Department of Health and Human Services
Part 1. Overview Information
Participating Organization(s)

National Institutes of Health (NIH)

Components of Participating Organizations

National Institute of Neurological Disorders and Stroke (NINDS)

Funding Opportunity Title

NINDS CREATE Bio Discovery Track: Optimization in Preparation for Development of Biotechnology Products and Biologics (U01)

Activity Code

U01 Research Project – Cooperative Agreements

Announcement Type

New

Related Notices

None

Funding Opportunity Announcement (FOA) Number

PAR-14-286

Companion Funding Opportunity

PAR-14-288, UH2/UH3 Phase Innovation Awards Cooperative Agreement

PAR-14-287, U44 Small Business Innovation Research (SBIR) Cooperative Agreement – Fast-Track

PAR-14-289, U44 Small Business Innovation Research (SBIR) Cooperative Agreement – Fast-Track

Catalog of Federal Domestic Assistance (CFDA) Number(s)

93.853 

Funding Opportunity Purpose

This Funding Opportunity Announcement (FOA) is dedicated to the discovery of therapeutic Biotechnology Products and Biologics (e.g., peptides, proteins, oligonucleotides, gene therapies, and cell therapies) for disorders that fall under the NINDS mission.  It supports the optimization of therapeutic lead(s) showing convincing proof-of-concept.   At the end of the funding period, projects that successfully advance through support from this program will have identified a optimized candidate, which has sufficient bioactivity, stability, manufacturability, bioavailability, in vivo efficacy and/or target engagement, and other favorable properties that are consistent with the desired clinical application, and will be ready for entry into the CREATE Bio Development track for further development to enable filing for an Investigational New Drug (IND).   

Key Dates
Posted Date

July 18, 2014

Open Date (Earliest Submission Date)

September 21, 2014

Letter of Intent Due Date(s)

Not Applicable  

Application Due Date(s)

October 21, 2014; February 11, 2015; August 11, 2015; February 11, 2016; August 11, 2016; February 8, 2017, by 5:00 PM local time of applicant organization. All types of non-AIDS applications allowed for this funding opportunity announcement are due on these dates.

Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

AIDS Application Due Date(s)

January 7, 2015; May 7, 2015; September 7, 2015; May 7, 2016; September 7, 2016; and May 7, 2017 by 5:00 PM local time of applicant organization. All types of AIDS and AIDS-related applications allowed for this funding opportunity announcement are due on these dates.

Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

Scientific Merit Review

February 2015; June 2015; November 2015; June 2016; November 2016, June 2017

Advisory Council Review

May 2015; October 2015; January 2016; October 2016; January 2017; October 2017  

Earliest Start Date

July 2015

Expiration Date

May 8, 2017

Due Dates for E.O. 12372

Not Applicable

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.



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Table of Contents

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


Part 2. Full Text of Announcement
Section I. Funding Opportunity Description
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 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 (see PAR-14-288 CREATE Development (UH2/UH3)).

For entry into the Discovery Track, projects must have convincing proof-of-concept data and one or more lead(s) that are sufficiently profiled so that the parameters to be optimized can be quantitatively specified (see entry criteria for details) in the application.  At the end of the funding period, a candidate should be in hand that has sufficient bioactivity, stability, manufacturability, bioavailability, in vivo efficacy and/or target engagement (measurement of target binding or proximal downstream effects) with defined minimal and optimal doses, and other favorable properties consistent with the desired clinical application (see Scope below for details).

Projects are funded through the U01 cooperative agreement award mechanism, which 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 familiarizing them with the therapeutic development process and the criteria needed to advance therapeutic leads to the clinic.  The expectations of the program are in line with those of industry with 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 should 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:

To be eligible for this Discovery Track FOA, projects must meet the following criteria:

(1) There must be a clear and convincing demonstration of proof-of-concept (e.g., clear dose-response relationship). The therapeutic leads should show either in vivo efficacy using clinically relevant outcome measures (e.g., anatomical, and functional when possible), and/or in vivo target engagement (measurement of target binding or proximal downstream effects) at the clinically intended site of action, using sufficient experimental and statistical rigor.  If an established animal model exists for the disease, demonstration of in vivo efficacy is the minimal requirement. 

(2) Applicants must have one or more therapeutic leads from which a candidate can potentially be derived.  For a therapeutic lead, a few final design characteristics may still need to be optimized. See Scope section for examples. The leads must have been sufficiently profiled so that all the essential key parameters to be optimized to fulfill criteria for a candidate can be quantitatively specified and prioritized. Critically, the preliminary findings need to be at a stage where IND-enabling studies are feasible at the end of the 4 years of funding.  Bioactive agents where little is known about their profile or where too many parameters (e.g., three or more) need to be optimized may not be advanced enough yet to enter the program.  

Note: NINDS recognizes that, depending on the type of agent and how it was identified and characterized, projects will enter at different stages, where certain required properties may have been optimized (repurposing a marketed therapy for a new indication is an extreme example). In the case of repurposing, the applications must show feasibility to proceed to an Investigation New Drug (IND) application and/or clinical evaluation, assuming the results from the Discovery Track funding period are positive.  For example, the applicants should have collaborations that enable access to existing toxicology or human trial data required by the Food and Drug Administration (FDA), and have the decision rights or partnership(s) to further the development of the agent for the proposed new indication.

(3) For key in vitro and in vivo assays proposed to optimize the leads, applicants must have pre-existing data demonstrating that the assays are suitable for the proposed purpose and available in either the applicant's or collaborator's laboratories.  Appropriate controls should be employed and efforts should be taken to demonstrate dynamic detection range and acceptable variability so the feasibility of conducting the proposed studies can be adequately assessed.

At the end of the Discovery U01, successful projects should minimally achieve 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.

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 in the Development Track.   The Discovery Track thus affords applicants the opportunity to build collaborations, conduct comparative studies among related agents and standard of care agents, and, ultimately, advance their most promising candidate therapeutics. 

Activities Appropriate for this FOA include, but are not limited to:

  • Optimization of the leads, like improvement of potency, specificity, bioavailability, and suitability for human testing, etc.  Specific examples include but are not limited to: optimize selectivity/specificity, selection of the best promoter or viral serotype for a gene therapy product, ideal length and/or sequence of an miRNA derivative to hone its specificity, optimization of a protein for an acceptable stability in vitro or half-life in vivo, humanization of a mouse monoclonal antibody, minimizing a predicted or previously encountered toxicity, acceptable level of production, optimization to have better suitability for the route of administration.
  • Characterization of identity and properties (e.g., cell phenotype, aggregation, epitope mapping, glycosylation or other post-translational modification, number of unpaired cysteines, oxidation, deamination, isomerization, proteolytic sites, sequences, viscosity, stability)
  • Assessment of in vitro activities (e.g., affinity, specificity, activity in cells, cellular uptake)
  • Assessment of in vivo pharmacology such as determination of dose range, dosing regimen and ideal time and duration of treatment. This includes but is not limited to assessment of efficacy  and/or target engagement; pharmacokinetics; pharmacodynamic measurement; relationships among pharmacokinetics, target engagement and/or pharmacodynamic measurement; correlations between in vitro and in vivo activities; bioavailbility at the site of action such as blood-brain-barrier penetration.
  • Assessment of efficacy in additional animal models if necessary to gain higher level of confidence for translation of the discovery to the clinic, along with the model in which the leads were shown to have efficacy. However, these activities are restricted to the purpose of supporting the proposed development of a therapy and should be a limited portion of the application.
  • Evaluation of metabolism, if applicable
  • Optimization of production (e.g., expression levels, purification yield, purity, yield of vector or cells)
  • Process development for scale-up manufacturing
  • Stage-appropriate bioanalytical assay development to develop and optimize bioanalytical assays in compliance with regulatory requirement
  • Optimization of delivery systems and special formulations (such as slow release, liposomes, nanoparticles, etc.), if applicable
  • Development of regulatory strategy and stage-appropriate interactions with regulatory agency
  • If projects at entry have in vivo efficacy data but do not have an optimized or validated target engagement assay (measurement of target binding or proximal downstream effects), the activities to optimize and validate the target engagement assays, including experiments using human specimens, are within the scope of this FOA. However, these activities are restricted to the purpose of supporting the proposed development of a therapy.

To minimize the funding gaps between the NINDS CREATE Bio Discovery and Development tracks, applicants of this Discovery Track FOA may propose limited initial work for the Development Track, such as starting to identify species for toxicology study or preliminary safety evaluations, preliminary biodistribution study, and piloting formulations.  These transitioning activities are generally restricted to the last year of the Discovery Track applications. Awardees are encouraged to apply to the Development Track FOA as soon as they are eligible, while finishing up these studies in the Discovery Track.

Examples of Activities Inappropriate for this FOA include:

  • Developing animal models
  • Basic research of disease mechanisms
  • Early activities such as target identification and validation
  • Development of risk, detection, diagnostic, prognostic, efficacy prediction biomarkers.  (NINDS recognizes that target engagement markers developed may evolve into predictive markers for making clinical decisions for treatment trials, but it is not the intent of this FOA to support development of predictive biomarkers.)
  • Manufacture of therapeutics for clinical trials
  • Clinical research and clinical trials involving human subjects except those described in scope to develop and validate target engagement assays
  • Stand-alone studies to identify, validate, or qualify a target engagement marker and other bioanalytical assays
  • Activities already performed utilizing other private or public funds to advance the agent
  • Activities that are supported through the NINDS CREATE Bio Development Track FOA (PAR-14-288 CREATE Development (UH2/UH3)), with the exception of the transitioning activities designed to enable easy transition from the Discovery to the Development Track as described above.
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 (for details see the Application and Submission section below).

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 approved 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 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.

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.

D. 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.

E. Pre-application Consultation

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. 

Section II. Award Information
Funding Instrument

Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, NIH scientific or program staff will assist, guide, coordinate, or participate in project activities.

Application Types Allowed

New
Resubmission
Revision

The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.

Funds Available and Anticipated Number of Awards

The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications.

Award Budget

Application budgets are not limited but must reflect the actual needs of the proposed project. Budgets for these projects will normally remain under $500,000 in direct costs in any given year and fluctuate over the funding period based on the stage of the project. 

Award Project Period

The project period is typically 3 years and may not exceed 4 years. 

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

Section III. Eligibility Information
1. Eligible Applicants
Eligible Organizations

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Governments

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

Other

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

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

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

Required Registrations

Applicant Organizations

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

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

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

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

Eligible Individuals (Program Director/Principal Investigator)

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

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

2. Cost Sharing

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

3. Additional Information on Eligibility
Number of Applications

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

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

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

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

  • To an RFA of an application that was submitted previously as an investigator-initiated application but not paid;
  • Of an investigator-initiated application that was originally submitted to an RFA but not paid; or
  • Of an application with a changed grant activity code.
Section IV. Application and Submission Information
1. Requesting an Application Package

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

2. Content and Form of Application Submission

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

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

Page Limitations

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

  • For this specific FOA, the Research Strategy section is limited to 30 pages.
Instructions for Application Submission

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

SF424(R&R) Cover

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

SF424(R&R) Project/Performance Site Locations

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

SF424(R&R) Other Project Information

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

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, either an investigational therapeutic, FDA-approved therapeutic, or other licensed product, the applicant should address 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 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.    

SF424(R&R) Senior/Key Person Profile

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

R&R Budget

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

R&R Subaward Budget

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

PHS 398 Cover Page Supplement

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

PHS 398 Research Plan

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

Specific Aims: List the aims for obtaining an optimized and a well characterized candidate.  A scientific hypothesis is not required.

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

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 therapeutic 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, data 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.

1. Proof-of-concept

  • 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.
  • Show evidence that the lead(s) modulates the target(s) in vitro.
  • Show clear and convincing evidence of proof-of-concept (e.g., clear dose-response relationship) that the lead(s) impacts the disease.  Efficacy should be measured using clinically relevant outcome measures and/or in vivo target engagement, with sufficient detail to allow reviewers to critically evaluate the findings. NINDS encourages discussion of robustness and reproducibility of the observed results. These include:
  • Explain the choice of model(s) or assay(s), primary, secondary and exploratory endpoints, and why they are clinically relevant.
  • 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. 
  • 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, have been reproduced, by the applicants or by independent investigators.
  • When showing figures, there should be associated text with information on the number of animals per group, how many times the experiments were repeated. Showing the most promising results of a series of tests is not acceptable.
  • Include quantitative information on purity and selectivity of the lead in these experiments for adequate evaluation and interpretation of the proof-of-concept data.

2. Lead(s)

  • Describe what is known about your lead(s) on the structure/identity, selectivity, bioactivity, potency, stability, production, etc.
  • Define what an optimized candidate would look like at the end of the Discovery Track.  Include quantitative characteristics for structure/identity, in vitro activities and in vivo pharmacology, specificity, selectivity, stability, etc. Explain how the desired quantitative characteristics are consistent with the desired TPP. Introduce what parameters of the lead(s) will be modified during the funding period.

3. Assays

  • Describe in vitro and in vivo assays that will be used to enable optimization of the lead(s) and/or to characterize the candidate. Provide data on how these assays work in the PD/PI or collaborator's laboratories using the lead(s) in the presence of appropriate controls, with sufficient information on dynamic range and variability. Demonstrate the assays fit for the proposed use in the project (if these were described under the proof-of-concept section, it can be referenced). 

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 related rationale. 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 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 how each parameter (such as potency, selectivity, stability etc.) will be optimized. If multiple parameters are to be optimized, whether they are done sequentially, in parallel, or in an iterative process.
  • Propose experiments such as demonstration of in vivo efficacy target engagement and/or with dose-response, bioavailability at the site of action (including brain penetration), pharmacokinetic-pharmacodynamics relationships. For proposed critical experiments, include 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 as described in Supporting Data Section, false positive and false negative tolerance), and detail the 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;
    • How minimal and optimal doses will be determined;
    • Whether and how the confirmation of the results will be performed;
    • The minimal purity of the test article to be used for the experiments;
  • If targets are known and the project will benefit from having a target engagement marker at the relevant site of action (measurement of binding to the target or proximal downstream effect) but the applicant does not yet have the assay validated, describe plans to develop/optimize the target engagement assay (e.g., binding, imaging, or other functional assays).  Describe in addition how target engagement assays will be incorporated into the program to support therapy development.
  • Describe how the production and reproducibility of production of the candidate will be optimized or evaluated.

Note: Applicants are encouraged to discuss impediments that could require a revision to the research plan, milestones, or timeline, with a discussion of alternative approaches.

At the end of the Plans for Specific Aim section, summarize milestones and timelines; an example is available for applicants (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 define what a state-of-the-art candidate would look like quantitatively for the intended clinical indication, and ensure gaps that need to be filled can clearly be defined and addressed during this funding period, to design the details of the plans and experiments, and to execute the research strategy. Describe how the team will work together (e.g., review and report of data across disciplines, decision-making, participate meetings with NINDS, communication etc.) over the course of the project (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.   

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.

Planned Enrollment Report

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

PHS 398 Cumulative Inclusion Enrollment Report

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

Foreign Institutions

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

3. Submission Dates and Times

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

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

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

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

4. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

5. Funding Restrictions

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

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

6. Other Submission Requirements and Information

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

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

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

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.

Requests of $500,000 or more for direct costs in any year

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 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.

Post Submission Materials

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-13-030.

Section V. Application Review Information
1. Criteria

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

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.

Overall Impact

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).

Scored Review Criteria

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

Significance

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

Specific to this announcement:

If the project is successful according to the proposed Target Product Profile, how will 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:

Proof-of-concept: 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 lead(s) show efficacy if animal models exist (or alternatively, target engagement in vivo at the clinically intended site of action when no efficacy models exist), using sufficient experimental and statistical rigor? For key experiments, 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? 

Are the leads sufficiently profiled so that all the parameters needing to be optimized to achieve the desired candidate profile are specified? Are the parameters to be optimized of high importance so that at the end of the day a candidate that is consistent with the TPP will be generated? Are the numbers of parameters to be optimized feasible to achieve within 3-4 years?

Are essential assays (in vitro and in vivo) that will be used to enable optimization of the lead(s) well characterized in the applicants or collaborator's laboratories, and suitable for the proposed use in the projects?

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

Are plans with all necessary steps to optimize the leads in order to obtain a candidate clearly spelled out?

Are there sound rationales for the choice of model(s), and advancement criteria?

How rigorous are the experimental design and methodological approaches?  For key critical experiments (such an in vivo demonstration of efficacy and/or target engagement with a dose response), does the application have the following:

  • A primary, secondary, exploratory endpoint (when applicable), and an explanation as to why they were chosen
  • Appropriate controls
  • An explanation of assumptions and reference to 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
  • Minimal requirement of the purity of the reagents

If applicable, is the plan to develop/validate the target engagement assays at site of action relevant to the proposed therapy development?


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?     

Additional Review Criteria

As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.

Milestones and Timelines

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

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

Are there additional key experiments that need to have milestones designated?

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

  • Optimization is finished and final characterization of the candidate, such as structure/identity, selectivity, stability, manufacturability, and other modality- specific characteristics are complete.
  • For a candidate with sufficient purity, have its minimal effective dose, optimal effective dose, time and duration of treatment, 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. 
  • Feasibility for production and reproducible production of the candidate.

Protections for Human Subjects

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

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

Inclusion of Women, Minorities, and Children 

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

Vertebrate Animals

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

Biohazards

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

Resubmissions

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

Renewals

Not Applicable

Revisions

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

Additional Review Considerations

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

Intellectual Property (IP) Strategy

Are 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?

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.

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by NINDS, in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

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

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications. Following initial peer review, recommended applications will receive a second level of review by the appropriate national Advisory Council or 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.
3. Anticipated Announcement and Award Dates

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

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

Section VI. Award Administration Information
1. Award Notices

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

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

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

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

2. Administrative and National Policy Requirements

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

Cooperative Agreement Terms and Conditions of Award

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 the 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 Research/Scientific 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 Research/Scientific 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 regulatory agencies, and other authorities, if applicable.

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 Research/Scientific 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 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 projects toward 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 Research/Scientific staff recommendations, programmatic prioritizations and budget considerations. NINDS Research/Scientific 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.

3. Reporting

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. 

Section VII. Agency Contacts

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

Application Submission Contacts

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

Finding Help Online: http://grants.nih.gov/support/index.html
Email: commons@od.nih.gov

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

Web ticketing system: https://grants-portal.psc.gov/ContactUs.aspx
Email: support@grants.gov

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone: 301-435-0714
Email: GrantsInfo@nih.gov

Scientific/Research Contact(s)

Hao Wang, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-1779

Email: CREATEinquiries@mail.nih.gov  

Peer Review Contact(s)

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

Financial/Grants Management Contact(s)

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

Section VIII. Other Information

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

Authority and Regulations

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

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