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 Phase III Investigator-Initiated Efficacy Clinical Trials (U01)

Activity Code

U01 Research Project – Cooperative Agreements

Announcement Type

Reissue of PAR-11-173

Related Notices

  • March 4, 2014 - See Notice NOT-NS-14-017. Notice to Correct the NINDS CFDA Number Associated with this FOA a new application package has been posted.
  • January 16, 2014 - See Notice NOT-NS-14-008. Notice of Correction of NINDS's CFDA number.
  • August 21, 2013: Removed reference to ASIST in section IV.3, since ASIST is curently only available for multi-project aplications.
  • NOT-NS-11-018
  • NOT-NS-13-006
  • PAR-13-281
  •   

Funding Opportunity Announcement (FOA) Number

PAR-13-278

Companion Funding Opportunity

None

Number of Applications

See Section III. 3. Additional Information on Eligibility.

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

93.853; 93.583

Funding Opportunity Purpose

The purpose of this Funding Opportunity Announcement (FOA) is to provide a vehicle for submitting grant applications to conduct multi-site, randomized, controlled, Phase 3 clinical trials to the National Institute of Neurological Disorders and Stroke (NINDS).  The trials may address questions within the mission and research interests of the NINDS.  Information about the mission and research interests of the NINDS can be found at the NINDS website (http://www.ninds.nih.gov/).  

Key Dates
Posted Date

July 22, 2013

Open Date (Earliest Submission Date)

September 5, 2013

Letter of Intent Due Date(s)

Not Applicable

Application Due Date(s)

Standard dates apply, by 5:00 PM local time of applicant organization.

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)

Standard AIDS dates apply, by 5:00 PM local time of applicant organization.

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

Standard dates apply

Advisory Council Review

Standard dates apply

Earliest Start Date

Standard dates apply

Expiration Date

September 8, 2016

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


Purpose

The purpose of this Funding Opportunity Announcement (FOA) is to provide a vehicle for submitting investigator-initiated grant applications for multi-site, Phase 3 clinical trials addressing questions within the mission and research interests of the NINDS.  Typically such trials will be randomized and controlled. 

NIH defines a Phase 3 trial as a prospective clinical investigation to evaluate an experimental intervention in comparison with a standard or control intervention, or to compare two or more existing treatments.  The definition includes drugs, biologics, and devices, as well as surgical, behavioral, and rehabilitation therapies.  Cluster-randomized and other population-based intervention trials also are included.

Multi-site clinical trials are trials that recruit study subjects from two or more geographically distinct clinical centers under one protocol.

Background

Phase 3 clinical trials evaluating the efficacy of an intervention are often challenging to design and implement, and extensive planning and proactive oversight are necessary to ensure completion within the funding period and budget awarded.  Prior to beginning subject enrollment, several steps need to be completed during a start–up stage, including  creating a manual of procedures, developing case report forms, building a database, contracting sites, obtaining IRB approval, training study personnel, etc.  The time and effort required to complete these steps are often underestimated.  In addition to lengthy study start-up, slow subject enrollment can delay trial completion.  Successful study planning, enrollment, and retention require anticipatory and flexible management to ensure that the completion of the trial is feasible within the award period and budget.  The purpose of this FOA is to provide a mechanism suitable for the submission and successful implementation of a Phase 3 clinical trial, incorporating several stages to allow investigators and NINDS to assess study progress and feasibility.

Objectives of the Program

A Phase 3 trial is conducted to provide a definitive answer regarding the safety and efficacy of an intervention or to compare the effectiveness of two or more interventions.  The proposed research must address a scientifically important question, provide valuable information to the existing knowledge base, and have public health relevance.  The trial design should ensure that high quality, complete data regarding the primary outcome will be collected in the most efficient manner in terms of time, resources, and burden to subjects.  Secondary outcomes should be included only when they are anticipated to provide important supportive or explanatory data.

This FOA also may be used for the submission of an adaptive trial utilizing a seamless phase 2/3 transition where data from subjects in Phase 2 are included in the analysis of Phase 3.  A transition plan from the Phase 2 component to the Phase 3 component should be described in the application, and trial termination plans should be defined in the event that the results of Phase 2 do not support continuation to Phase 3. 

NINDS recognizes that devices can differ greatly in terms of basic form and function, physiological bases for therapy, degree of invasiveness, etc.  A Pivotal device study, for example, could potentially be used in support of an off-label indication of an existing market approved device, or to provide evidence for a novel device design in support of a Pre-Market Approval (PMA), Humanitarian Device Exemption (HDE), 510(k) or 510(k) De Novo submission.  Due to the broad scope of possible medical devices and the varied nature of the regulatory path, investigators considering applications to evaluate devices l are strongly encouraged to contact Program Staff as early as possible to discuss these issues and determine the suitability of their project for this funding mechanism.

Clinical trials needed in preparation for a Phase 3 trial, such as the evaluation of pharmacokinetics, pharmacodynamics, or preliminary efficacy, are not appropriate for this FOA but should be evaluated in an appropriately designed exploratory clinical trial.  Such applicants should refer to the NINDS Exploratory Clinical Trials announcement PAR-13-281

Ancillary studies, defined as research undertaken to address scientific questions relevant to the parent study and that require access to data or records from the parent study, and/or involve collection of additional data, specimens, or records, are not permitted within the Phase 3 clinical trial application.  Applicants are advised to discuss such ideas with NINDS for consideration of an independent investigator-initiated application for an ancillary study.

NINDS requires separate applications for the Clinical Coordinating Center (CCC) and the Data Coordinating Center (DCC) when submitting under this FOA.  The CCC application should present and discuss the scientific rationale and the supporting data.  The clinical protocol should be described in the application, and the full protocol should be included in an appendix of the CCC application.  The DCC application should present and discuss the statistical and data management plans for the study, including plans for using NINDS Common Data Elements (http://www.commondataelements.ninds.nih.gov/#page=Default) and sharing of data following the conclusion of the trial.  To increase the value of its funded research, NINDS will serve as a repository for de-identified datasets.  The expectation is that a complete de-identified dataset containing all variables collected in the trial and a data dictionary will be submitted to NINDS for data sharing within an agreed upon timeframe, ideally within one year of publication of the primary outcome paper.  Please refer to the NINDS website for details http://www.ninds.nih.gov/research/clinical_research/toolkit/data_sharing.htm.  Applicants are encouraged to describe the process in their data sharing plan, and to budget for the preparation and submission of the dataset as described. 

For the purposes of peer review, the CCC and DCC applications will be considered as a cluster, will be reviewed together, and will receive the same impact score and summary statement.  Applicants requesting direct costs of $500,000 or more in any one year (excluding consortium F&A costs) should consult the NINDS Guidelines in order to obtain Institute approval to submit the application (http://www.ninds.nih.gov/research/clinical_research/policies/large_projects.htm). 

Applicants are strongly encouraged to consult with NINDS Scientific/Research Contact no later than 12 weeks prior to the anticipated application submission date (see Agency Contacts, Section VIII).

Experimental Approach and Implementation

IRB documentation:  IRB approval is not required at the time of application submission, but is required prior to funding.  As such, NINDS encourages investigators to begin these processes as early as possible.  NINDS also will require documentation of any other necessary regulatory approvals (e.g., Recombinant DNA Advisory Committee) prior to funding. 

Due to the unique requirements of the NINDS Phase 3 Clinical Trials program, applicants are strongly encouraged to consult with NINDS Program Staff well in advance of submitting an application.  This early contact will provide an opportunity to clarify the applicant's understanding of NINDS’ policies and guidelines, including the scope of projects within the NINDS mission and the requirement that trial implementation be milestone-driven.  These discussions may also provide guidance on timelines and milestone plans, which are subject to peer review. 

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
Renewal
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 need to reflect the actual needs of the proposed project.

Award Project Period

The maximum request cannot exceed 5 years; yet, the actual funded project period is dependent on reaching specific milestones as described in this FOA.  

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

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

Nonprofits Other Than Institutions of Higher Education

For-Profit Organizations

Governments

Other

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.

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

All PD(s)/PI(s) must have an eRA Commons account and should work with their organizational officials to either create a new account or to affiliate an existing account with the applicant organization’s eRA Commons account. 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.

NIH will not accept any application that is essentially the same as one already reviewed within the past thirty-seven months (as described in the NIH Grants Policy Statement), except for submission:

Applicants may submit a renewal application.  See also NINDS policy for continuation of phase 3 clinical trials (NOT-NS-10-009).

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, 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.

Required and Optional Components

The forms package associated with this FOA includes all applicable components, required and optional. Please note that some components marked optional in the application package are required for submission of applications for this FOA. Follow all instructions in the SF424 (R&R) Application Guide to ensure you complete all appropriate “optional” components.

SF424(R&R) Cover

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

It is important that applicants who submit linked applications clearly indicate at the time of submission that the applications are linked.  This linkage should be mentioned in (i) the cover letter included with the application, (ii) the title of the application, and (iii) the abstract.

Application title

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:

The body of the application must present an overview of the state of the science, current status of therapeutics for the disease, supporting preclinical and clinical data, and relevance of the trial for treatment of the disease.  The body of the application should also include a summary of (i) the methodological aspects of the protocol, (ii) the approach to data collection and (iii) plans for data analysis; references to additional information and details provided in the protocol (submitted as an appendix to the application) should be indicated. 

The experimental approach should include a description of the overall trial design including:  hypotheses, subject eligibility criteria,  recruitment and retention strategies, randomization method, methods of minimizing bias (e.g., blinding), primary and secondary outcome measures, details regarding the intervention, schedule of evaluations, and quality control procedures (e.g., site monitoring, endpoint adjudication), etc.  Under exceptional circumstances, a concurrent control group may not be needed.  In such instances, applicants must make a strong argument for their approach, including how bias will be mitigated.

Statistical methods should be appropriately matched to the study design and include sample size and power calculations, plans for primary and secondary analyses, pre-specified interim analyses, and data management.  Data management plans should incorporate Common Data Elements (CDE; see http://www.commondataelements.ninds.nih.gov).  Applicants should also include a data sharing plan (see NINDS website http://www.ninds.nih.gov/research/clinical_research/toolkit/data_sharing.htm). 

Computer simulations are sometimes used to investigate the operating characteristics of complex clinical trial designs (such as adaptive designs), to choose between alternative outcome measures, or to determine sample size, by taking into account the impact of noncompliance, missing data, and subject eligibility criteria, etc.  If simulations were performed to aid in the design of the trial, sufficient details about the simulations should be provided as a separate appendix for peer review.  See the article, “The design of simulation studies in medical statistics”, by Burton et al., Statist. Med. 2006: 25:4279-4292 for guidance on how to document a simulation study.  It is particularly important to discuss the range of conditions that were considered in the simulation and why this range was considered appropriate, how robust the findings were across the range of conditions considered, and how the study will adjust for any design deficiencies (e.g., bias, loss of power) the simulations revealed.

Project stages:  The implementation of the clinical trial should be divided into three stages that include the activities listed below.  All activities must be able to be completed within the proposed project period and should be presented as milestones with associated timelines:

1. Start-up stage

2. Feasibility stage

3. Completion stage

Inclusion of Women and Minorities in Phase 3 Clinical Trials: NIH policy requires that women and minorities be included in clinical trials, unless it is not scientifically justifiable.  Applicants must include:

Relationships with patient groups:  Applicants are strongly encouraged to establish relationships with patient groups and solicit their input on recruitment, the clinical meaningfulness of the question under study, the relevance of the proposed clinical outcomes, and approaches to minimizing the burden on study subjects.  Applicants are encouraged to include letters from patient organizations or other supporting documentation to show that patients were included as partners in the concept development and design of the trial.

Considerations for rare diseases:  Trials in rare diseases are encouraged, and it is recognized that available patient pools may not be adequate to meet the sample size requirements typically seen in Phase 3 trials.  Innovative trial designs, including adaptive designs, may allow for the most efficient evaluation of the limited subjects available for study.  For trials in rare diseases, it is especially important to ensure that the study design will meet the stated objectives, and the approach should carefully be justified.  Applicants proposing Phase 3 studies aiming to demonstrate evidence of efficacy to support a licensing application are encouraged to contact the FDA to gain concurrence on the trial design.  Applicants are also advised to contact NINDS program staff early in the planning process.

FDA documentation: As per NINDS policy (http://grants.nih.gov/grants/guide/notice-files/NOT-NS-11-018.html), at the time of grant submission, if the intervention is a drug, biologic, or device, applicants must provide documentation from the FDA providing information on one of the following three scenarios:

(a) The protocol has been submitted under an open IND/IDE and the IND/IDE is not under full or partial hold.  Under this scenario, applicants must provide documentation such as a "may proceed" email or letter from the FDA.

(b) The protocol has been submitted under an IND/IDE and is on full or partial hold.  Under this scenario applicants must provide full documentation from the FDA on the reasons for hold and the FDA recommendations.

(c) The protocol is exempt from an IND/IDE.  Under this scenario applicants must provide a copy of the exemption letter from the FDA.

Applications that do not include this information will be withdrawn and not reviewed.  Prior to grant award, awardees who do not have an exemption from the FDA must provide any additional FDA correspondence regarding the status of the protocol to the NINDS, especially if the trial has been placed under full or partial hold.

Other Attachments: Provide the following information in PDF files with the name indicated in the following instructions:

Milestone Plan:  Applicants are required to provide detailed project performance and timeline objectives in a section entitled “Milestone Plan”.  The filename "Milestone Plan.pdf" should be used and will be reflected in the final image bookmarking for easy access for reviewers. The milestones must include achievable goals for the start-up stage, feasibility stage, and completion stage. This section must include:

Applications that lack the Milestone Plan are incomplete and will not be reviewed.

Facilities and Other Resources:

SF424(R&R) Senior/Key Person Profile

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

The clinical trial must be directed by an investigator with experience in the conduct of clinical trials and expertise in the disease area. Such experience must be documented, including timely submission of primary publications from previous trials, ideally within one year of completion of subject follow-up.  The application also should indicate the prior experience of study team members in clinical trial design and implementation. Biographical sketches for all key personnel must be provided.

R&R Budget

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

The release of funds will be milestone-driven, according to milestones pre-specified in the Notice of Grant Award.

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: The hypotheses and specific aims of the trial must be clearly and concisely stated. The primary and secondary outcomes to be measured must be defined.  The inclusion of secondary aims should be justified by describing the importance of the supportive or explanatory data.

Research Strategy:

The scientific rationale and preliminary data supporting the proposed Phase 3 trial, including results from preclinical and clinical studies, must be included in the application.  Applicants should ensure that the data supporting the proposed clinical trial are referenced and meet the NINDS scientific rigor guidelines (http://grants.nih.gov/grants/guide/notice-files/NOT-NS-11-023.html; http://www.ninds.nih.gov/funding/transparency_in_reporting_guidance.pdf).  If a proposed trial plans to test the efficacy of an intervention based upon preclinical mechanistic studies, results from such studies should be summarized and referenced.  If preclinical data (e.g., animal studies) do not meet the rigor guidelines, the applicant should discuss the limitations of those data. 

Significance and Biological Relevance: The significance of the proposed clinical trial must be clearly stated, and a discussion of the costs and benefits should be included. It is particularly important to discuss how the trial will test the hypotheses proposed and how results of the trial (positive or negative) will advance the field. The application should state why the proposed study is necessary with an emphasis on the public health relevance or significance of the question and how the results will advance knowledge or clinical practice in this disease area.

Preliminary Studies:  The major findings of the preclinical and clinical studies that led to the proposed clinical trial should be presented and discussed in the context of the NINDS rigor guidelines (http://grants.nih.gov/grants/guide/notice-files/NOT-NS-11-023.html).  Data from exploratory studies that support the proposed hypotheses and the feasibility of the trial should also be included.  Study conceptualization and planning must be at a stage sufficient to allow for an assessment of the likelihood of trial success.

Approach: A concise summary of the proposed research plan should include:

Study Organization and Administration:

Human Subjects: NIH’s policy requiring education on the protection of human research participants must be followed for all key personnel (see http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html).

Applicants should refer to Part II of the SF424 Application Guide, “Supplemental Instructions for Preparing the Human Subjects Section of the Research Plan” (http://grants.nih.gov/grants/funding/424/SF424_RR_Guide_General_Adobe_VerB.pdf).

Assurance of the protection of human participants and the biohazard safety of employees (if applicable) must be provided for the overall study and for each clinical site.  The applicant must discuss any issues which might lead to concern for the welfare of participants.  Drafts of the Informed Consent Forms to be provided as templates to the sites must be included in an appendix.  Additionally, the human subjects section of the application must address data security measures and confidentiality.

Data and Safety Monitoring (DSM) Plan: The DSM plan should be commensurate with the risk level of the proposed clinical research and must be included for all clinical trials (see http://grants.nih.gov/grants/guide/notice-files/not98-084.html). All applications and study protocols must include a general description of the monitoring plan, policies, procedures, responsible entities, and approaches to identifying, managing and reporting reportable events, adverse events, and unanticipated problems to the applicable regulatory agencies (e.g., Institutional Review Board (IRB), the Office of Biotechnology Activities (as appropriate), the Office of Human Research Protections, the Food and Drug Administration, and the Data and Safety Monitoring Board.

The DSM Plan must address the following areas:

Applicants should refer to NIH’s policy on data and safety monitoring (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html) as well as the NINDS Guidelines for Data and Safety Monitoring (http://www.ninds.nih.gov/research/clinical_research/policies/data_safety_monitoring.htm). 

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:

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, with the following modifications:

The following additional documents must be included in the Appendix material of the CCC application in the order listed below:

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 for 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-10-115.

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.

Applications selected for a full discussion by the review committee will be evaluated from two perspectives:  the scientific rationale/premise of the study and the study design as outlined in detail below.  Where applicable, preclinical data used to support the rationale for the study will be evaluated for the scientific rigor of the experimental design, for the strategies used to minimize bias, for the robustness and reproducibility of the reported results and for consideration of alternative interpretations.  The scientific review also will focus on the overall impact of the study which will also include the evaluation of the experimental design and all of the review criteria described below.

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?  Is there a sufficient body of preclinical and/or clinical research of high scientific rigor to support the study rationale and is the intervention ready for Phase 3 evaluation? Is the proposed intervention justified in terms of potential advances in clinical practice, public health, and/or patient quality of life? Is there evidence of equipoise in the medical and patient communities?  Are there any ethical concerns? 

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? Is there evidence that the PD/PI has led projects of similar scientific and administrative complexity?  Is there evidence that the primary results of prior trials have been submitted within one year of subject follow-up?   

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?  Are the primary and secondary outcome measures appropriate?  Are the eligibility criteria, randomization plan, methods of blinding, sample size, study power, and training of site personnel described and appropriate to complete the trial?  Are NINDS Common Data Elements considered? Are the milestones appropriate? 

If the project involves clinical research, are the plans for 1) protection of human subjects from research risks, and 2) inclusion of minorities and members of both sexes/genders, as well as the inclusion 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?   Is there evidence that the study drug or device will be available in sufficient quantities?  Have agreements with industry partners, if necessary, been established?  Is there evidence of commitment of subcontractors, consultants, and/or service agreements for personnel and facilities? 

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.

FOA-Specific Review Criteria

Clinical Trial Documentation (Study protocol, Clinical Investigator's Brochure or equivalent, etc.)

Plans for Patient Recruitment/Retention

Does the application document the following?

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 Human Subjects Protection and Inclusion Guidelines.

Inclusion of Women, Minorities, and Children 

When the proposed project involves clinical research, the committee will evaluate the proposed plans for inclusion of minorities and members of both genders, as well as the inclusion of children. For additional information on review of the Inclusion section, please refer to the Human Subjects Protection and Inclusion Guidelines.

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

For Renewals, the committee will consider the progress made in the last funding period.

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.

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.

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 the 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:

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 NINDS National Advisory Council. The following will be considered in making funding decisions:

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.     

The award and administrative continuation of funding are subject to milestones to be specified in the notice of grant award according to NINDS policies (see NINDS policy for continuation of Phase 3 clinical trials NOT-NS-10-009).  The Terms and Conditions will include site activation and recruitment milestones, accrual goals for women and minorities (as appropriate), and any other identified requirements for completion of the approved research.

As with any award, continuation is conditional upon satisfactory progress, even during the period recommended for support.  If recruitment falls significantly below the projected milestones at any time, the NINDS may consider ending support and implementing a phase-out of the award.  The NINDS retains the option to obtain periodic external peer review of progress. 

Any application awarded in response to this FOA will be subject to the DUNS, SAM Registration, and Transparency Act requirements as noted on the Award Conditions and Information for NIH Grants 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 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 NIH purpose 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 the primary responsibility for:

Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies.

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

An NINDS Project Scientist will have substantial programmatic involvement that is above and beyond the typical stewardship role in other awards, as described below.  In addition to the Project Scientist, an NINDS Administrative Program Director will be responsible for programmatic stewardship of the award and will be named in the award notice.  This stewardship will include detailed monitoring of trial progress and milestones as described below.  A third NINDS Program Official from the Office of Clinical Research will serve as the NINDS liaison to the NINDS appointed Data and Safety Monitoring Board.

NINDS staff will:

NINDS reserves the right to terminate or curtail the study (or an individual award) under a range of scenarios including but not limited to (a) failure to implement the study protocol, (b) a substantial shortfall in subject recruitment, follow-up, data reporting and dissemination, quality control, or other major breach of the protocol, (c) substantive changes in the agreed-upon protocol with which NINDS does not concur, (d) reaching a major study objective substantially before schedule with persuasive statistical evidence, or (e) human subject safety or ethical issues that may dictate a premature termination, (f) a change in the state of science that changes equipoise or has other significant impact on the relevance of the question.

Areas of Joint Responsibility include:

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: 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 individual 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.

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)

Web ticketing system: https://public.era.nih.gov/commonshelp
TTY: 301-451-5939
Email: commons@od.nih.gov

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact Center Telephone: 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
TTY: 301-451-5936
Email: GrantsInfo@nih.gov

Scientific/Research Contact(s)

Wendy Galpern, MD, PhD
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-9135
Email: Phase3Trial@ninds.nih.gov

Peer Review Contact(s)

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

Financial/Grants Management Contact(s)

Tijuanna DeCoster, MPA
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-9231
Email: decostert@ninds.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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