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 SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from 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.

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. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

This funding opportunity announcement is to solicit applications for neurological clinical trials to be carried out in the Strategies to Innovate EmeRgENcy Care Clinical Trials Network (SIREN). SIREN provides a robust and readily accessible infrastructure for the implementation of clinical trials in a breadth of emergency indications related to neurology such as status epilepticus, traumatic brain or spinal cord injury and headache. The network also undertakes studies related to the mission of the National Heart, Lung and Blood Institute (NHLBI). Investigators who will submit a SIREN trial through the NHLBI should not use this FOA. Instead they should use the NHLBI PAR-19-329 Clinical Coordinating Center for Multi-Site Investigator-Initiated Clinical Trials (Collaborative UG3/UH3 Clinical Trial Required), and the NHLBI PAR-19-330, Data Coordinating Center for Multi-Site Investigator-Initiated Clinical Trials (Collaborative U24 Clinical Trial Required), or their reissue.

SIREN consists of a Clinical Coordinating Center (CCC), a Data Coordinating Center (DCC) and 14 clinical centers with their satellite sites (Hub and Spoke clinical site model). The SIREN infrastructure can accommodate several simultaneous large (>1,000 patient), simple, pragmatic trials in the Emergency Department (ED) and pre-hospital (e.g., transportation, EMS) settings.

This FOA uses the UG3/UH3 mechanism. Only projects that successfully meet milestones in the UG3 phase may move to the UH3 phase.

Scope of the Program

NINDS and NHLBI have established the SIREN network to facilitate the execution of clinical trials in neurological and cardiovascular emergencies. It is expected that all multi-center clinical trials supported by NINDS and NHLBI in these areas will be considered for implementation through SIREN.

This FOA encourages and provides a mechanism for the submission of applications that will use the SIREN network for multi-center clinical studies in the area of neurologic emergencies. Simple, pragmatic clinical trials are of special interest. Typical features include brief, inclusive patient eligibility criteria, procedures which integrate easily into or with standard of care practices and limited, focused data collection. Other trials may test novel devices, medications or procedures or may compare effectiveness of existing therapeutic approaches. Trials in SIREN must be hypothesis driven. Registries or descriptive observational studies will not be supported.

It is the intention of NHLBI and NINDS that SIREN will maintain a balanced portfolio of studies in each of these two areas, defined as follows:

Neurological emergencies (excluding stroke) studies of agents, devices, or strategies to treat conditions in the pre-hospital setting or the emergency department, such as (but not limited to) seizures, headaches, traumatic brain injury, anoxic brain injury, spinal cord injury and meningitis. Stroke trials should be directed to the NINDS supported StrokeNet.

Heart, lung and blood emergencies studies of agents, devices, or strategies to treat conditions in the pre-hospital setting or the emergency department, such as (but not limited to) cardiac arrest, chest pain, myocardial ischemia and infarction, and cardiac arrhythmias. Other emergency conditions affecting the lungs and blood are also of interest, including asthma, pulmonary embolism and the use of blood products in traumatic injury. Investigators who will submit a SIREN trial through the NHLBI should not use this FOA. Instead they should use the NHLBI PAR-19-329 Clinical Coordinating Center for Multi-Site Investigator-Initiated Clinical Trials (Collaborative UG3/UH3 Clinical Trial Required) FOA, and the NHLBI PAR-19-330,Data Coordinating Center for Multi-Site Investigator-Initiated Clinical Trials (Collaborative U24 Clinical Trial Required), or their reissue.

Applications for exploratory studies (for example, early dose ranging studies with biomarker outcome, early proof of mechanism or proof of concept trials) are not supported by this FOA. Late Phase II trials are within the scope of this FOA. Clinical 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 use of innovative and efficient trial designs is encouraged, such as adaptive dose-finding designs and designs incorporating plans for sample size recalculation. 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.

The priority of proposed network trials deemed by peer review to be highly meritorious will be based on factors including infrastructure capacity and availability of patient populations considering current ongoing trials within the network. The timing of funding and initiation of the trial will be determined by the NHLBI and NINDS with input from the SIREN leadership as necessary. This will insure that studies can be conducted within the proposed timeline included in the research plan of the application.

Applications will be expected to use the SIREN clinical sites, the CCC to manage the clinical operations and the DCC to manage data collection, compliance and analysis.

Applications are encouraged from investigators whose institutions are not part of the funded SIREN network.

Implementation

Applicants should make note of the following:

Working with SIREN is a cooperative venture between NINDS, NHLBI, and the SIREN leadership, and the applicant. Potential applicants to NINDS will be provided guidance by Program Staff at NINDS and the SIREN Executive and Steering Committees. Potential applicants are strongly encouraged to contact the Scientific/Research Contacts at whichever agency is appropriate (see Section VII. Agency Contacts) in order to discuss the appropriateness of the proposed trial to be conducted within SIREN. Applicants should contact the SIREN Clinical Coordinating Center prior to submission, to develop their research plan, assess the feasibility of the trial, and develop an appropriate budget to conduct the research. In addition, they should contact the Data Coordinating Center to develop the statistical and data analysis plan. The additional interaction with the network is intended to harness its scientific clinical trial expertise 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., 4-6 months) to prepare and submit a competitive SIREN project application.

Applicants to this FOA will be required to incorporate the NIH SIREN infrastructure into their proposed trial, including central coordination through the CCC, data management through the DCC, and subject recruitment and trial implementation at the clinical. All applicants and clinical sites will be required to use the master clinical trial agreements and central IRB that have been established for SIREN.

As well as the DCC and CCC, the SIREN infrastructure supports fourteen clinical hubs and their spoke sites. NINDS recognizes that to complete a specific clinical trial, additional clinical sites may be needed. The use of these additional sites, should be justified in the application. As described above, any additional sites will need to use the SIREN master clinical trial agreements and central IRB.

While NINDS and NHLBI provide infrastructure funding for SIREN, this funding alone is not sufficient to support large clinical trials. Investigators should work with SIREN team members and NINDS program staff to ensure an appropriate budget.

During the UG3 phase of the award, the operational clinical protocol for trials selected for funding will be finalized by the PD/PI together with the SIREN leadership. The SIREN DCC and CCC were established by NINDS and NHLBI based on peer and Council review to form a group of outstanding clinical trial experts from the fields of neurology, cardiology and data management with a proven record of developing high quality protocols. Final protocols will be reviewed and approved by NINDS prior to funding the application.

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

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 trial in support of an eventual Pre-Market Approval submission, or may require a more limited trial 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 SIREN network, 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 SIREN network may best be utilized in support of their specific device project. NINDS anticipates that the majority of device projects utilizing SIREN will be traditional Feasibility Studies in order to optimally leverage network advantages. A Traditional Feasibility Trial 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 Trial.

Rationale: Clinical trials proposed for this network must anchor their rationale in:

1. an unmet medical need;
2. a plausible biological mechanism;
3. rigorous preclinical (in vitro and/or in vivo) data; and/or
4. early clinical data.

The individual weight given to each of these four 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 or clinical, that led to the proposed clinical trial should provide a compelling rationale 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. While NINDS recognize that animal models in emergency neurological conditions may be of limited informative value, the applicant should specifically address the rigor of any animal studies being used as support, including the strengths and possible weaknesses of these studies (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 judged inadequate to support the rationale for the trial.

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

Project Stages: The implementation of a clinical trial in the SIREN Network should be divided into two stages that include the activities listed below. The first stage will be supported under the UG3 mechanism, and in most cases it will last for 1 year. Only studies that have satisfactorily met all of the milestones of the UG3 phase will be allowed to proceed to the full clinical trial.

UG3 Stage (usually 1 year)

1. Development of data management system, case report forms and data dictionaries, incorporating applicable NINDS Common Data Elements (CDEs) and other NIH-funded CDE Projects (e.g. PhenX Toolkit);
2. Development of tools for data and quality management;
3. Development of recruitment and retention strategies, and plans to minimize losses to follow-up, and acceptable attrition rates;
4. Finalization of protocol, manual of procedures, consent forms, and data management plan. (The team may wish to use the NIH Clinical Trial Protocol Template available at (https://grants.nih.gov/policy/clinical-trials/protocol-template.htm;)
5. Finalization of statistical analysis plan (including interim analyses, if appropriate);
6. Finalization of the study data sharing plan;
7. Protocol approval from Data and Safety Monitoring Board;
8. Registration of trial with clinicaltrials.gov;
9. Initiation of contracts and training of clinical site personnel (NINDS expects the initiation of all study sites to occur in the start-up stage; if a large number of sites is needed, a plan that describes how additional sites will be added after the initiation of the study should be included);
10. Initiation of processes for including proposed international clinical sites, if applicable;
11. FDA determination of EFIC (Exemption from Informed Consent) if applicable;
12. IRB Approval of EFIC plan, if applicable;
13. EFIC approval at at least 25% of the sites where patients will be enrolled; ?
14. Plans for site activation, execution of contracts and training of additional clinical sites, including any international sites, if applicable;
15. Enroll at least one patient from each site. (For studies that require EFIC, a determination of the number of sites required to have enrolled a patient will be determined by NINDS program staff in conjunction with the study leadership.)

UH3 Stage (usually 4 years)

1. Complete enrollment and follow-up of all subjects;
2. Minimize losses to follow-up;
3. Register results with www.clinicaltrials.gov as per FDAAA 801 requirements: https://clinicaltrials.gov/ct2/manage-recs/fdaaa;
4. Submit the primary publication within one year of completion of subject follow-up;
5. Provide a complete, cleaned, and de-identified dataset and any supporting documentation (including but not limited to the study protocol, statistical analysis plan, and data dictionary) required for the analysis of the data within one year of the primary publication or within 18 months of the last study visit of the last subject, whichever occurs first. See the NIH guidelines on sharing research data (https://grants.nih.gov/grants/policy/data_sharing/) and the NINDS Procedures for Submitting Datasets (https://www.ninds.nih.gov/Current-Research/Research-Funded-NINDS/Clinical-Research/Archived-Clinical-Research-Datasets)(https://grants.nih.gov/grants/policy/data_sharing/).

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

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

underrepresented in the biomedical, behavioral, clinical and social sciences, For definition of diverse populations, see NIH's Interest in Diversity statement (NOT-OD-20-031 - https://grants.nih.gov/grants/guide/notice-files/NOT-OD-20-031.html). Institutions are, therefore, encouraged to identify and sustain the interest of diverse candidates, including those from underrepresented groups in the scientific workforce at all career stages that will increase diversity. Examples of potential activities to increase diversity may include student engagement, research training, mentoring, and faculty development within the SIREN Network.

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 FOA.

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 Institutions)

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

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

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

Applicant Organizations

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

• 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 his/her 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.

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

2. Cost Sharing

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

3. Additional Information on Eligibility

Number of Applications

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

The NIH will not accept duplicate or highly overlapping applications under review at the same time, per 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 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 FOA. 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 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.

Letter of Intent

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.

By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:

• Descriptive title of proposed activity
• Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
• Names of other key personnel
• Participating institution(s)
• Number and title of this funding opportunity

The letter of intent should be sent to:

National Institute of Neurological Disorders and Stroke (NINDS)
Email: [email protected]

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

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.

Note: Effective for due dates on or after January 25, 2023, the Data Management and Sharing Plan will be attached in the Other Plan(s) attachment in FORMS-H application forms packages.

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:

Other Attachments: The following documents must be included in the application in the order listed below:

1. Documentation of availability of interventional agent(s) or device(s) as well as plans and support for acquisition and distribution of interventional agent(s) or device(s).

2. Regulatory approvals for investigational new drugs or devices:

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). Include up to ten pages of correspondence with the FDA. (Also see below under post-submission materials).

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

R&R Budget

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

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

• The protocol PD(s)/PI(s) (even if that person is also a SIREN clinical hub PD(s)/PI(s) for development of the trial during the UG3 phase.
• Support for a trial-specific clinical coordinator at the applicant's site.
• Trial-related procedures/materials.
• Clinical site operations for any proposed non-NIH SIREN ad-hoc sites.
• Subject monitoring costs and protocol-specific costs required for the CCC or DCC operations not otherwise covered by the CCC and DCC awards. Applicants should work with the CCC and DCC staff to determine protocol-specific costs to be included in the budget.
• All SIREN projects will utilize the DCC for data management and reporting activities. Applicants should use of statistical expertise at the DCC when planning a trial.

The budget must not include costs that are already covered by the SIREN infrastructure.

Applicants should discuss the costs per patient randomized with NINDS Scientific/Research staff. NINDS expects that the total cost for the proposed project (direct cost-plus F&A) will not exceed $25,000 per subject randomized into the trial. Budgets exceeding this guideline should be adequately justified in the application. The NINDS strongly encourages applicants to consider simple and/or pragmatic trial designs that minimize per-subject data collection and cost.

R&R Subaward Budget

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. 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 trial. 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. The applicant should also identify other (industry or academic) current or planned trials that potentially overlap with the proposed trial. The timeliness of the proposed trial should be discussed in the application.

Prior Studies and Rationale for Development: Applicants should describe the full body of rigorous evidence being used to support the proposed trial and comment on the justification for moving forward with this proposed clinical trial. 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. It is expected that this consideration includes attention to the rigor of the previous experimental designs, as well as the incorporation of relevant biological variables and authentication of key resources. Applicants are expected to include plans to address any weaknesses or gaps identified. While animal models 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). Applicants are expected to include plans to address any weaknesses or gaps identified.

Applications for drugs or biologics should provide compelling scientific evidence that the investigational agent and dose proposed for trial 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 condition.

Resource Sharing Plan:

Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R& R ) Application Guide.

Other Plan(s):

Note: Effective for due dates on or after January 25, 2023, the Data Management and Sharing Plan will be attached in the Other Plan(s) attachment in FORMS-H application forms packages.

All instructions in the SF424 (R&R) 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.
• Applicants must provide a complete, cleaned, and de-identified dataset and any supporting documentation (including but not limited to the study protocol, statistical analysis plan, and data dictionary) required for the analysis of the data within one year of the primary publication or within 18 months of the last study visit of the last subject, whichever occurs first. See the NIH guidelines on sharing research data (https://grants.nih.gov/grants/policy/data_sharing/) and the NINDS Procedures for Submitting Datasets (https://www.ninds.nih.gov/Current-Research/Research-Funded-NINDS/Clinical-Research/Archived-Clinical-Research-Datasets).

Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

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

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 SF424 (R&R) 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 SF424 (R&R) Application Guide must be followed.

Section 2 Study Population Characteristics

2.5 Recruitment and Retention Plan

For a multicenter trial, applicants should survey the potential clinical sites to ensure that recruitment targets can be met. Present the survey results using a table where the rows represent potential clinical sites and the columns include responses to questions from the survey. The survey questions will depend on the nature of the trial and the protocol-specified screening procedures but might include these:

• Has the PD/PI previously recruited patients with this disease into a clinical trial?
• Does this site have all necessary equipment to complete eligibility evaluations?
• If not, how far (in miles) will patients need to travel to complete eligibility evaluations?
• What is the total number of patients seen at this site in the past 12 months?
• How many of these appear to meet the pre-screening eligibility criteria?
• How many of these are likely to be found fully eligible and consent to be enrolled?
• Do the sites have an appropriate demographics to comply with the Inclusion of women and minorities NIH Policy?
• Is there a clear plan for recruitment of participants, based on the patient population seen at that facility or in the local community?
• If applicable, are participants across the lifespan included in the target population?
• Develop a strategy and communication plan to conduct regular community engagement activities and events, for example, convene and maintain a Community Advisory Board (CAB).
• Describe planned activities to enhance the capacity of communities to sustain delivery of information and results from the study (e.g., translation of materials into appropriate languages of relevant populations in UG3 and UH3 phase).
• Describe the plan to include engagement of community stakeholders throughout the research process. Examples of stakeholders could be derived from relevant community organizations, patients with lived experience, patient or consumer advocacy groups, limited English proficiency advocacy groups, community champions, community-based organizations, federally qualified health centers (FQHC), health care systems, and faith-based organizations.
• Describe the workflow schema and practices of the research teams.

2.7 Study Timeline

Milestone Plan. Applications must include proposed milestones for both the UG3 and UH3 phases. While final milestones will be determined at the time of grant award, the applicant should propose clear milestones that provide objective, quantitative outcomes that will justify continuing the project. Milestones are not equivalent to aims but rather are determinants of whether a trial continues or stops. The proposed milestones must include achievable goals for the UG3, and completion stage (UH3) of the project as follows:

Completion of UG3 start-up activities (finalization of protocol, contracting of sites, registration in ClinicalTrials.gov, completion of any final regulatory approvals, and agreements with third parties when a product, drug, or device is integral to the research.)

Enrollment of the first subject

Ongoing UH3 activities. These include:

• Enrollment of 25%, 50%, 75% and 100% of the projected recruitment for all trial subjects, including women, minorities and children (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 trial report.
• Publication of primary trial results
• Reporting of results in ClinicalTrials.gov
• Submission of final public use dataset to NINDS

Proposed milestones should be included for both the UG3 and UH3 phases of the entire trial, including any anticipated time beyond the five-year 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 DSMP.

Note that the Recruitment and Retention plans, and the Protection and Monitoring Plans will developed in conjunction with the SIREN DCC and CCC.

3.5 Overall Structure of the Study Team

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 a Data Management Plan including the methods and systems for data collection and quality control, security, confidentiality, and privacy, and the process for locking the final dataset, data sharing, both short and long-term data storage, and eventual destruction activities. Describe the plans, if any, to use non-traditional data collection approaches (e.g., digital/mobile/sensor technologies and web-based systems) and why these are appropriate.

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. Study Design

4.1.a Detailed Description

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

• NINDS Common Data Elements (https://www.commondataelements.ninds.nih.gov/#page=Default);
• NeuroQOL (http://www.healthmeasures.net/explore-measurement-systems/neuro-qol);
• NIH Toolbox (http://www.healthmeasures.net/explore-measurement-systems/nih-toolbox); and
• PROMIS (http://www.healthmeasures.net/explore-measurement-systems/promis).

4.3 Statistical Design and Power

Statistical Analysis Plan (SAP). This document should provide details on the analyses described in the protocol, including a detailed 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, by taking into account the impact of noncompliance, missing data, subject eligibility criteria, etc., sufficient details about the simulations should be provided if 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 trial 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?

.If yes, describe the availability of Investigational Product (IP) and Investigational New Drug (IND)/Investigational Device Exemption (IDE) status. Include a one page summary describing any interactions with the FDA as well correspondence with the FDA.

Section 5 Other Clinical Trial Related Attachments

Other Clinical Trial Related Attachments

Documentation of availability of eligible subjects at clinical sites, presented in tabular format and a supporting letter from SIREN indicating their ability and capacity to collaborate and conduct the proposed trial must be submitted.

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 SF424 (R&R) Application Guide must be followed.

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

Foreign Institutions

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

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

See Part 1. 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

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 Policy on Late Application Submission.

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.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

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

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

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

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

For assistance with your electronic application or for more information on the electronic submission process, visit 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 fieldof 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 FOA 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 SF424 (R&R) 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

Applicants requesting $500,000 or more in direct costs in any year (excluding consortium F&A) must contact a Scientific/ Research Contact at least 6 weeks before submitting the application and follow the Policy on the Acceptance for Review of Unsolicited Applications that Request $500,000 or More in Direct Costs as described in the SF424 (R&R) Application Guide.

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

IRB Communications (Optional 5 pages max). Submissions that exceed this limit will not be accepted:

• This attachment should be entitled IRB Communications.pdf .
• Applicants should submit relevant approval letters and associated attachments.
• For projects requiring non-clinical testing to support an IRB Non Significant Risk (NSR) designation, preliminary communications (e.g., letter or other documentation) with the IRB indicating what non-clinical testing will be necessary to support the NSR clinical study.

FDA Communications ( - 10 pages max): If this has not been included in the application, please provide the following:

Applicants should include a one page summary describing any interactions with the FDA, in addition to no more than nine pages of additional documentation such as:

• Approved minutes from all pre-submission meetings.
• Notice of approval and any associated attachments.
• Notification of risk determination.
• Breakthrough device designation (if applicable).
• 513(g) letter (if applicable).
• Communications on official FDA letterhead.
• Email communications with substantive information regarding the review or outcome.

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 Grants Officer, especially if the trial has been placed under full or partial hold.

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.

Note: Effective for due dates on or after January 25, 2023, the Data Sharing Plan and Genomic Data Sharing Plan (GDS) will not be evaluated at time of review.

For this particular announcement, note the following:

1. Approved projects will be implemented through the SIREN infrastructure and will make use of previously approved sites, resources, and investigators at the SIREN Clinical Coordinating Center, Data Coordinating Center, and the clinical hubs and their satellite centers. Timing of a grant award and initiation of projects approved by Council will be determined by NINDS with input from the SIREN leadership 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, a balanced portfolio, as well as the availability of patient populations considering current ongoing trials within the network.

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

3. Environment: The SIREN infrastructure (CCC, DCC and clinical hubs) 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 SIREN projects, the PD(s)/PI(s) will work closely with the SIREN CCC and DCC investigators, who have been selected for their experience and training in conducting emergency care research. While some applicants will be relatively junior in their careers, SIREN 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-SIREN project.

A proposed Clinical Trial application may include study design, methods, and intervention 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.

Overall Impact

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

Scored Review Criteria

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

Significance

Does the project address an important problem or a critical barrier to progress in the field? Is the prior research that serves as the key support for the proposed project rigorous? 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?

Are the scientific rationale and need for a clinical trial to test the proposed hypothesis or intervention well supported by preliminary data, clinical and/or preclinical studies, or information in the literature or knowledge of biological mechanisms? For trials focusing on clinical or public health endpoints, is this clinical trial necessary for testing the safety, efficacy or effectiveness of an intervention that could lead to a change in clinical practice, community behaviors or health care policy? For trials focusing on mechanistic, behavioral, physiological, biochemical, or other biomedical endpoints, is this trial needed to advance scientific understanding?

Specific to this FOA:

Is there adequate and scientifically rigorous preclinical or clinical research to support the trial rationale? Have the applicants described the general strengths and weaknesses in the rigor of the prior research that serves as the key support for the proposed project. Have they addressed the incorporation of relevant biological variables?

How compelling is the justification for the development of the proposed intervention in terms of potential advances in clinical practice, public health, and/or patient quality of life? How convincing is the evidence that equipoise exists in the medical and patient communities and the intervention is ready for clinical development?

What is the potential of the trial to advance the field as related to clinical practice, public health, unmet medical need, and/or patient quality of life even if (a) the proposed trial design, methods, and intervention are not innovative, or (b) the results of the trial are negative? How would the intervention or treatment approach affect management and care of patients?

Are there any ethical concerns?

Does the proposed trial have 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 trial 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?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or those 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?

With regard to the proposed leadership for the project, do the PD/PI(s) and key personnel have the expertise, experience, and ability to organize, manage and implement the proposed clinical trial and meet milestones and timelines? Do they have appropriate expertise in study coordination, data management and statistics? For a multicenter trial, is the organizational structure appropriate and does the application identify a core of potential center investigators and staffing for a coordinating center?

Specific to this FOA:

Are the PDs)/PI(s) of the project well-positioned to provide scientific leadership to the proposed trial while collaborating with the SIREN CCC, DCC, and clinical investigators.

Innovation

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

Does the design/research plan include innovative elements, as appropriate, that enhance its sensitivity, potential for information or potential to advance scientific knowledge or clinical practice?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? 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? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

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 individuals of all ages (including children and older adults), justified in terms of the scientific goals and research strategy proposed?

Does the application adequately address the following, if applicable

Study Design

Is the study design justified and appropriate to address primary and secondary outcome variable(s)/endpoints that will be clear, informative and relevant to the hypothesis being tested? Is the scientific rationale/premise of the study based on previously well-designed preclinical and/or clinical research? Given the methods used to assign participants and deliver interventions, is the study design adequately powered to answer the research question(s), test the proposed hypothesis/hypotheses, and provide interpretable results? Is the trial appropriately designed to conduct the research efficiently? Are the study populations (size, gender, age, demographic group), proposed intervention arms/dose, and duration of the trial, appropriate and well justified?

Are potential ethical issues adequately addressed? Is the process for obtaining informed consent or assent appropriate? Is the eligible population available? Are the plans for recruitment outreach, enrollment, retention, handling dropouts, missed visits, and losses to follow-up appropriate to ensure robust data collection? Are the planned recruitment timelines feasible and is the plan to monitor accrual adequate? Has the need for randomization (or not), masking (if appropriate), controls, and inclusion/exclusion criteria been addressed? Are differences addressed, if applicable, in the intervention effect due to sex/gender and race/ethnicity?

Are the plans to standardize, assure quality of, and monitor adherence to, the trial protocol and data collection or distribution guidelines appropriate? Is there a plan to obtain required study agent(s)? Does the application propose to use existing available resources, as applicable?

Data Management and Statistical Analysis

Are planned analyses and statistical approach appropriate for the proposed study design and methods used to assign participants and deliver interventions? Are the procedures for data management and quality control of data adequate at clinical site(s) or at center laboratories, as applicable? Have the methods for standardization of procedures for data management to assess the effect of the intervention and quality control been addressed? Is there a plan to complete data analysis within the proposed period of the award?

Specific to this FOA:

Does the application include adequate plans in the proposed approach to address any weaknesses or gaps identified in the rigor of the prior research?

How appropriate are the primary and secondary outcome measures? How appropriate are the eligibility criteria, randomization plan (if applicable), methods of blinding, sample size, trial power, data management plans, statistical analysis plans, and plans for training of site personnel?

How appropriate are the plans for subject outreach, recruitment, retention and follow-up?

How appropriate are the milestones? How likely is the trial to be completed within the project period?

How well does the project leverage the use of existing NIH tools, and/or other resources?

How rigorous are the plans for community engagement?

To what extent are the roles of all community partners clearly articulated?

Are appropriate linguistic and cultural competence strategies (i.e., translation of consent and research instruments, appropriate collaborators, team/partner training, accessibility measures etc.) incorporated into the engagement plan to reduce obstacles and enable recruitment and retention of diverse cohorts of participants (see NIH policy on Inclusion https://grants.nih.gov/policy/inclusion.htm)?

How well does the project monitors key performance indicators (KPI) to evaluate the study quality and accrual?

How appropriate are the plans for incorporating patient reported outcome measures and participant experience throughout the research study design?

Is there evidence that the trial's investigational compounds, drugs and or devices will be available in sufficient quantities, delivered on time, and managed per Good Clinical Practices to ensure the feasibility of the project?

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?

For studies using Exemption from Informed Consent (EFIC) is there a reasonable plan ?to obtain IRB and site approval for such a study?

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?

If proposed, are the administrative, data coordinating, enrollment and laboratory/testing centers, appropriate for the trial proposed?

Does the application adequately address the capability and ability to conduct the trial at the proposed site(s) or centers? Are the plans to add or drop enrollment centers, as needed, appropriate?

If international site(s) is/are proposed, does the application adequately address the complexity of executing the clinical trial?

If multi-sites/centers, is there evidence of the ability of the individual site or center to: (1) enroll the proposed numbers; (2) adhere to the protocol; (3) collect and transmit data in an accurate and timely fashion; and, (4) operate within the proposed organizational structure?

Specific to this FOA:

While the SIREN infrastructure 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 participants that they expect to be able to enroll? Does this project include a partnership with the private sector (e.g. patient advocacy groups, community groupls, and/or industry), and if so, have agreements with proposed partners been established? Have any foreign organizations involved in the proposed trial documented the compatibility of their data collection methods with U.S. data collection methods? Are substantive letters of support or other documentation provided to assure commitment of subcontractors, consultants, and/or service agreements for personnel and facilities?

Additional Review Criteria

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

Study Timeline

Is the study timeline described in detail, taking into account start-up activities, the anticipated rate of enrollment, and planned follow-up assessment? Is the projected timeline feasible and well justified? Does the project incorporate efficiencies and utilize existing resources (e.g., CTSAs, practice-based research networks, electronic medical records, administrative database, or patient registries) to increase the efficiency of participant enrollment and data collection, as appropriate?

Are potential challenges and corresponding solutions discussed (e.g., strategies that can be implemented in the event of enrollment shortfalls)?

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, 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 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 Individuals Across the Lifespan

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 individuals of all ages (including children and older adults) to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

Vertebrate Animals

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following 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. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animals Section.

Biohazards

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

Resubmissions

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

Renewals

Not Applicable.

Revisions

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

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

Note: Effective for due dates on or after January 25, 2023, the Data Sharing Plan and Genomic Data Sharing Plan (GDS) will not be evaluated at time of review.

Reviewers will comment on whether the Resource Sharing Plan(s) (i.e., Sharing Model Organisms) or the rationale for not sharing the resources, is reasonable.

Authentication of Key Biological and/or Chemical Resources:

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

Budget and Period of Support

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

2. Review and Selection Process

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

As part of the scientific peer review, all applications 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.

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

3. Anticipated Announcement and Award Dates

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

1. Award Notices

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

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

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

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

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

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, Recipients, and Activities, including of note, but not limited to:

• Federal wide Research Terms and Conditions
• Prohibition on Certain Telecommunications and Video Surveillance Services or Equipment
• Acknowledgment of Federal Funding

If a recipient is successful and receives a Notice of Award, 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.

Should the applicant organization successfully compete for an award, recipients of federal financial assistance (FFA) from HHS will be required to complete an HHS Assurance of Compliance form (HHS 690) in which the recipient agrees, as a term and condition of receiving the grant, to administer their programs in compliance with federal civil rights laws that prohibit discrimination on the basis of race, color, national origin, age, sex and disability, and agreeing to comply with federal conscience laws, where applicable. This includes ensuring that entities take meaningful steps to provide meaningful access to persons with limited English proficiency; and ensuring effective communication with persons with disabilities. Where applicable, Title XI and Section 1557 prohibit discrimination on the basis of sexual orientation, and gender identity. The HHS Office for Civil Rights provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-providers/provider-obligations/index.html and https://www.hhs.gov/civil-rights/for-individuals/nondiscrimination/index.html

HHS recognizes that 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 FOA.

• Recipients of FFA must ensure that their programs are accessible to persons with limited English proficiency. For guidance on meeting the legal obligation to take reasonable steps to ensure meaningful access to programs or activities by limited English proficient individuals see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/fact-sheet-guidance/index.htmlandhttps://www.lep.gov.

• For information on an institution’s specific legal obligations for serving qualified individuals with disabilities, including providing program access, reasonable modifications, and to provide effective communication, see https://www.hhs.gov/civil-rights/for-individuals/disability/index.html.

• HHS funded health and education programs must be administered in an environment free of sexual harassment, see https://www.hhs.gov/civil-rights/for-individuals/sex-discrimination/index.html. For information about NIH's commitment to supporting a safe and respectful work environment, who to contact with questions or concerns, and what NIH's expectations are for institutions and the individuals supported on NIH-funded awards, please see https://grants.nih.gov/grants/policy/harassment.htm.

• For guidance on administering programs in compliance with applicable federal religious nondiscrimination laws and applicable federal conscience protection and associated anti-discrimination laws see https://www.hhs.gov/conscience/conscience-protections/index.html and https://www.hhs.gov/conscience/religious-freedom/index.html.

Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.html or call 1-800-368-1019 or TDD 1-800-537-7697.

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 and 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.

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR part 75 and 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 recipient is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the recipient for the project as a whole, although specific tasks and activities may be shared among the recipient and the NIH as defined below.

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

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

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

• A NINDS Project Scientist working with the Principal Investigator and network investigators will develop milestones for the trial. Failure to meet the agreed upon milestones may result in reduced funding or early termination of the cooperative agreement. The NINDS retains the option to obtain periodic external peer review of progress.
• The NINDS Project Scientist will function as one of several co-investigators, collaborating and interacting as necessary with the Principal Investigators in accomplishing the overall goals of the Research Program.
• In addition, an NINDS or NHLBI Program Official will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.
• A separate NINDS Program Official, from the Office of Clinical Research, will serve as the NINDS liaison to the Data and Safety Monitoring Board (DSMB).
• If the proposed trial should require that FDA issue an IND/IDE, the NINDS or NHLBI 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 during both the UG3 and UH3 phases. 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 may make an award for 2 to 3 years in order to start-up the trial and establish performance feasibility. Continuation of the award past this feasibility period will be contingent upon a demonstrated ability to meet milestones indicating that the trial can be implemented as planned. Feasibility milestones will be defined at the start of each trial and will be monitored closely by the Institute-appointed DSMB and NINDS HLBI Program Official. Achievement of these milestones will be evaluated by NINDS prior to releasing funds for each year of the award and failure to achieve these milestones may lead to trial termination.

Areas of Joint Responsibility include:

• Have access to data generated under this Cooperative Agreement and may periodically review the data and administrative progress reports. Program staff may use information obtained from the data for the preparation of internal reports on the activities of the study. However, recipients will retain custody of and maintain primary rights to all data developed under these awards, subject to Government rights of access consistent with HHS, PHS, and NIH policies.
• Serve as a resource to provide scientific/programmatic support during the accomplishment of the research by participating in the design of the activities, advising in the selection of sources or resources (e.g., determining where a particular reagent can be found), provision of research resources and reagents available from NINDS grantees and contractors, advising in management and technical performance, or participating in the preparation of publications.
• Oversee the adequacy of adverse event management and reporting, and have regular communications with the PD/PI and study team, which may include attendance at the DSMB and related committee meetings.
• Review the progress of the study, and of each participating facility, through consideration of the annual reports, site visits, screening logs, etc. This review may include, but is not limited to, compliance with the study protocol, meeting enrollment targets, adherence to uniform data collection procedures, and the timeliness and quality of data reporting.
• Monitor progress of study milestones; as with any award, continuation, even during the period recommended for support, is contingent upon satisfactory progress. Progress will be monitored by NINDS. The schedule for these interim reviews will be based upon the duration of the clinical trial period. Continuation of funding will be dependent upon the awardee’s ability to show adequate progress towards milestone accomplishment.
• Compare, at each scheduled interim review, actual enrollment to the benchmarks and criteria identified in the application and negotiated prior to award. Recipients who do not accomplish the negotiated milestones shall submit a milestone report which will include a discussion of why the milestones were not met in the agreed upon timeframe and propose a corrective recruitment action plan. The corrective recruitment action plan shall include: amended milestones, plans to achieve the amended milestones and any additional items required by Program staff. The plan shall be provided to Program staff no later than 2 months following the missed milestone. Studies in which recruitment milestones are not met as per criteria established pre-award, or for which regulatory approval has not been met within one year, and are unlikely to improve sufficiently to bring the study to completion within an acceptable budget or time frame, may be closed for lack of progress. If NINDS or the recipient concludes that the study is no longer feasible, the investigator will be required to submit a close-out plan to NINDS within 2 months. The plan must be approved and signed by the Institutional Officials and the PI/PD(s) listed on the awards prior to submission.
• The NINDS Project Scientist will serve on the primary leadership committee. In addition, the Project Scientist, or other NINDS Program Officials, may serve on other study committees regarding recruitment, intervention, follow-up, quality control, protocol adherence, assessment of problems affecting the study and potential changes in the protocol, interim data and safety monitoring, final data analysis and interpretation, preparation of publications, and development of solutions to major problems such as insufficient participant enrollment. The NINDS Project Scientist will have voting membership on the primary leadership committee and its subcommittees.
• Each full member will have one vote. Recipient members of the Steering Committee will be required to accept and implement policies approved by the Steering Committee.

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual 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 DHHS regulation 45 CFR Part 16.

3. Data Management and Sharing

Note: The NIH Policy for Data Management and Sharing is effective for due dates on or after January 25, 2023.

Consistent with the 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.

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. NIH FOAs 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 45 CFR Part 75.301 and 2 CFR Part 200.301.

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

In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period. The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 Award Term and Conditions for Recipient Integrity and Performance Matters.

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]

National Institute of Neurological Disorders & Stroke (NINDS)
Email: [email protected]

Scientific Review Branch
National Institute of Neurological Disorders and Stroke (NINDS)
Email: [email protected]

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

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 45 CFR Part 75 and 2 CFR Part 200.