Part 1. Overview Information

Key Dates

All applications are due 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.

It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide, except where instructed to do otherwise (in this NOFO or in a Notice from NIH Guide for Grants and Contracts).

Conformance to all requirements (both in the Application Guide and the NOFO) 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.

There are several options available to submit your application through Grants.gov to NIH and Department of Health and Human Services partners. You must use one of these submission options to access the application forms for this opportunity.

1. Use the NIH ASSIST system to prepare, submit and track your application online.
2. Use an institutional system-to-system (S2S) solution to prepare and submit your application to Grants.gov and eRA Commons to track your application. Check with your institutional officials regarding availability.
   
   
3. Use Grants.gov Workspace to prepare and submit your application and eRA Commons to track your application.



Table of Contents
Part 1. Overview Information
Key Dates
Part 2. Full Text of Announcement
Section I. Notice of 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. Notice of Funding Opportunity Description

Purpose

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 formed the NIH Stroke Clinical Trials Research Network (NIH StrokeNet). The NIH StrokeNet comprises a National Clinical Coordinating Center (NCC), a National Data Management Center (NDMC) and 27 geographically distributed Regional Coordinating Centers (RCC) which involve approximately 500 affiliated stroke centers in the United States.

Studies conducted within the NIH StrokeNet network encompass the breadth of cerebrovascular disease, including treatments of acute stroke, stroke rehabilitation therapies, and primary and secondary stroke preventions for pediatric and adult patients.

The network provides a robust, standardized, and accessible infrastructure to facilitate rapid development and implementation of NINDS-funded stroke trials. The network's infrastructure 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 comparisons between approaches.

Scope of the Program

NINDS has established the NIH 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 the NIH StrokeNet.

This NOFO  provides the primary opportunity for the submission of applications for multi-center exploratory and confirmatory stroke clinical trials focused on promising interventions, including pragmatic trials performed in large numbers of patients with minimal alteration from clinical practice and low per-patient costs. Exploratory clinical trials must include a clearly defined  pathway, with go/no-go decision points to guide  advancement to a future Phase 3 trial. Also eligible for support under this NOFO are biomarker- and outcome-validation studies that are immediately preparatory to trials in stroke prevention, treatment, or recovery, as well as ancillary studies designed to add scientific aims to active studies being conducted within StrokeNet. It is NINDS’s intention that NIH 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. This may include pre-hospital as well as emergency department or in-patient approaches and 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, such as adaptive dose-finding designs, designs incorporating plans for sample size recalculation, and futility designs are highly encouraged. Trials will also be encouraged to include domain-specific or modality-specific endpoints (e.g., that specifically target motor deficits, walking ability, cognitive ability, spatial neglect, etc.) in addition to traditional global endpoints that may foster a more common language across all stroke trials.  Applications for exploratory studies (e.g., early dose finding studies with biomarker outcomes, early proof of mechanism or proof of concept trials) are also encouraged. For medical devices, Early Feasibility and Traditional Feasibility study designs may include single-arm case series, within subject designs, device comparisons, comparisons to historic controls, comparisons to performance controls, or adaptive/Bayesian designs.

Initiation of proposed trials in the network will be based on highly meritorious applications by peer review and high funding priority by the NANDS Council considering also the infrastructure capacity and availability of patient populations considering current ongoing trials within the network. Applicants may submit a proposed study for any receipt date, but timing of funding and initiation of the study will be determined by the NINDS with input from the NIH StrokeNet leadership as necessary to assure that studies can be conducted within the proposed timeline included in the research plan of the application.

While applications may propose sites outside the NIH StrokeNet network, NINDS expects that any confirmatory (Phase 3) trial conducted within the network will utilize most or all  the NIH StrokeNet RCCs. The addition of clinical sites outside the U.S. may be considered for large phase 3 trials when necessary.  Information about the country and proposed clinical sites must be included in the application.   Smaller multi-site exploratory trials and biomarker validation studies generally needing more than 4-5 clinical sites for subject accrual are appropriate for the network.  In cases where early phase clinical trials that require a limited number of clinical sites to control for variability (i.e., generally fewer than 3-4 sites) may be directed to submit using the NINDS Exploratory Clinical Trials NOFO (https://grants.nih.gov/grants/guide/pa-files/PAR-21-236.html).  Potential applicants are highly encouraged to discuss the potential suitability of the proposal with NINDS program staff prior to submission.  The final number of sites needed for a proposed study will be determined following a feasibility assessment by the NIH StrokeNet.

The NIH recognizes that diverse teams working together and capitalizing on innovative ideas and distinct perspectives outperform homogeneous teams. (Please refer to NOT-OD-20-031: Notice of NIH's Interest in Diversity for more details.) There are many benefits that flow from a diverse scientific workforce, including: fostering scientific innovation, enhancing global competitiveness, contributing to robust learning environments, improving the quality of the research, advancing the likelihood that underserved populations participate in, and benefit from research, and enhancing public trust.

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 patient/researcher burden. Pragmatic trials requiring minimal data collection and low cost per subject are encouraged.

This NOFO 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.

Exploratory Trials

Examples of appropriate exploratory studies under this NOFO 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 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.
• To inform the next phase of development of medical devices, 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, in addition to providing initial safety data.

Biomarker and Clinical Endpoint Studies

Biomarkers, especially neuroimaging markers of vascular pathology, brain ischemia, or recovery after injury, have been developed for stroke research. Applications of biomarkers may 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 roadblock to evaluating a therapeutic approach may be the lack of a validated clinical endpoint.

This NOFO encourages the submission of studies to clinically validate biomarkers or clinical outcomes with demonstrated promise to inform Phase 2 clinical 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 (ancillary study; see below). Studies designed for biomarker discovery are not suitable for this NOFO. Applicants interested in support for biomarker discovery studies should refer to PAR-22-089, Development of Biomarkers or Biomarker Signatures for Neurological and Neuromuscular Disorders. 

Ancillary studies

NINDS also encourages submission of ancillary studies designed to add scientific aims to active studies being conducted within StrokeNet and that address questions relevant to stroke treatment, prevention, and recovery. For the purposes of this NOFO, ancillary studies are defined as research activities undertaken to address a scientific question 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 from patients enrolled in the parent study.

Depending on the scientific questions posed, ancillary studies supported under this program might involve the entire cohort participating in the ongoing clinical trial or selected subsets of the participants. In general, all patients in the ancillary study must be participants in the parent trial; however, recruitment of a small number of normal controls may be acceptable provided adequate scientific rationale and reasonable cost. The research plan should include a justification for why the proposed study requires the use of patients in the parent clinical trial. Ancillary studies must not interfere with the parent study or unduly burden participants. Approved procedures and policies from the parent study must be followed.

Research questions addressed by the ancillary study might include, among others, the study of:

• Mechanism of action of a disease intervention;
• Mechanism(s) of disease pathogenesis;
• Characterization of disease pathology and phenotypes;
• Development and validation of diagnostic tool and markers;
• Validation of markers for disease stage, progression, activity, or therapy response;
• Extension of the scope of participant data collection and assessment to address additional questions related to the primary trial hypotheses (e.g. addition of imaging data at specified time points; addition of clinical or patient-reported outcomes to gain better understanding of impact of intervention).

Implementation

Applicants should make note of the following:

(1) Working with NIH StrokeNet is a cooperative venture between NINDS, the NIH StrokeNet and the applicant. Potential applicants will be provided guidance by NINDS Program Staff and the NIH 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 appropriateness of the proposed study to be conducted within the NIH StrokeNet. Prior to submission of the grant application, applicants will  work closely with the NIH StrokeNet  in developing their research plan, assessing the feasibility of the study, and developing an appropriate budget to conduct the research. The additional interaction with the network is intended to harness the scientific clinical trial expertise in the network and to establish early collaborations necessary for successful conduct of the research plan. Potential applicants are strongly encouraged to start the process early and allow ample time (i.e., 6-8 months) to prepare and submit a competitive NIH StrokeNet project application.

(2) Applicants to this NOFO will be required to incorporate the NIH StrokeNet infrastructure 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 NIH StrokeNet sites may be proposed to fulfill specific study requirements. All applicants and ad-hoc non-NIH StrokeNet sites will be required to use the clinical trial agreements and central IRB that have been established for NIH StrokeNet.

(3) Following review and prior to the award, the operational clinical protocol for trials selected for funding will be finalized by the NIH StrokeNet protocol working group and are expected to incorporate recommendations that may come from the peer review and NANDS Council process. The NIH 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, neurosurgery, rehabilitation, and statistics with a proven record of developing high quality protocols. Final protocols will be reviewed and approved by NINDS prior to study initiation.

(4) This NOFO is intended to support studies in patients, not healthy volunteers. Applications to conduct exploratory trials in healthy volunteers should be submitted to a separate clinical trial announcement,  https://grants.nih.gov/grants/guide/pa-files/PAR-21-236.html. All trials proposing to use 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 NOT-NS-11-018).

(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 study and/or 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 all the centers that are part of the NIH StrokeNet, or a more limited subset of centers selected based on appropriate expertise for the given device. Investigators are encouraged to contact the NINDS Scientific/Research Contact as early as possible to discuss how the NIH StrokeNet  may best be utilized in support of their specific device project. NINDS anticipates that the majority of device projects utilizing NIH StrokeNet will be traditional Feasibility Studies in order to optimally leverage network advantages. An Early Feasibility Study should be designed [in accordance with FDA’s  guidance, “Investigational Device Exemptions (IDE) for Early Feasibility Medical Device Clinical Studies, Including Certain First in Human (FIH) Studies”, see https://www.fda.gov/regulatory-information/search-fda-guidance-documents/investigational-device-exemptions-ides-early-feasibility-medical-device-clinical-studies-including 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 (i) an unmet medical need; (ii) a plausible biological mechanism; (iii) rigorous preclinical (in vitro and/or in vivo) data; and/or (iv) early clinical data. The individual weight given to each of these 4 criteria should be carefully assessed in the context of the specific application; there is no requirement to provide support from all four areas. The major findings of the studies, whether preclinical and/or clinical, that are offered in support of the proposed clinical trial should provide a compelling justification for the phase of study and  that the proposed intervention will be effective. Data from preclinical and pilot studies demonstrating the need for and the feasibility of the trial should be presented when available. Applicants 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). Preclinical data (such as from animal studies) that do not sufficiently meet the rigor guidelines or are not sufficiently associated with the human condition may be inadequate to support the rationale for the study.

(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.

(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;
• NeuroQOL;
• NIH Toolbox;
• PROMIS; and
• NINDS Common Data Elements.

(10) Mobile Technologies: Applicants are strongly encouraged to consider utilizing mobile technologies when appropriate to increase study efficiency, facilitate data collection, and support protocol adherence on the part of research participants and study site staff.

Structure of Award

This NOFO will utilize a bi-phasic, milestone-driven cooperative agreement (UG3/UH3) mechanism consisting of a start-up phase of up to one year (UG3) and a full enrollment and execution phase (UH3) of up to 6 years. Applicants must address objectives for both a UG3 and a UH3 phase.

Phases of Award

The UG3 phase will support the development of the final protocol, development of case report forms and other resources necessary to the performance of the study; further development of study partnerships; finalization and Institutional Review Board/Data and Safety Monitoring Board approval of the trial protocol, informed consent(s), manual of operations, and clinical trial project management plans. All necessary regulatory approvals not already provided, including FDA "may proceed" letter if applicable, as well as provision of the necessary drugs, devices or other resources, should be obtained by the end of the UG3 award to allow for the successful launch and execution of the proposed clinical trial, biomarker or ancillary study in the UH3 phase. In addition, it is expected that enrollment in the study will begin by the end of the UG3 phase or sooner. Subject to NINDS funding availability and scientific priorities, UH3 awards will be made after administrative review with particular attention to the extent to which agreed-upon milestones have been met. If the UH3 is funded, an additional administrative review will be scheduled during the UH3 phase to assess progress towards UH3 milestones or enrollment milestones.

Milestones

Delineation of milestones is a key characteristic of this NOFO. A milestone is defined as a scheduled event in the project timeline that signifies the completion of a major project stage or activity. Milestones should be reached at the end of the UG3 phase. Milestones must be performance-based to achieve completion of the trial on time and on budget. Satisfactory completion of UG3 milestones will be assessed administratively to determine eligibility to transition to the UH3 implementation phase.

This NOFO will support applications that include a series of annual milestones for completion of the study (UH3 phase) and provide contingency plans to proactively confront potential delays or disturbances in meeting the milestones. NINDS staff in collaboration with the awardee will closely monitor progress at all stages, including milestones, accrual, and safety. If, at any time, recruitment falls significantly below the projected milestones for recruitment, NINDS may consider an interim no-cost extension or ending support and negotiating a phase-out of the award. Continuation of the award is conditional upon satisfactory progress in meeting milestones and subject to the availability of funds.

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

Investigators proposing NIH-defined clinical trials may refer to the Research Methods Resources website for information about developing statistical methods and study designs.

Section II. Award Information

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

Section III. Eligibility Information

1. Eligible Applicants

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)

Local 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).

Federal Government

• 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 Organizations) are not eligible to apply.

Non-domestic (non-U.S.) components of U.S. Organizations are not 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 How to Apply-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. Failure to complete registrations in advance of  a due date is not a valid reason for a late submission, please reference the NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications.

• System for Award Management (SAM) – 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.
  • Unique Entity Identifier (UEI) - A UEI is issued as part of the SAM.gov registration process. The same UEI must be used for all registrations, as well as on the grant application.
• eRA Commons - Once the unique organization identifier is established, organizations can register with eRA Commons in tandem with completing their Grants.gov registration; all registrations must be in place by time of submission. 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 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 their organization to develop an application for support. Individuals from diverse backgrounds, including underrepresented racial and ethnic groups, individuals with disabilities, and women are always encouraged to apply for NIH support. See, Reminder: Notice of NIH's Encouragement of Applications Supporting Individuals from Underrepresented Ethnic and Racial Groups as well as Individuals with Disabilities, NOT-OD-22-019 and Notice of NIH's Interest in Diversity, NOT-OD-20-031.

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 How to Apply- Application Guide.

The designated study PD(s)/PI(s) is/are not required to be part of the NIH StrokeNet infrastructure in order to be eligible to apply to this NOFO.

2. Cost Sharing

This NOFO does not require cost sharing as defined in the NIH Grants Policy Statement Section 1.2 Definition of Terms.

3. Additional Information on Eligibility

Number of Applications

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

The NIH will not accept duplicate or highly overlapping applications under review at the same time, per NIH Grants Policy Statement Section 2.3.7.4 Submission of Resubmission Application. This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see NIH Grants Policy Statement 2.3.9.4 Similar, Essentially Identical, or Identical Applications).

Section IV. Application and Submission Information

1. Requesting an Application Package

The application forms package specific to this opportunity must be accessed through ASSIST, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace are available in Part 1 of this NOFO. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide except where instructed in this notice of funding opportunity 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.

Page Limitations

All page limitations described in the How to Apply- Application Guide and the Table of Page Limits must be followed.

The following section supplements the instructions found in the How to Apply- Application Guide and should be used for preparing an application to this NOFO.

SF424(R&R) Cover

All instructions in the How to Apply- Application Guide must be followed.

SF424(R&R) Project/Performance Site Locations

All instructions in the How to Apply-Application Guide must be followed.

SF424(R&R) Other Project Information

All instructions in the How to Apply-Application Guide must be followed.

Other Attachments:

All applications must complete relevant sections of the PHS Human Subjects and Clinical Trials Information section of the form. Applications proposing research that does not meet the definition of a clinical trial (e.g., biomarker validation study, ancillary study that is not a clinical trial) must include as an attachment a synopsis of the clinical protocol. The filename "Clinical Protocol Synopsis.pdf" should be used. Note that applications proposing an NIH-defined clinical trial must include the clinical trial protocol synopsis as part of the PHS Human Subjects and Clinical Trials Information section.

Applicants proposing ancillary studies must provide documentation from StrokeNet leadership of approval to use existing network infrastructure, patient cohorts, patient samples, and other data from the parent study. The filename "Ancillary Study Approval.pdf" should be used. In addition, applications for ancillary studies must include the protocol of the parent study, using "{Name of Parent Study} Protocol.pdf" as the filename, substituting the name of the parent study as indicated.

SF424(R&R) Senior/Key Person Profile

All instructions in the How to Apply- Application Guide must be followed.

All Key Personnel who are major contributors to the study must provide an NIH Biosketch whether or not they are budgeted. Do not include NIH Biosketches for key personnel at the StrokeNet NCC or the NDMC unless they have a separate specific role in the proposed study.

The PD(s)/PI(s) of the clinical trial must be experienced in the conduct of multi-center clinical trial coordination and management, including success in meeting milestones and timelines, and have expertise in the content area of the proposed clinical trial. The experience of each PD/PI and all Key Personnel must be carefully documented and roles and responsibilities must be well-defined. In addition, the responsibilities and authority of each PD/PI must be specified.

R&R Budget

All instructions in the How to Apply- Application Guide must be followed.

This application must include all study-related costs not covered by StrokeNet infrastructure awards. The application must provide detailed annual budgets that will enable the network to meet study milestones. Separate itemized budgets must be prepared for each subcontract and/or for each collaborating center or core, including the NCC and the NDMC.

If parts of the costs of the trial are to be provided by sources other than NIH (e.g., industry, other US or foreign funding agencies, private donation), these contributions must be presented in detail in the budget justification. Third Party support of the proposed research activity (if approved) will be incorporated as a Special Award Condition. If the Third-Party support ceases and the trial is no longer tenable without the Third-Party support, a close-out plan may be requested. Applicants are reminded that although Cost Sharing is not required, if these types of costs are included in the research application and peer reviewed, it is expected that these costs will not be covered by NIH.

The budget for all clinical projects proposed to be conducted within NIH 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 6 person-months for the protocol PD(s)/PI(s) (even if that person is also an NIH StrokeNet RCC PD(s)/PI(s)).
• Support for a study-specific clinical coordinator at the applicant's site.
• Study-related procedures/materials.
• Study-specific site start-up costs at clinical sites.
• Clinical site infrastructure support for any proposed non-NIH 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. Applicants must work with the NCC and NDMC staff to determine protocol-specific costs to be included in the budget, which may include a study-specific coordinator at the NCC as well as study-specific staff at the NDMC with appropriate justification that describes their distinct roles and responsibilities.
• Support for key personnel to travel to a yearly in-person StrokeNet Steering Committee meeting, DSMB meeting, and/or other meeting of investigators and NINDS program staff.

All NIH 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:

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

As general guidance, NINDS expects that the total cost for the proposed project (direct cost plus F&A) will calculate to less than $25,000 per subject enrolled into the study. Budgets that need to exceed this guidance should be adequately justified and detailed in the application. The NINDS strongly encourages applicants to consider simple and/or pragmatic trial designs that minimize per-subject data collection and cost. Applicants are also encouraged to discuss their project needs with NINDS prior to submission.

R&R Subaward Budget

All instructions in the How to Apply-Application Guide must be followed.

PHS 398 Cover Page Supplement

All instructions in the How to Apply- Application Guide must be followed.

PHS 398 Research Plan

All instructions in the How to Apply- Application Guide must be followed, with the following additional instructions:

he Research Strategy must present an overview of the state of the science and supporting data, current status and relevance of the proposed project, a detailed discussion of the specific protocol, and the approach to data collection. Provide a brief description of study research objectives.

The following criteria must be addressed:

Specific Aims: Applicants should describe the potential impact of the proposed research. The hypotheses and specific aims of the research 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:

Significance and Biological Relevance: Applicants must state concisely the need, rationale, timeliness, and scientific relevance of the proposed study. It is particularly important that there be a discussion of how the study will test the hypothesis proposed and how results of the study (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 study for stroke prevention, treatment, or recovery. The applicant should also identify other (industry or academic) current or planned studies that potentially overlap with the proposed research. The timeliness of the proposed study should be discussed in the application.

Potential Impact of the research:   - regardless of the results - an estimate the public health impact relative to the number of afflicted individuals in the U.S. and/or global population annually.

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 this proposed clinical study. Proposed clinical studies 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. Applicants 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). For clinical trials: The major findings of the prior studies, whether preclinical or clinical, that led to the proposed research should provide a compelling rationale for the phase of the proposed trial and 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. Applications for trials of 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 concise summary of the protocol including the items listed below. Information that is required as part of the PHS Human Subjects and Clinical Trials Information Form need not be described in detail in this section; specific details can be referenced to the attached full protocol or the PHS Human Subjects and Clinical Trials Information Form. NINDS expects that the full protocol included in the application should support this concise summary.

Include a brief summary of the following, without duplicating details provided in the PHS Human Subjects and Clinical Trials Information Form:

• A description and rationale for the selected study design.
• Rationale for selecting the study population (as described in section 2 of the PHS Human Subjects and Clinical Trials Information form) and why it is an appropriate group to answer the question under study.
• Rationale for selection of the intervention(s) to be tested and study outcomes and endpoints (for clinical trials).
• A list of subject inclusion/exclusion criteria, or of group eligibility criteria (for group-randomized trials).
• For confirmatory (Phase 3) trials, a discussion of the evidence regarding whether clinically important sex/gender and race/ethnicity differences in the intervention effect are to be expected and plans for valid design and analysis. (see instructions for Section 2.4)
• A description of all assessments, including clinical, laboratory, physiological, behavioral, patient-centered, or other outcomes addressing the primary and secondary research questions. Use of patient reported outcomes, including those available through PROMIS and NeuroQoL, as well as non-traditional data collection approaches (e.g., telephone, mobile devices or web-based systems) should be considered.
• A discussion of potential biases and/or challenges in the protocol and how they will be addressed.
• A discussion of how the study investigators will be kept blinded to treatment group-specific data during the course of the clinical trial, if applicable. Applicants should describe how study statistical personnel will interact with the NDMC, who will serve as blinded and un-blinded statisticians, etc.

For an exploratory trial (e.g., a drug, device, biologic, rehab intervention, etc.), specific plans for the next steps of the therapy's development (such as a future efficacy trial) and proposed go/no-go criteria must be succinctly stated. 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.

For ancillary studies, provide the scientific rationale for adding the research to the parent clinical trial. Describe the procedures to incorporate the research into the parent trial and discuss the expected impact on the parent study, including timeline, recruitment, and effect on the scientific objectives of the parent study.

Milestones: Propose and justify milestones that will be subject to peer-review. A milestone is defined as a scheduled event in the project timeline that signifies the completion of a major project stage or activity. Milestones must be relevant, measurable, results-focused and time-bound, and should address timing of overall recruitment/enrollment and retention goals. The milestones should address accrual goals for women, minorities, and individuals of all ages, including children and older adults, and any other identified requirements for completion of the approved research.

Briefly describe the milestones that will be met in the UG3 and UH3 phases to address the specific aims and ensure the successful completion of the clinical trial and dissemination of its results (detailed milestones are described in the PHS Human Subjects and Clinical Trials Information section 2.7.).

Milestones of particular interest may include, but are not limited to:

Examples of UG3 Milestones to be addressed in the first year (if applicable):

• Complete protocol and informed consent documents
• DSMB review and approval of final protocol, template consent(s) and/or assent(s), and data and safety monitoring plan
• Obtaining final regulatory approvals
• Securing investigational drug/device as appropriate
• IRB approval of final protocol and consent and/or assent
• Enrollment of the first participant during the UG3 phase
• 25% of sites released for enrollment

Examples of UH3 Milestones (if applicable):

• Enrollment of 25%, 50%, 75% and 100% of the projected recruitment for all study participants, including women, minorities and individuals of all ages, including children and older adults (as appropriate)
• Study closure and completion plans
• Collection of data related to primary and secondary endpoints and database lock
• Submission of primary manuscript to peer-reviewed scientific journal(s) and dissemination of results

Letters of Support: If there will be subcontracts or service agreements for personnel or facilities, include documentation of such commitments, co-signed by a business official and the investigator at the participating center.

If there are agreements with collaborating industry partners, include documentation of the agreements, co-signed by a business official and an appropriate official at the company.

If CTSA resources will be utilized, include letter of support from each site CTSA program officer concurring with the specific plan for using these resources.

If some trial costs are to be borne by sources other than NIH, include documentation of this support, signed by individuals who have the authority to make a commitment on behalf of the organization they represent.

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.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the How to Apply- Application Guide. 

Other Plan(s): 

All instructions in the How to Apply-Application Guide must be followed, with the following additional instructions:

• All applicants planning research (funded or conducted in whole or in part by NIH) that results in the generation of scientific data are required to comply with the instructions for the Data Management and Sharing Plan. All applications, regardless of the amount of direct costs requested for any one year, must address a Data Management and Sharing Plan.

Appendix: Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the How to Apply- Application Guide.

• No publications or other material, with the exception of blank questionnaires or blank surveys, may be included in the Appendix.

PHS Human Subjects and Clinical Trials Information

When involving human subjects research, clinical research, and/or NIH-defined clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the How to Apply- Application Guide, with the following additional instructions:

If you answered “Yes” to the question “Are Human Subjects Involved?” on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

All instructions in the How to Apply- Application Guide must be followed.

In addition to the instructions in the SF424 Application Guide, the following additional instructions apply to this funding opportunity. Section numbers below refer to the Human Subjects and Clinical Trials Information form sections and subsections for which additional information is required for applications responding to this NOFO.

Section 2 - Study Population Characteristics  

2.3.a Inclusion of Individuals Across the Lifespan
Applicants must include a plan to enroll individuals across the lifespan. Considerations that may contribute to successful inclusion are appropriate site selection, patient-or community-engagement for the major elements of the projects, use of focus groups to address barriers to inclusion, etc. For clinical trials, applicants should also include a discussion of how the findings in individuals across the lifespan will be reported to the NINDS. For exploratory trial applications, investigators should consider including a section that addresses how the results in individuals across the lifespan will inform the design of the next steps.

2.4 Inclusion of Women and Minorities

Applicants must include a plan to enroll women and minorities (as appropriate). 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. For clinical trials, 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.

2.5 Recruitment and Retention Plan

Include a discussion of the ability of sites to recruit and retain the proposed number of subjects, including women, minorities, and individuals across the lifespan. Evidence should be provided that relevant stakeholders (e.g. potential subjects, referring and treating physicians, patient groups) have equipoise, view the question to be important and consider the study acceptable.

Include documentation of availability of eligible subjects at clinical sites presented in tabular format and a supporting letter from the StrokeNet Executive Committee indicating their ability and capacity to collaborate and conduct the proposed study.

2.7 Study Timeline

Applicants should provide detailed project performance and timeline objectives for the UG3 and UH3 phases. The proposed milestones must include achievable goals for each stage of the project as applicable:

• Completion of start-up activities (finalization of protocol, contracting of sites, registration in ClinicalTrials.gov, completion of any final regulatory approvals, etc.)
• Enrollment of the first subject
• Enrollment of 25%, 50%, 75% and 100% of the projected recruitment for all study subjects, including women, minorities and individuals across the lifespan(as appropriate)
• Expected timing of proposed interim analyses and, for adaptive designs, implementation of pre-specified adaptation plan
• Completion of data collection time period
• Completion of primary endpoint and secondary endpoint data analyses
• Completion of final study report
• Publication of primary study results
• Reporting of results in ClinicalTrials.gov
• Submission of final public use dataset to NINDS

Milestones and timelines will be refined and finalized in consultation with Program staff at the time of award.

Proposed milestones should be included for the entire trial, including any anticipated time beyond the award. This information will be used for planning purposes and to support the rationale for the full trial but does not guarantee continued funding beyond the initial funding cycle.

Section 3 - Protection and Monitoring Plans

3.3 Data and Safety Monitoring Plan

Applicants should refer to the NINDS Guidelines for Data and Safety Monitoring in Clinical Trials (https://www.ninds.nih.gov/Funding/Apply-Funding/Application-Support-Library/NINDS-Guidelines-Data-and-Safety-Monitoring) when developing their Data and Safety Monitoring Plan.

3.5 Overall Structure of the Study Team

Clinical Site Monitoring Plan. Describe a Clinical Site Monitoring Plan including how site adherence to the protocol and consenting process will be ensured, who is responsible for site monitoring, the frequency of planned monitoring activities, and the plan for handling deficiencies. Also describe plans for training and, if needed, certifying site personnel to complete study procedures.

Describe the composition and role of any advisory committees.

Discuss the responsibilities, oversight and coordination of any centers or cores.

Describe any subcontracts or service agreements for personnel or facilities.

If applicable, include a statement regarding how Clinical and Translational Science award (CTSA) program (https://ctsacentral.org/) resources will be leveraged. Describe what CTSA services will be used at each participating CTSA site and how the use of the CTSA impacts the trial budget.

Section 4 - Protocol Synopsis  

 4.1.a. Detailed Description  

Describe the protocol to be followed in each arm of the trial. Include a brief description of how adherence to the protocol will be standardized and optimized across network sites. Any concomitant interventions should be specified. Describe the proposed experimental design including a discussion of the clinical trial design and the rationale for the particular design chosen (pragmatic, explanatory, cluster-randomized, adaptive, etc.).

As applicable, state how the following resources for clinical research will be utilized:

• NINDS Common Data Elements;
• NeuroQOL;
• NIH Toolbox; and
• PROMIS.

For later-stage exploratory studies, state the go/no-go criteria that will be used at the end of this exploratory trial to decide whether to proceed with a subsequent efficacy clinical trial.

 4.3 Statistical Design and Power 

Statistical Analysis Plan (SAP). Applicants should provide a Statistical Analysis Plan (SAP) including details on the analyses specified in the study protocol; a description of how the statistical analysis of the primary, secondary and other endpoints will be performed; how the sample size was determined; how missing data will be handled; plans for interim analyses for safety, efficacy and futility; plans for recalculation of the sample size midway through the trial, if applicable, etc. If computer simulations were 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 (e.g., effects of noncompliance, missing data, subject eligibility criteria, etc.), sufficient details about the simulations should be provided in the SAP. 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.  

4.5 Will the study use an FDA-regulated intervention?

 4.5.a If yes, describe the availability of Investigational Product (IP) and Investigational New Drug (IND)/Investigational Device Exemption (IDE) status:

 Regulatory Approvals.  If the intervention is a drug, biologic, or device, applicants must provide documentation from the FDA providing information on one of the following scenarios:

(a) The protocol has been submitted under an open IND and the IND 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 as an original IDE or as a new study under an open IDE, and FDA has fully approved the IDE or IDE supplement. Under this scenario, applicants must provide documentation of an IDE or IDE supplement full approval letter from the FDA.

(c) The protocol has been submitted under an IND 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. Applicants should discuss how they intend to address the hold issues and when they believe they will have FDA approval to proceed with trial implementation.

(d) The protocol has been submitted as an original IDE or as a new study under an open IDE, and FDA has conditionally approved the IDE or IDE supplement. Under this scenario applicants must provide full documentation from the FDA on the conditions of approval. Applicants should discuss how they intend to address these conditions and when they believe they will have FDA approval to proceed with trial implementation.

(e) The protocol is exempt from an IND. Under this scenario applicants must provide a copy of the exemption email or letter from the FDA.

(f) The protocol is either exempt from the IDE regulations or does not require IDE approval because it is determined to be nonsignificant risk. Under this scenario applicants must provide either an IDE exemption letter or a copy of the risk determination 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.

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start). All instructions in the How to Apply-Application Guide must be followed.

PHS Assignment Request Form

All instructions in the How to Apply-Application Guide must be followed.

3. Unique Entity Identifier and System for Award Management (SAM)

See Part 2. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov.

4. Submission Dates and Times

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

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time.  If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications.

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 How to Apply- Application Guide.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. 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 Section 7.9.1 Selected Items of Cost.

Applications must be submitted electronically following the instructions described in the How to Apply-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 How to Apply – Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile form. 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 NOFO for information on registration requirements.

The applicant organization must ensure that the unique entity identifier provided on the application is the same identifier used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the How to Apply-Application Guide.

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review, NIH. Applications that are incomplete or non-compliant will not be reviewed.

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

As all applications to be submitted under this NOFO will use the NIH StrokeNet infrastructure resource, NINDS has determined that all applications to this NOFO must receive prior approval to submit, regardless of cost. Applicants should contact the appropriate NINDS Scientific/Research Contact at least 6 to 8 months prior to the planned submission date and follow the Policy on Acceptance for Review of Unsolicited Applications that Request $500,000 or More in Direct Costs as described in the SF424 (R&R) Application Guide.

Recipients or subrecipients must submit any information related to violations of federal criminal law involving fraud, bribery, or gratuity violations potentially affecting the federal award. See Mandatory Disclosures, 2 CFR 200.113  and NIH Grants Policy Statement Section 4.1.35.

Send written disclosures to the NIH Chief Grants Management Officer listed on the Notice of Award for the IC that funded the award and to the HHS Office of Inspector Grant Self Disclosure Program at [email protected].

Post Submission Materials

Applicants are required to follow the instructions for post-submission materials, as described in the policy

In addition, the NINDS Scientific Review Officer (SRO) will accept updated documentation of regulatory status not later than 30 calendar days prior to the review meeting.  

Section V. Application Review Information

1. Criteria

Only the review criteria described below will be considered in the review process. Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.

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

For this particular announcement, note the following:

1. Approved projects will be implemented through the NIH StrokeNet infrastructure and will make use of previously approved sites, resources, and investigators at the NIH StrokeNet National Coordinating Center, National Data Management Center, and Regional Coordinating Centers and their satellite stroke 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 NIH 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: The NIH StrokeNet includes a strong, flexible consortium of sites with capacity to implement trials. Trial enrollment will be overseen by the consortium.

3. Environment: The NIH 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 NIH StrokeNet projects, the PD(s)/PI(s) will work closely with the NIH 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, NIH 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-NIH StrokeNet project.

5. Applications will be evaluated for the scientific rationale, rigor of the supporting research and clinical need for 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. Assessment of the overall impact will include the evaluation of the experimental design and all 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). An application does not need to be strong in all categories to be judged likely to have a major scientific impact.

Review Criteria

Reviewers will consider Factors 1, 2 and 3 in the determination of scientific merit, and in providing an overall impact score. In addition, Factors 1 and 2 will each receive a separate factor score. 

Factor 1: Importance of the Research

Significance

• Evaluate the importance of the proposed research in the context of current scientific challenges and opportunities, either for advancing knowledge within the field, or more broadly. Assess whether the application addresses an important gap in knowledge in the field, would solve a critical problem, or create a valuable conceptual or technical advance.
• Evaluate the rationale for undertaking the study, the rigor of the scientific background for the work (e.g. prior literature and/or preliminary data) and whether the scientific background justifies the proposed study.

Innovation

• Evaluate the extent to which innovation influences the importance of undertaking the proposed research. Note that while technical or conceptual innovation can influence the importance of the proposed research, a project that is not applying novel concepts or approaches may be of critical importance for the field.
• Evaluate whether the proposed work applies novel concepts, methods or technologies, or uses existing concepts, methods, technologies in novel ways, to enhance the overall impact of the project.

Factor 2. Rigor and Feasibility

Approach

• Evaluate the scientific quality of the proposed work. Evaluate the likelihood that compelling, reproducible findings will result (rigor) and assess whether the proposed studies can be done well and within the timeframes proposed (feasibility).

Rigor:

• Evaluate the potential to produce unbiased, reproducible, robust data.
• Evaluate the rigor of experimental design and whether appropriate controls are in place.
• Evaluate whether the sample size is sufficient and well-justified.
• Assess the quality of the plans for analysis, interpretation, and reporting of results.
• Evaluate whether the investigators presented adequate plans to address relevant biological variables, such as sex or age, in the design, analysis, and reporting.
• For applications involving human subjects or vertebrate animals, also evaluate:
  • the rigor of the intervention or study manipulation (if applicable to the study design).
  • whether outcome variables are justified.
  • whether the results will be generalizable or, in the case of a rare disease/special group, relevant to the particular subgroup.
  • whether the sample is appropriate and sufficiently diverse to address the proposed question(s).
• For applications involving human subjects, including clinical trials, assess the adequacy of inclusion plans as appropriate for the scientific goals of the research. Considerations of appropriateness may include disease/condition/behavior incidence, prevalence, or population burden, population representation, and/or current state of the science.

Feasibility:

• Evaluate whether the proposed approach is sound and achievable, including plans to address problems or new challenges that emerge in the work. For proposed studies in which feasibility may be less certain, evaluate whether the uncertainty is balanced by the potential for major advances.
• For applications involving human subjects, including clinical trials, evaluate the adequacy and feasibility of the plan to recruit and retain an appropriately diverse population of participants. Additionally, evaluate the likelihood of successfully achieving the proposed enrollment based on age, racial, ethnic, and sex/gender categories.
• For clinical trial applications, evaluate whether the study timeline and milestones are feasible.

Factor 3. Expertise and Resources

Investigator(s)

• Evaluate whether the investigator(s) have demonstrated background, training, and expertise, as appropriate for their career stage, to conduct the proposed work. For Multiple Principal Investigator (MPI) applications, assess the quality of the leadership plan to facilitate coordination and collaboration.

Environment

• Evaluate whether the institutional resources are appropriate to ensure the successful execution of the proposed work.

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 categories of research that are exempt under 45 CFR Part 46, 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 categories of research that are exempt under 45 CFR Part 46, 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.

Vertebrate Animals

When the proposed research includes Vertebrate Animals, evaluate the involvement of live vertebrate animals according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animals Section.

Biohazards

When the proposed research includes Biohazards, evaluate whether specific materials or procedures that will be used are significantly hazardous to research personnel and/or the environment, and whether adequate protection is proposed.

Resubmissions

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

Renewals

Not Applicable

Revisions

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

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

Authentication of Key Biological and/or Chemical Resources:

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

Budget and Period of Support

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

2. Review and Selection Process

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

As part of the scientific peer review, all applications will receive a written critique.

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.

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 submitted in response to this NOFO. Following initial peer review, recommended applications will receive a second level of review by the National Advisory Neurological Disorders and Stroke 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.

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 Section 2.5.1. Just-in-Time Procedures. This request is not a Notice of Award nor should it be construed to be an indicator of possible funding.

Prior to making an award, NIH reviews an applicant’s federal award history in SAM.gov to ensure sound business practices. An applicant can review and comment on any information in the Responsibility/Qualification records available in SAM.gov.  NIH will consider any comments by the applicant in the Responsibility/Qualification records in SAM.gov to ascertain the applicant’s integrity, business ethics, and performance record of managing Federal awards per 2 CFR Part 200.206 “Federal awarding agency review of risk posed by applicants.”  This provision will apply to all NIH grants and cooperative agreements except fellowships.

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. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

Information regarding the disposition of applications is available in the NIH Grants Policy Statement Section 2.4.4 Disposition of Applications.

Section VI. Award Administration Information

1. Award Notices

A Notice of Award (NoA) is the official authorizing document notifying the applicant that an award has been made and that funds may be requested from the designated HHS payment system or office. The NoA is signed by the Grants Management Officer and emailed to the recipient’s business official.

In accepting the award, the recipient agrees that any activities under the award are subject to all provisions currently in effect or implemented during the period of the award, other Department regulations and policies in effect at the time of the award, and applicable statutory provisions.

Recipients must comply with any funding restrictions described in Section IV.6. Funding Restrictions. Any pre-award costs incurred before receipt of the NoA are at the applicant's own risk. For more information on the Notice of Award, please refer to the NIH Grants Policy Statement Section 5. The Notice of Award and NIH Grants & Funding website, see Award Process.

Individual awards are based on the application submitted to, and as approved by, the NIH and are subject to the IC-specific terms and conditions identified in the NoA.

ClinicalTrials.gov: If an award provides for one or more clinical trials. By law (Title VIII, Section 801 of Public Law 110-85), the "responsible party" must register and submit results information for certain “applicable clinical trials” on the ClinicalTrials.gov Protocol Registration and Results System Information Website (https://register.clinicaltrials.gov). NIH expects registration and results reporting of all trials whether required under the law or not. For more information, see https://grants.nih.gov/policy/clinical-trials/reporting/index.htm

Institutional Review Board or Independent Ethics Committee Approval: Recipient institutions must ensure that all protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the recipient must provide NIH copies of documents related to all major changes in the status of ongoing protocols.

Data and Safety Monitoring Requirements: The NIH policy for data and safety monitoring requires oversight and monitoring of all NIH-conducted or -supported human biomedical and behavioral intervention studies (clinical trials) to ensure the safety of participants and the validity and integrity of the data. Further information concerning these requirements is found at http://grants.nih.gov/grants/policy/hs/data_safety.htm and in the application instructions (SF424 (R&R) and PHS 398).

Investigational New Drug or Investigational Device Exemption Requirements: Consistent with federal regulations, clinical research projects involving the use of investigational therapeutics, vaccines, or other medical interventions (including licensed products and devices for a purpose other than that for which they were licensed) in humans under a research protocol must be performed under a Food and Drug Administration (FDA) investigational new drug (IND) or investigational device exemption (IDE).

2. Administrative and National Policy Requirements

The following Federal wide and HHS-specific policy requirements apply to awards funded through NIH:

• The rules listed at 2 CFR Part 200, Uniform Administrative Requirements, Cost Principles, and Audit Requirements for Federal Awards.
• All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the terms and conditions in the Notice of Award (NoA). The NoA includes the requirements of this NOFO. 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, Recipients, and Activities.
• If a recipient receives an award, the recipient must follow all applicable nondiscrimination laws. The recipient agrees to this when registering in SAM.gov. The recipient must also submit an Assurance of Compliance (HHS-690). To learn more, see the Laws and Regulations Enforced by the HHS Office for Civil Rights website.
  • HHS recognizes that NIH research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research. For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this NOFO.

All federal statutes and regulations relevant to federal financial assistance, including those highlighted in NIH Grants Policy Statement Section 4 Public Policy Requirements, Objectives and Other Appropriation Mandates.

Recipients are responsible for ensuring that their activities comply with all applicable federal regulations.  NIH may terminate awards under certain circumstances.  See 2 CFR Part 200.340 Termination and NIH Grants Policy Statement Section 8.5.2 Remedies for Noncompliance or Enforcement Actions: Suspension, Termination, and Withholding of Support. 

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 (HHS) grant administration regulations at 2 CFR Part 200, 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 recipients 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 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 recipients for the project as a whole, although specific tasks and activities may be shared among the recipients and NIH as defined below.

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

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

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

Additionally, an agency program official or IC program director will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.

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 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 PI 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 Division of Clinical Research, will serve as the NINDS liaison to the StrokeNet Data and Safety Monitoring Board.
• 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 1 year (UG3) in order to start up the trial and establish performance feasibility. Continuation of the award past this feasibility period (transition to UH3) 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 NINDS-appointed Data and Safety Monitoring Board (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 discontinuation of funding.

Areas of Joint Responsibility include:

None; all responsibilities are divided between recipients 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 recipients and 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 recipient. This special dispute resolution procedure does not alter the recipient's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and HHS regulation 45 CFR Part 16.

Consistent with the 2023 NIH Policy for Data Management and Sharing, when data management and sharing is applicable to the award, recipients will be required to adhere to the Data Management and Sharing requirements as outlined in the NIH Grants Policy Statement. Upon the approval of a Data Management and Sharing Plan, it is required for recipients to implement the plan as described.

4. Reporting

When multiple years are involved, recipients will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement Section 8.4.1 Reporting. To learn more about post-award monitoring and reporting, see the NIH Grants & Funding website, see Post-Award Monitoring and Reporting.

A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement Section 8.6 Closeout. NIH NOFOs outline intended research goals and objectives. Post award, NIH will review and measure performance based on the details and outcomes that are shared within the RPPR, as described at 2 CFR Part 200.301.

Section VII. Agency Contacts

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, application errors and warnings, documenting system problems that threaten submission by the due date, and post-submission issues)

Finding Help Online: https://www.era.nih.gov/need-help (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: [email protected] (preferred method of contact)
Telephone: 301-480-7075

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: [email protected]

Scott Janis, Ph.D.
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].

Chief Grants Management Officer
National Institute of Neurological Disorders and Stroke (NINDS)
Email: [email protected]v

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.

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 2 CFR Part 200.