Required Application Instructions

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

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

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 has formed the NIH Stroke Clinical Trials Research Network (NIH StrokeNet, http://www.ninds.nih.gov/research/clinical_research/NINDS_stroke_trials_network.htm). The StrokeNet comprises a National Clinical Coordinating Center (NCC), a National Data Management Center (NDMC) and 25 geographically distributed Regional Coordinating Centers (RCC) and their affiliated stroke centers.

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

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

This FOA provides one of a set of three different means by which teams of investigators can submit trials or studies that are to be conducted within the StrokeNet infrastructure. This FOA uses the X01 mechanism to provide access to the StrokeNet infrastructure resource to both For-profit and Non-profit organizations. Others may wish to consider applying through PAR-14-220 "StrokeNet Research Project - Cooperative Agreement (U01) or PAR-14-252 StrokeNet Small Business Innovation Research (SBIR) Cooperative Agreement .

Scope of the Program

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

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

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

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

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

Exploratory Trials

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

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

Confirmatory (Phase 3) Trials

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

This FOA also may be used for the submission of an adaptive trial utilizing a seamless Phase 2/3 transition where data from subjects in Phase 2 are included in the analysis of Phase 3.

Biomarker and Clinical Endpoint Studies

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

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

Applicants should make note of the following:

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

(2) Successful applicants will be given access to the StrokeNet infrastructure. The StrokeNet NCC will work with applicants to finalize the protocol and to implement the proposed study, including securing of all site subcontracts. The StrokeNet NDMC will provide statistical and data management support. The StrokeNet RCCs and affiliated sites will provide recruitment/retention support as well as on-site implementation of the clinical protocol.

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

(4) The X01 applicant must hold intellectual property rights (IP) to the investigational agent/device proposed for study.

(5) This FOA is intended to support studies in patients, not healthy volunteers. All trials proposing use of an investigational agent/device must have an active IND/IDE or documentation of exemption prior to submission of the application (see https://grants.nih.gov/grants/guide/notice-files/NOT-NS-11-018.html).

(6) Network access will be contingent on the issuance of an appropriate technology transfer agreement, possibly a Cooperative Research and Development Agreement (CRADA), between NINDS and Applicant.

(7) NINDS will provide the infrastructure and related support for trials approved through the X01 mechanism. The applicant will be expected to make a financial contribution to cover the clinical trial costs above the NINDS-covered infrastructure costs. Costs associated with drug or device production and preparation, including but not limited to testing, quality control, labeling, packing, distribution, and shipping costs, as well as any related consultant services and regulatory monitoring, are not covered by the StrokeNet infrastructure awards.

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

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

(10) 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.

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

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)

Other

• Non-domestic (non-U.S.) Entities (Foreign Institutions)

Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are 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 SF 424 (R&R) Application Guide to be eligible to apply for or receive an award.

• All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.
• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• System for Award Management (SAM) (formerly CCR) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
• NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
• eRA Commons - Applicants must have an active DUNS number and SAM registration in order to complete the eRA Commons registration. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

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

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

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

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

It is not necessary that the designated study PD(s)/PI(s) be part of the StrokeNet infrastructure in order to be eligible to apply to this FOA. Access to StrokeNet will be contingent on the issuance of an appropriate technology transfer agreement, possibly a Cooperative Research and Development Agreement (CRADA), between NINDS and Applicant.

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

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

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

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

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

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

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

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

• For this specific FOA, the Research Strategy section is limited to 12 pages.

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

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

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

Total Federal Funds Requested: Enter $0.

Total Federal & Non-Federal Funds: $0.

Estimated Program Income: Enter $0.

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

Other Attachments: Include a discussion of enrollment feasibility within the network and expected enrollment timelines, including enrollment of women and minorities.

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

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

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

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

Research Strategy:

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

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

Approach: Applicants should provide a brief description of their proposed study, including a discussion of the potential biases in the study and how they will be addressed. Clinical pharmacology justifying the proposed dosing regimen should be provided if applicable. A detailed protocol is not required for submission. Following peer review, applicants who are granted network access will work with the StrokeNet team and the NINDS to develop a detailed protocol. The StrokeNet team was established by NINDS based on peer- and Council review to form a group of outstanding clinical trial experts from the fields of neurology and statistics with a proven record of developing high quality protocols.

For applications proposing to conduct a seamless Phase 2/3 trial, where data from subjects in Phase 2 are included in the analysis of Phase 3, a transition plan from the Phase 2 component to the Phase 3 component should be described and trial termination plans should be defined in the event that the results of Phase 2 do not support continuation to Phase 3.

For an exploratory trial of a drug or biologic, specific plans for the next steps of the therapy's development (such as a future efficacy trial) must be succinctly stated.

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

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

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

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

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

Below are items to be included in the appendix:

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

Applicant should NOT provide

• CMC information
• Safety toxicology information
• Clinical pharmacology other than justification of the proposed dosing regimen.

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

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

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

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

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

This initiative is not subject to intergovernmental review.

Not Applicable

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

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

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

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

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

See more tips for avoiding common errors.

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

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

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

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

For this particular announcement, note the following:

1. The X01 Resource Access Program invites eligible institutions to seek access to the NIH StrokeNet resource. Important factors in the peer review of X01 applications are the need for, and potential benefit of, gaining access to the resource, specifications for the proposed research, timelines for completion and plans for follow-on studies.

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

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

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

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

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

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

Significance

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

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

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

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

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, or in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

Innovation

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

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

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Evaluate the extent to which the proposed clinical outcomes would be considered "clinically meaningful" and whether the clinical outcome assessment methods are well described with regard to training and reproducibility. Is the statistical design appropriate and efficient to address the proposed aims? Is the study likely to be completed within the project period?

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of children, justified in terms of the scientific goals and research strategy proposed? Does the application document the availability of sufficient eligible subjects at the proposed clinical sites and plans for subject outreach, recruitment, retention, and follow-up? What is the status of evidence indicating whether or not clinically important sex/gender and race/ethnicity differences in the intervention effect are to be expected?

Environment

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

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

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

Protections for Human Subjects

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

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

Inclusion of Women, Minorities, and Children

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

Vertebrate Animals

Not Applicable

Biohazards

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

Resubmissions

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

Renewals

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

Revisions

Not Applicable

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

Applications from Foreign Organizations

Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.

Select Agent Research

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

Resource Sharing Plans

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

Budget and Period of Support

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

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

As part of the scientific peer review, all applications:

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

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications. Following initial peer review, recommended applications will receive a second level of review by the NINDS National Advisory Council. The following will be considered in making decisions to provide access to the requested resources:

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

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

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

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

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

Cooperative Agreement Terms and Conditions of Award

Not Applicable

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

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

eRA Service Desk (Questions regarding ASSIST, eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)
Finding Help Online: https://grants.nih.gov/support/index.html
TTY: 301-451-5939
Email: commons@od.nih.gov

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

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone: 301-945-7573
TTY: 301-451-5936
Email: GrantsInfo@nih.gov

Claudia Scala Moy, PhD
National Institute of Neurological Disorders & Stroke (NINDS)
Telephone: 301-496-9135
Email: moyc@ninds.nih.gov

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

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

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

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