratory Clinical Trials program (https://grants.nih.gov/grants/guide/pa-files/PAR-13-281.html), or to the NIH StrokeNet program for stroke indications (http://www.ninds.nih.gov/research/clinical_research/NINDS_stroke_trials_network.htm

C. Milestones

Because therapy development is an inherently high-risk process, it is anticipated that there may be significant attrition as projects move through the therapy development process. Milestones are goals that are quantifiable for measuring success that can be used for go/no-go decision-making for the project, and should have quantitative criteria associated with them (see Section IV.2 for details).

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 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 project period. 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.

Since the primary focus of the Development Track is to determine the safety and toxicology of the product that will move into humans, 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 has to carefully assess toxicity in relationship to efficacy. NINDS intends to only move forward agents that are both efficacious and safe. Although the primary goals of the 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.

UH2/UH3 transition

An administrative review will be conducted by NINDS Program staff to decide whether a project will be considered for transition from the UH2 phase to the UH3 phase. UH3 eligible projects must have a candidate that has been manufactured with satisfactory purity and stability, verified to have activity in vivo and/or in vitro as necessary, have bioavailability with a proper formulation, and have a good preliminary safety profile. Specifically, projects entering the UH3 phase must satisfy the following:

• For certain therapeutic modalities, the final manufactured material for IND-enabling toxicology studies needs to have final characterization and definitive verification for in vitro and in vivo activities. In these cases, these studies should have been satisfactorily completed prior to the UH3 phase
• Have bioavailability with a proper formulation; addressed blood-brain-barrier penetrant issues if it is a CNS target
• Pharmacokinetics and pharmacokinetics-pharmacodynamics relationships are known and allow feasible dose for human testing
• Preliminary toxicology studies in animal models have been completed; any safety concerns raised based on these studies can be addressed
• Evidence that IND-enabling preclinical testing plans and study protocols have been reviewed by the FDA and input received in the context of pre-submission interaction with the agency (e.g., Pre-IND meeting with FDA)

Transition to Small, Early-Phase Clinical Trial

Clinical Trial preparatory activities may be performed concurrently with IND-enabling preclinical UH3 activities with approval of NINDS staff. General criteria for starting clinical preparatory activities, if applicable, will be based on:

• Meeting previous milestone criteria during UH2 and UH3
• Progress in IND-enabling studies
• Assessment that submission of an IND appears feasible on a timeline allowable within the grant

Prior to commencement of the clinical trial (defined as first subject signature on an informed consent form), the applicant must provide sufficient documentation to NINDS for review. On scientific or clinical grounds, NINDS may require inclusion of additional procedures beyond those required by the FDA. Therefore, approval must be received from NINDS prior to commencement of the clinical trial.

General criteria for starting a clinical trial:

• Successful achievement of the defined milestones for the preclinical portions of the UH3 period;
• Successful completion of any clinical preparatory milestones
• Submission of an IND with a "may proceed" letter or email from the FDA
• Submission of the clinical protocol and supporting documents to the NINDS
• Agreement with NINDS staff on updated timeline, milestones and budget for clinical trial
• NINDS approval of protocol and safety monitoring plan

D. Quality and Compliance Requirements

Since the goal of this program is to generate therapeutics which will be eligible for FDA approval, adherence to compliance and quality criteria is required.

• It is expected that all IND-enabling nonclinical studies will be performed in a manner consistent with Good Laboratory Practices (GLP).
• All clinical trials must be performed following Good Clinical Practices (GCP) and be in accord with NINDS Policy: http://www.ninds.nih.gov/research/clinical_research/policies/data_safety_monitoring.htm.
• Investigational products should be produced under current Good Manufacturing Practices (cGMP). Bioassays such as pharmacokinetics, pharmacodynamics or immunogenicity should, when possible, be performed under GLP guidelines.

E. Intellectual Property (IP)

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). Recipients of awards are encouraged to identify and foster relationships with potential licensing and commercialization partners early in the therapy development process. PDs/PIs are expected to work closely with their institutional technology transfer officials to ensure that royalty agreements, patent filings, and all other necessary IP arrangements are completed in a timely manner and that commercialization plans are developed and updated over the course of the project. 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.

F. Pre-application Consultation

As an UH2/UH3 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.

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

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Governments

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

Other

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

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

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

Applicant Organizations

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

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

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

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

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

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

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

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

The NIH will not accept duplicate or highly overlapping applications under review at the same time. This means that the NIH will not accept:

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

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

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

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

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

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

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed, with the following exceptions or additional requirements:

• 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. In addition, note the following additional instructions:

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, if applicable.

Applicants should describe the IP landscape surrounding their therapy. Applicants should describe any known constraints that could impede the development of their therapy (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, either an investigational therapeutic, FDA-approved therapeutic, or other licensed product, the applicant should address to the best of their knowledge, any questions of freedom to operate. 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 are filed, and application status, and associated United States Patent and Trademark Office (USPTO) database links, if applicable.

Applicants should discuss future IP filing plans. For a multiple-PD/PIs multi-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 there are multiple PD/PIs and institutions 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: The Specific Aims section should include separate Aims delineated for each of the UH2 and UH3 phases. A scientific hypothesis is not required.

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

A. Significance: Clinical Impact and Feasibility

B. Supporting Data for Entry

C. Detailed Plans for Research Strategy (Including Milestones and Timelines)

D. Team Management

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 preclinical 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 new agent has. 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) based on the FDA guidance (see guidance and example at http://www.ninds.nih.gov/funding/areas/translational_research/CREATE-Bio-Example-TPP.htm) 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 one page or less, 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).

B. Supporting Data for Entry

The Supporting Data for Entry section contains, but is not limited to, comprehensive data to 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) 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
• Demonstrate selectivity/specificity
• 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 phamacokinetics, CNS penetration, and pharmacokinetics-pharmacodynamics relationship. NINDS encourages discussion of robustness and reproducibility of the observed results (guidance available at http://www.ninds.nih.gov/funding/transparency_in_reporting_guidance.pdf).

• Explain the choice of models or assays, primary, secondary and exploratory endpoints, 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.
• Describe power analyses and associated assumptions for the determination of sample 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 discussion of effect size in relation to potential 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.

C. Detailed Plans for Research Strategy (Including Milestones and Timelines)

In this section applicants should elaborate on their research plans. Describe milestones to be used for measuring success in achieving each of the research plan’s objectives. One or more milestone should be used for 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. Most of the time 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. 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).

Plans could include but are not limited to:

• Describe experimental designs, delineated for the UH2 and UH3 phase. If the studies proposed are planned to be done in a Contract Research Organization (CRO), Contract Manufacturing Organizations (CMO), list the name(s) of the CRO(s) for the activities.
• Present a plan for the UH2 phase for the 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 preclinical IND-enabling toxicology studies, etc.
• Present a plan for how the UH3 phase preclinical 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 preclinical studies, like definitive verification of the activities of the candidate (if needed) in preclinical 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.

Early-Phase Clinical Trial Synopsis:

If requesting funding to conduct the first-in-human study, provide a brief synopsis that includes the following:

Planned population (e.g, adult, pediatric, newly diagnosed, advanced disease, subtype and/or screened for molecular/cellular target)

• Objectives
• Study design
• Route of administration and determination of dose levels
• Safety assessments
• Pharmacokinetics and pharmacodynamics assessments, with attention to demonstration of CNS penetration (if appropriate) and target engagement or modulation
• Correlative or surrogate analyses designed to assess target engagement (e.g, using blood, urine, saliva, cerebral spinal fluid (CSF), or imaging measures)
• Safety management plan (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html and http://www.ninds.nih.gov/research/clinical_research/policies/data_safety_monitoring.htm).

It is understood that at the time of application, some of the above may be limited or even unavailable, but an effort should be made to predict trial design when possible. Since details of the trial may change in the course of therapeutic development, the overview might not reflect/include the final details of the protocol that will be implemented.

At the end of the Plans for Specific Aim section, summarize milestones and timelines an example of how material can be presented is provided at http://www.ninds.nih.gov/funding/areas/translational_research/CREATE-Bio-Example-Timeline.htm.

D. Team Management Plan

NINDS strongly encourages applicants to form multidisciplinary teams that consist of preclinical and clinical scientists, CMC experts, regulatory experts, statisticians, and other academic/industry experts relevant to the therapeutic modality. This multidisciplinary team should be able to define a desired TPP (see details in Section IV-Research Strategy), to design the details of the plans and experiments, and to execute the research strategy. Describe how the team will work together (e.g., data generation, reporting of data and integrated review across teams with various disciplines, decision-making, participate meetings with NINDS, communication etc.) over the course of the project (and include letters of support). 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.

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

• If applying from an academic institution, include a letter of support from the technology transfer official who will be managing intellectual property associated with this project.
• If research will be performed at more than one institution, include a letter of support from each institution clarifying how intellectual property will be shared or otherwise managed across the institutions.
• If collaborating with a private entity, include a letter of support that addresses any agreement to provide agent(s), any limits on the studies that can be performed with said agent(s), any limitations on sharing of data (including negative results), and whether a licensing agreement(s) is in place. This letter should come from a high official within the private entity who has authority to speak on these issues.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS)) as provided in the SF424 (R&R) Application Guide, with the following modification:

Investigators should include a brief one-paragraph description of how the final research data will be shared or why data-sharing is not possible. If patent protection is being sought, investigators should explain how data will be shared after patent protection is secured to allow for further research and commercial development to continue unimpeded, consistent with achieving the goals of this program.

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

When conducting clinical research, follow all instructions for completing Planned Enrollment Reports as described in the SF424 (R&R) Application Guide.

When conducting clinical research, follow all instructions for completing Cumulative Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.

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

Part I. Overview Information contains information about Key Dates. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission.

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

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

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

This initiative is not subject to intergovernmental review.

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

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

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

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

For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically.

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 by the Center for Scientific Review, NIH. Applications that are incomplete will not be reviewed.

Applicants requesting $500,000 or more in direct costs in any year (excluding consortium F&A) must contact NIH program staff at least 6 weeks (at least 12 weeks is strongly encouraged) 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 our Post Submission Application Materials policy.

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

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

Specific to this announcement:

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 incident disorders that fall under the mission of NINDS.

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.

Significance

Does the project address an important problem or a critical barrier to progress in the field? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Specific to this announcement:

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?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, or 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:

Have researchers with preclinical and clinical expertise, necessary statistical expertise, and experts in relevant therapy modality development been included in the conception, design, and proposed implementation of the project?

Innovation

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

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed?

Specific to this announcement:

Regarding the Section on Supporting Data for Entry:

Is there a complete description of the candidate such as structure/identity, selectivity/specificity, stability, manufacturability, and other modality-specific characteristics? Only the most promising agents that have undergone rigorous preclinical testing and are considered state-of-the-art for the disease of interest will be considered for advancement to next stage of development such as CREATE Bio Development Track. Does this candidate represent a competitive, state of the art agent that should be moved forward 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 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? What is the robustness of the data used in support of the application? For key experiments, did the application include the following?

• The choice of models or assays, primary, secondary and exploratory endpoints, and how they are clinically relevant.
• Power analyses and associated assumptions for the determination of sample 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.
• Alternative interpretations of the experimental data, relevant literature in support of or in disagreement with the results, and discussion of effect size in relation to potential clinical impact, when interpreting the results.
• What key data, if any, have been reproduced, by the applicants or independently?

Regarding the Section on Detailed Plans for Research Strategy (Including Milestones and Timelines):

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

For key preclinical experiments (if needed for final verification), do the proposed analyses include the following?

• A primary endpoint and/or other endpoints and an explanation as to why they were chosen
• Appropriate controls
• An explanation of assumptions and supporting data for 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

Will the project reach a point at the end of UH2 where the package has sufficient information to receive FDA Pre-IND guidance?

Are the therapy development plan and activities in the UH3 phase appropriate for enabling final toxicology and safety studies, and, if applicable, early-phase clinical development, that is consistent with the desired TPP?

If a clinical trial is proposed, what are the general quality and appropriateness of the clinical trial synopsis, including proposed study design; study population; number of subjects; duration of clinical study; feasibility of proposed safety, pharmacokinetic and pharmacodynamic endpoints; and ability to complete the activities within the grant period?

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

Environment

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

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?

Are the timelines proposed for achieving the milestones realistic and inclusive of necessary steps, but also efficient without adding unnecessary steps?

Are there additional key experiments that need to have milestones?

Protections for Human Subjects

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

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

Inclusion of Women, Minorities, and Children

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

Vertebrate Animals

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

Biohazards

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

Resubmissions

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

Renewals

Not Applicable

Revisions

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

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 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?

Applications from Foreign Organizations

Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources. Note the feedback/requirements from foreign equivalents of the FDA to guide or justify research are not accepted by the program. .

Select Agent Research

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

Resource Sharing Plans

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

Budget and Period of Support

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

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.

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

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the grantee’s business official.

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

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

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

Cooperative Agreement Terms and Conditions of Award

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 UH2/UH3 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 as a whole, 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 Data and Safety Monitoring in Clinical Trials: http://www.ninds.nih.gov/research/clinical_research/policies/data_safety_monitoring.htm, 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 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 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 annual Non-Competing Progress Report (PHS 2590 or RPPR) and financial statements as required in the NIH Grants Policy Statement.

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

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

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

eRA Service Desk (Questions regarding ASSIST, eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

Finding Help Online: https://grants.nih.gov/support/index.html
Email: [email protected]

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact CenterTelephone: 800-518-4726
Email: [email protected]

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone: 301-945-7573
Email: [email protected]

Chris Boshoff, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-1779
Email: [email protected]

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

Tijuanna E. DeCoster, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-9231
Email: [email protected]

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 Parts 74 and 92.