Required Application Instructions

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

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

To facilitate the cooperation and partnering of public and private funding organizations, universities, academic medical centers, research institutes, contract research organizations, biotechnology companies, and pharmaceutical companies in the advancement of interventions for stroke prevention, treatment, and rehabilitation, NINDS has formed the NIH Stroke Clinical Trials Research Network (NIH StrokeNet, http://www.ninds.nih.gov/research/clinical_research/NINDS_stroke_trials_network.htm). The StrokeNet comprises a National Clinical Coordinating Center (NCC), a National Data Management Center (NDMC) and 25 geographically distributed Regional Coordinating Centers (RCC) and their affiliated stroke centers.

The StrokeNet network will consider the breadth of cerebrovascular disease, beginning with patients identified with an acute stroke through stroke rehabilitation and stroke prevention for pediatric and adult patients.

The network will provide a robust, standardized, and accessible infrastructure to facilitate rapid development and implementation of NINDS-funded stroke trials. The network is designed to increase the efficiency of stroke clinical trials by facilitating patient recruitment and retention, supporting novel methodologies and streamlined approaches to accelerate the development of promising stroke therapies, and enabling comparison between approaches.

NINDS has established StrokeNet to facilitate and streamline the execution of clinical trials in stroke. Thus, it is expected that all multi-center clinical trials for stroke treatment, prevention, and recovery supported by NINDS will be considered for implementation through StrokeNet. Only in exceptional circumstances will NINDS consider funding stroke clinical trials outside of this program.

This FOA encourages and provides a mechanism for the submission of applications for multi-center exploratory and confirmatory clinical trials focused on promising interventions, as well as biomarker- and outcomes-validation studies that are immediately preparatory to trials in stroke prevention, treatment, or recovery. It is NINDS intention that StrokeNet will maintain a balanced portfolio of studies in each of these three areas, defined as follows:

• Primary and secondary prevention stroke trials studies of agents, devices, or strategies to prevent recurrent stroke in survivors of stroke or transient ischemic attack (TIA), or to prevent first stroke in high-risk populations.
• Emergent management or acute stroke treatment trials studies of agents, devices, or strategies to intervene during the acute phase of stroke with the goal of reducing brain injury and promoting optimal patient recovery; may include pre-hospital as well as emergency department or in-patient approaches; includes all stroke types.
• Neuro-recovery and rehabilitation stroke trials studies of agents, devices, or strategies to improve long-term recovery, including cognitive, behavioral and/or motor function or quality of life outcomes, and/or to reduce the time to optimal recovery in patients after the acute period.

The use of innovative and efficient study designs is encouraged, such as adaptive dose-finding designs, designs incorporating plans for sample size recalculation, and futility designs. Applications for exploratory studies (for example, early dose ranging studies with biomarker outcome, early proof of mechanism or proof of concept trials) are encouraged when appropriate. For medical devices, Early Feasibility and Traditional Feasibility study designs may include single-arm case series, on-off interventions (patients as own controls), device-device comparisons, comparisons to historic controls, comparisons to performance controls, or adaptive/Bayesian designs.

Priority of proposed network trials deemed by peer review to be highly meritorious will be based on factors including infrastructure capacity as well as availability of patient populations considering current ongoing trials within the network. Applicants may submit a proposed study at any time but timing of funding and initiation of the study will be determined by the NINDS with input from the StrokeNet leadership as necessary in order to assure that studies can be conducted within the proposed timeline included in the research plan of the application.

Exploratory Trials

Examples of appropriate exploratory studies under this FOA include, but are not limited to, multi-center studies designed for the following purposes:

• To evaluate and optimize the dose, formulation, safety, tolerability or pharmacokinetics of an intervention in the target population.
• To evaluate whether an intervention produces sufficient evidence of short-term activity (e.g., biomarker activity, pharmacodynamic response, target engagement, dose-response trends) in a human proof of concept trial.
• To select or rank the best of two or more potential interventions or dosing regimens to be evaluated in a subsequent trial, based on tolerability, safety data, biological activity, or preliminary clinical efficacy (e.g., futility trials).
• To evaluate biological activity relative to clinical endpoints.
• eFor medical devices, in addition to providing initial clinical safety data, appropriate studies are those that inform the next phase of development, usually by finalizing the device design, establishing operator technique, and/or finalizing the choice of study endpoints for the design of a pivotal clinical trial.

Confirmatory (Phase 3) Trials

Confirmatory trials are 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. The necessity of each secondary endpoint must be justified in light of cost and burden.

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.

Biomarker and Clinical Endpoint Studies

Biomarkers, especially neuroimaging markers of vascular pathology, brain ischemia, or recovery after injury, have been developed for stroke research. The potential applications of biomarkers include guiding early neuroprotective and reperfusion interventions, monitoring neuroplasticity in stroke recovery, and expediting therapy development. Some biomarkers have been validated in multi-center studies, but their full potential to advance research awaits standardization and adoption across a clinical trials network. Similarly, for certain stroke trials the road block to evaluating a therapeutic approach may be the lack of a suitable valid clinical endpoint.

This FOA encourages the submission of biomarker- or clinical outcome-validation studies that are immediately preparatory to trials. Depending on the scientific questions posed, biomarker studies supported under this program might be stand-alone protocols or could be embedded within a network stroke trial.

Applicants should make note of the following:

(1) Working with StrokeNet is a cooperative venture between NINDS, the StrokeNet network and the applicant. Potential applicants will be provided guidance by NINDS Program Staff and the StrokeNet Executive and Steering Committees. Potential applicants are strongly encouraged to contact NINDS Scientific/Research Contacts (see Section VII. Agency Contacts) in order to discuss the feasibility of conducting the proposed trial through the StrokeNet infrastructure before submitting an application. This early contact will provide an opportunity to clarify NINDS policies and guidelines as well as to discuss how to develop an appropriate project timeline and milestone plan, as well as strategies for recruitment and retention of women and minorities. Pre-application consultation may include an introductory teleconference (at least 3 months prior to submission), followed by a conference call or in-person meeting with NINDS staff, if needed.

(2) Applicants to this FOA will be required to incorporate the StrokeNet infrastructure (http://www.ninds.nih.gov/research/clinical_research/NINDS_stroke_trials_network.htm) into their proposed study, including central coordination through the NCC, data management through the NDMC, and subject recruitment and trial implementation at the RCCs and affiliated sites. It is not required that all sites participate in every trial. Additional (ad hoc) performance sites that are not currently StrokeNet sites may be proposed to fulfill specific study requirements. All applicants and ad-hoc non-StrokeNet sites will be required to use the master clinical trial agreements and central IRB that have been established for StrokeNet.

(3) The operational clinical protocol for trials under this FOA will be constructed after peer review and then reviewed by NINDS for funding consideration. Funding decisions will also be based on a study's fit for the network relative to other proposed and ongoing trials

(4) This FOA is intended to support studies in patients, not healthy volunteers. Applications to conduct exploratory trials in healthy volunteers should be submitted in response to a separate announcement, PAR-13-281. All trials proposing use of an investigational agent or device must have an active IND or IDE or documentation of exemption at the time of submission of the application (see https://grants.nih.gov/grants/guide/notice-files/NOT-NS-11-018.html).

(5) Device trials: The NIH recognizes that devices can vary greatly in terms of basic form and function, physiological bases for therapy, degree of invasiveness, etc. Consequently, the appropriate pathway to market may require a traditional Feasibility and Pivotal study in support of an eventual Pre-Market Approval submission, or may require a more limited study to address specific issues in support of an FDA 510(k) or 510(k) De Novo submission. Clinical studies involving devices may utilize the entire StrokeNet network, or a more limited subset of centers selected based on appropriate expertise for the given device. Investigators are encouraged to contacts NINDS Scientific/Research contact as early as possible to discuss how the StrokeNet network may best be utilized in support of their specific device project. NINDS anticipates that the majority of device projects utilizing StrokeNet will be traditional Feasibility Studies in order to leverage the advantages of the network optimally. An Early Feasibility Study should be designed [in accordance with FDA’s draft guidance, Investigational Device Exemptions (IDE) for Early Feasibility Medical Device Clinical Studies, Including Certain First in Human (FIH) Studies , see http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm277670.htm] to allow for early clinical evaluation of devices to provide proof of principle and initial clinical safety data while device design and operations are still in development. A Traditional Feasibility Study is a clinical investigation that is commonly used to capture preliminary safety and effectiveness information on a near-final or final device design to adequately plan a Pivotal Study.

(6) Rationale: Exploratory and confirmatory clinical trials proposed for this network must anchor their rationale in (1) an unmet medical need; (2) a plausible biological mechanism; (3) preclinical (in vitro and/or in vivo) data; and/or (4) early clinical data. Their individual weight should be carefully assessed in the specific context of the application at hand; there is no requirement to provide support from all four areas. The major findings of the studies, whether preclinical or clinical, that led to the proposed clinical trial should provide a compelling rationale for the belief that the proposed intervention may be effective. Data from preclinical and pilot studies demonstrating the need for and the feasibility of the trial should be presented when available. While the NINDS recognizes that animal models for stroke prevention, treatment, and recovery may be of limited informative value, the applicant should specifically address the rigor of any animal studies being used as support (https://grants.nih.gov/grants/guide/notice-files/NOT-NS-11-023.html). If the animal model and efficacy read-out are not sufficiently associated with the human condition, and/or if preclinical data (such as animal studies) do not sufficiently meet the rigor guidelines, then applicants should consider not using them as primary support of the study rationale.

(7) Pharmacometrics: Applications seeking to obtain data needed for pharmacometric modeling are permitted, with the ultimate aim of enabling the optimal design of a future efficacy trial of an intervention.

(8) The award and continuation of funding are subject to milestones to be specified in the notice of grant award according to NINDS policies.

(9) NIH Resources: As appropriate, applicants are strongly encouraged to make use of the following resources for clinical research including:

• Clinical and Translational Science Award (CTSA) program (https://www.ctsacentral.org/);
• NeuroQOL( http://www.neuroqol.org/);
• NIH Toolbox (http://www.nihtoolbox.org/);
• PROMIS (http://www.nihpromis.org/); and
• NINDS Common Data Elements (http://www.commondataelements.ninds.nih.gov/).

(10) Mobile Technologies: Applicants are strongly encouraged to consider utilizing (at least experimentally) mobile technologies to facilitate data collection and protocol adherence on the part of research participants and study site staff.

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

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Governments

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

Other

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

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

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

Applicant Organizations

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

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

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

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

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

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

It is not necessary that the designated study PD(s)/PI(s) be part of the StrokeNet infrastructure in order to be eligible to apply to this FOA.

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

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

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:

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

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

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

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

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed.

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.

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

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

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

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

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

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

The budget for all clinical projects proposed to be conducted within StrokeNet should be largely planned on a fee-for-service basis with detailed per-patient costs. That budget may include clinical trial costs such as:

• Up to 2.4 person-months for the protocol PD(s)/PI(s) (even if that person is also a StrokeNet RCC PD(s)/PI(s).
• Up to 3 person-months support for a study-specific clinical coordinator at the applicant's site if the NIH-funded site coordinator is at capacity with StrokeNet trials or does not have necessary expertise to assist with the proposed study. If the applicant is not at a StrokeNet clinical site, up to 12 person-months support for a study-specific clinical coordinator may be included.
• Study-related procedures/materials.
• Clinical site operations for any proposed non-StrokeNet ad-hoc sites.
• Subject monitoring costs and protocol-specific costs required for NCC or NDMC operations not otherwise covered by the NCC and NDMC awards.
• All StrokeNet projects will utilize the NDMC for data management and reporting activities. Applicants are encouraged to include a statistician to provide study-specific leadership in statistical design and analysis; however, applicants who do not have access to a statistician may propose to make use of statistical expertise at the NDMC.

The budget will not include costs that are already covered by the NINDS infrastructure:

• StrokeNet RCC PD(s)/PI(s) effort, other than the protocol PD(s)/PI(s)
• StrokeNet RCC coordinator time.

For a seamless Phase 2/3 trial, the budget must include costs adequate to complete both phases of the adaptive design.

NINDS expects that the total direct cost for the proposed project will not exceed $6000 per subject for acute treatment trials with short-term (typically 90-day) outcomes; $20,000 per subject for prevention trials with extended follow-up; and $15,000 for recovery trials with follow-up for up to 12 months. These targets are based on dividing the total direct cost by the number of subjects to be enrolled. Budgets exceeding these guidelines should be adequately justified in the application.

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

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

Specific Aims: Applicants should describe the potential impact of the proposed research. The hypotheses and specific aims of the trial must be clearly and concisely stated.

Research Strategy:

Significance and Biological Relevance: Applicants must state concisely the need, rationale, timeliness, and scientific relevance of the proposed research. It is particularly important that there be a discussion of how the trial will test the hypothesis proposed and how results of the trial (positive or negative) may be explained based on the biological action of the proposed intervention. The application must present an overview of the state of the science, current status of therapeutics for the disease, and relevance of the trial for stroke prevention, treatment, or recovery.

Prior Studies and Rationale for Development: Applicants should describe the full body of evidence being used to support the proposed study and comment on the justification for moving forward with the proposed clinical study. Proposed clinical trials must anchor their rationale in (1) an unmet medical need; (2) a plausible biological mechanism, as well as (3) preclinical (in vitro and/or in vivo) data and/or (4) early clinical data. Their individual weight should be carefully assessed in the specific context of the application at hand; the applicant is not required to provide support from all four areas. The major findings of the studies, whether preclinical or clinical, that led to the proposed clinical trial should provide a compelling rationale for the belief that the proposed intervention may be effective. Data from preclinical and pilot studies demonstrating the need for and the feasibility of the trial should be presented when available. While the NINDS recognizes that animal models for stroke prevention, treatment, and recovery may be of limited informative value, the applicant should specifically address the rigor of any animal studies being used as support (https://grants.nih.gov/grants/guide/notice-files/NOT-NS-11-023.html). Applications for drugs or biologics should provide compelling scientific evidence that the investigational agent and dose proposed for study will reach/act upon the designated target or that its mechanism of action is such that it is expected to be of benefit in ameliorating a specific aspect of the disease.

Approach: Applicants should provide a brief description of their proposed study, including a discussion of the potential biases in the study and how they will be addressed. Clinical pharmacology justifying the proposed dosing regimen should be provided if applicable. For an exploratory trial of a drug or biologic, specific plans for the next steps of the therapy's development (such as a future efficacy trial) must be succinctly stated. A detailed protocol is not required for submission. Following peer review, applicants who are granted network access will work with the StrokeNet team and the NINDS to develop a detailed protocol. The StrokeNet team was established by NINDS based on peer- and Council review to form a group of outstanding clinical trial experts from the fields of neurology and statistics with a proven record of developing high quality protocols.

For applications proposing to conduct a seamless Phase 2/3 trial, 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 and trial termination plans should be defined in the event that the results of Phase 2 do not support continuation to Phase 3.

Applicants must include a plan to enroll women and minorities. Considerations that may contribute to successful inclusion are appropriate site selection, patient- or community-engagement for the major elements of the project, use of focus groups to address barriers to inclusion, etc. Applicants should also include a discussion of how the gender and minority findings will be reported to the NINDS. For exploratory trial applications, investigators should consider including a section that addresses how the results in women and minorities will inform the design of the next steps. A discussion of enrollment feasibility within the network and expected enrollment timelines, including estimates of numbers of patients expected to be enrolled at each site as well as approaches to enrollment of women and minorities, should be included in the facilities section of the application.

Milestones: Applications must include proposed yearly go/no-go milestones. While final milestones will be determined at the time of grant award, the applicant should propose clear milestones that provide objective, quantitative outcomes that will justify continuing the project. Milestones are not equivalent to aims but rather are determinants of whether a study continues or stops. The applicant should endeavor to present: (a) the goals and timeline for completion while setting milestones to be achieved at the end of each funding year, (b) the criteria for success, defined as justification for continuation of the project, and (c) the rationale for the choice of parameters tested and quantitative values as decision points, where possible. Achievement of these milestones will be evaluated by NINDS prior to releasing funding for each year of the award.

Information for the Use of NINDS Common Data Elements: The NINDS expects that applications will use the NINDS Common Data Elements resource when constructing data collection forms. The Common Data Element website (see: http://www.commondataelements.ninds.nih.gov/) serves as a repository and dissemination tool for all NINDS CDEs for Investigators to utilize.

Letters of Support:

Where relevant, include letters of support or other documentation of partnerships with the private sector (e.g., patient groups and/or industry), foreign organizations, subcontractors, consultants, and/or other providers of personnel and facilities. For drug or device trials, provide evidence that the study drug or device will be available in sufficient quantities to ensure study feasibility. For foreign organizations that will be involved in the proposed research, provide documentation of compatibility of their data collection methods with U.S. data collection methods.

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:

• All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan in accordance with the StrokeNet data sharing policies.
• Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and GWAS Sharing Plan) are expected when applicable.

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.

Below are items to be included in the appendix:

• The protocol synopsis, which should not exceed 5 pages, including the following:
  • A description of the study objectives (primary, secondary, exploratory)
  • A description of the study design and study outcomes
  • A description of the intervention to be tested (if applicable)
  • A description of sample size, study population (with key inclusion/exclusion criteria), and recruitment plan, including enrollment of women and minorities.
  • Discussion of the potential biases in the study and how they will be addressed.
  • A timeline of study evaluations with an overall statement about study duration/participant.
• Informed consent documents
• At the applicant’s discretion, the following optional elements may also be provided in the appendix:
  • Non-referenced or non-published, non-standardized clinical assessments and data collection tools.
  • Investigator Brochures, see 21 CFR 312.23 (a)(5) for format
  • Clinical pharmacology justifying the proposed dosing regimen

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

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

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

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

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

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

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

This initiative is not subject to intergovernmental review.

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

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

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

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

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

Important reminders:
All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.

The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness by the Center for Scientific Review, NIH. Applications that are incomplete will not be reviewed.

In order to expedite review, applicants are requested to notify the NINDS Referral Office by email at [email protected] when the application has been submitted. Please include the FOA number and title, PD/PI name, and title of the application.

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.

Applicants are required to follow our Post Submission Application Materials policy.

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

For this particular announcement, note the following:

1. Approved projects will be implemented through the StrokeNet infrastructure and will make use of previously approved sites, resources, and investigators at the StrokeNet National Coordinating Center, National Data Management Center, and Regional Coordinating Centers. Timing of a grant award and initiation of projects approved by peer review and Council will be determined by the NINDS with input from the StrokeNet leadership as necessary in order to assure that studies can be conducted within the proposed timeline included in the research plan of the application. Prioritization of trials to be conducted in the network will be determined based on factors including infrastructure capacity as well as availability of patient populations considering current ongoing trials within the network.

2. Participant Enrollment: StrokeNet includes a strong, flexible consortium of sites with capacity to implement trials. Trial enrollment will be overseen by the consortium.

3. Environment: The StrokeNet infrastructure (NCC, NDMC and RCCs) was selected following peer review to provide an optimal environment and mechanism for conducting relevant projects, including centralized clinical trial management, data management, and oversight of activities at clinical centers.

4. Investigators: For StrokeNet projects, the PD(s)/PI(s) will work closely with the StrokeNet investigators, who have been selected for their experience and training in stroke clinical research. While some applicants will be relatively junior in their careers, StrokeNet provides a cadre of experienced clinical trial experts who can ensure high quality implementation and oversight of studies. The PD(s)/PI(s) therefore do not need to bring as much clinical research experience as they would have to bring to a non-StrokeNet project.

5. Applications will be evaluated from two separate perspectives with an initial focus on the scientific rationale/premise of the study. Proposed clinical trials must anchor their rationale in (1) an unmet medical need; (2) a plausible biological mechanism; (3) preclinical (in vitro and/or in vivo) data; and/or (4) early clinical data. Their individual weight should be carefully assessed in the specific context of the application at hand; the applicant is not required to provide support from all four areas. The second stage of the evaluation for all applications 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.

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

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

Significance

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

For clinical trials, evaluate the justification for the development of the proposed intervention in terms of potential advances in clinical practice, public health, unmet medical need, and/or patient quality of life. How would the intervention, if it were ultimately successful, affect stroke patients? How would the project advance the field regardless of its outcome?

For exploratory trials, biomarker studies, or clinical endpoint studies, evaluate whether the proposed project is likely to yield the answers needed to proceed to the next step in developing the intervention. Is it clear why the proposed study is essential to inform the design and implementation of a subsequent efficacy trial, or enable a go/no-go decision regarding further clinical development of the intervention?

For confirmatory trials, assess whether there is a sufficient body of preclinical and/or clinical research of high scientific rigor to support the study rationale and whether the intervention is 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? Evaluate whether the PDs)/PI(s) of the project is/are well-positioned to provide scientific leadership to the proposed study while collaborating with the StrokeNet NCC, NDMC, and RCC investigators.

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? Assess the extent to which the proposed study has the potential to advance the field (e.g., by evaluating a new target mechanism, or by advancing the validation of a biological or clinical outcome) even if (a) the proposed study design, methods, and intervention are not innovative, and/or (b) the results of the trial indicate that further clinical development of the intervention is unwarranted

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? Evaluate the extent to which the proposed clinical outcomes would be considered "clinically meaningful" and whether the clinical outcome assessment methods are well described with regard to training and reproducibility. Is the statistical design appropriate and efficient to address the proposed aims?

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? Does the application document the availability of sufficient eligible subjects at the proposed clinical sites and plans for subject outreach, recruitment, retention, and follow-up? What is the status of evidence indicating whether or not clinically important sex/gender and race/ethnicity differences in the intervention effect are to be expected.

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?

While the StrokeNet environment has already undergone peer review and is fully established, the following issues should be considered with respect to each application: Have the sites provided adequate or reasonable estimates of the number of patients that they expect to be able to enroll? Does this project include a partnership with the private sector (e.g. patient groups and/or industry)? Have any Foreign Organizations involved in the proposed study documented the compatibility of their data collection methods with U.S. data collection methods? Is there evidence that the study drug or device will be available in sufficient quantities to ensure feasibility of the project? Have agreements with industry partners, if necessary, been established? Are substantive letters of support or other documentation provided to assure commitment of subcontractors, consultants, and/or service agreements for personnel and facilities?

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.

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

Not Applicable

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.

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.

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. The following will be considered in making funding decisions:

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

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

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

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

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

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

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

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

Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, HHS 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:

• Defining of research objectives and approaches.
• Planning, conducting, analyzing, and publishing results, interpretations, and conclusion of their studies and for providing overall scientific and administrative leadership for the Research Project.
• Supervising of the clinical study with consistent emphasis on collaborative interactions between investigators, advisory and steering committees, and NINDS representatives.
• Interacting with the StrokeNet National Coordinating Center and the StrokeNet National Data Management Center as well as StrokeNet Regional Coordinating Centers and any ad-hoc sites.
• Acquiring an IND or IDE from the FDA if an investigational agent or device is to be used.
• Acting as a member of the StrokeNet Steering Committee for the duration of the study with possible participation in steering groups for planning, quality control, capitation, publications etc.
• Retaining custody of and maintaining primary rights to data and software developed under this award, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.

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

NINDS staff involvement will include oversight of the IRB-approved protocol by the NINDS Program Official, documentation of adequate serious adverse event management and reporting, and regular communications with the Principal Investigator and staff; additional involvement generally includes participation in meetings of the steering committee and other leadership committees. Specifically:

• An NINDS Project Scientist working with the Principal Investigator and network investigators will develop milestones for the study. Failure to meet the agreed upon milestones may result in reduced funding or early termination of the cooperative agreement. The NINDS retains the option to obtain periodic external peer review of progress.
• The NINDS Project Scientist will function as one of several co-investigators, collaborating and interacting as necessary with the Principal Investigators in accomplishing the overall goals of the Research Program.
• In addition, an NINDS Program Official will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.
• A separate NINDS Program Official, from the Office of Clinical Research, will serve as the NINDS liaison to the Data and Safety Monitoring Board (DSMB).
• If the proposed trial should require that FDA issue an IND/IDE, the NINDS Project Scientist and/or Program Official(s) will be present at any meetings held with the FDA related to this NIH-funded protocol.

As with any award, even during the period recommended for support, continuation is conditional upon satisfactory progress. If, at any time, recruitment falls significantly below the projected milestones for recruitment, the NINDS will consider ending support and negotiating a phase-out of the award. The NINDS retains the option to obtain periodic external peer review of progress. Milestones will be established by the NINDS prior to the award of the grant based on recommendations from the primary review group. NINDs will make an award for 2 to 3 years in order to start-up the trial and establish performance feasibility. Continuation of the award past this feasibility period will be contingent upon a demonstrated ability to meet milestones indicating that the trial can be implemented as planned. Feasibility milestones will be defined at the start of each trial and will be monitored closely by the Institute-appointed DSMB and NINDS Program Official. Achievement of these milestones will be evaluated by NINDS prior to releasing funding for each year of the award and failure to achieve these milestones may lead to study termination.

Areas of Joint Responsibility include:

None; all responsibilities are divided between awardees and NIH staff as described above.

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 individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure in no way affects the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulations 42 CFR Part 50, Subpart D and HHS regulations 45 CFR Part 16

When multiple years are involved, awardees will be required to submit the annual Non-Competing Progress Report (PHS 2590 or RPPR) and financial statements as required in the NIH Grants Policy Statement.

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

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

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

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

Finding Help Online: https://grants.nih.gov/support/index.html

TTY: 301-451-5939
Email: [email protected]

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

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone: 301-945-7573
TTY: 301-451-5936
Email: [email protected]

Claudia Scala Moy, PhD
National Institute of Neurological Disorders & Stroke (NINDS)
Telephone: 301-496-9135
Email: [email protected]

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

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

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

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