Part 1. Overview Information

Key Dates

All applications are due by 5:00 PM local time of applicant organization. 

Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

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

Conformance to all requirements (both in the Application Guide and the NOFO) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions.

Applications that do not comply with these instructions may be delayed or not accepted for review.

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

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

Part 2. Full Text of Announcement

Section I. Notice of Funding Opportunity Description

Purpose

The purpose of this Notice of Funding Opportunity (NOFO) is to encourage grant applications for investigator-initiated clinical trials to the National Institute of Neurological Disorders and Stroke (NINDS) that are intended to develop interventions to prevent or improve outcomes of neurological disorders.  Applications addressing questions within the mission and research interests of the NINDS may include studies of drugs, biologics, or devices, as well as surgical, behavioral, diet-based, or other types of interventions meant to prevent or treat disorders within the NINDS mission. This NOFO uses the UG3/UH3 phased award mechanism. Projects that demonstrate satisfactory progress during the UG3 phase are eligible to transition to the UH3 phase.

Scope of the Program

This NOFO provides the primary opportunity for the submission of applications for early and middle phase exploratory trials, confirmatory/pivotal clinical trials, and comparative effectiveness clinical trials aimed at testing promising interventions for neurological disorders. Pragmatic trials performed in large numbers of participants with minimal alteration from clinical practice and low per-patient costs are also encouraged.

For medical devices, early feasibility and traditional feasibility study designs may include single-arm case series, within subject designs, device comparisons, comparisons to historic controls, comparisons to performance controls, or adaptive/Bayesian designs.

Types of projects permitted under this NOFO:

Early and Middle phase Exploratory Trials

Under this NOFO, NINDS considers exploratory clinical trials as early-stage projects in the development of the intervention for a neurological condition that statistically informs the potential or need for further study of the interventions. These trials generally fall within the scope of what are considered Phase 1 or Phase 2 clinical trials.

Examples of appropriate goals for early phase studies supported under this NOFO include, but are not limited to:

• Evaluating and optimizing the dose, formulation, safety, tolerability or pharmacokinetics of an intervention in the target population.
• Selecting or ranking the best of two or more potential interventions or dosing regimens to be evaluated in a subsequent trial, based on tolerability, safety data, biological activity, or preliminary clinical efficacy (e.g., futility trials).
• Evaluating biological activity relative to clinical endpoints.
• Informing the next phase of development of medical devices, usually by finalizing the device design/settings, establishing operator technique, and/or finalizing the choice of study endpoints for the design of a pivotal clinical trial, in addition to providing initial safety data.

Confirmatory, Pivotal, and Comparative Effectiveness Trials

Confirmatory, pivotal, and comparative effectiveness clinical trials submitted under this NOFO are intended to be prospective studies that are adequately powered (e.g., greater than 80%) that compare two or more interventions to establish a scientific basis for changes in health policy or standard of care. These trials generally fall within the scope of what are considered Phase 3 and Phase 4 clinical trials. Confirmatory and pivotal 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. Comparative effectiveness trials compare the benefits and harms of different existing interventions and strategies to prevent, diagnose, treat, and monitor health conditions in real world settings and/or in specific populations.

This NOFO also may be used for the submission of an adaptive trial utilizing a seamless Phase 2/3 transition where data from subjects in Phase 2 are included in the analysis of Phase 3.  Pragmatic trials requiring minimal data collection and low cost per subject are also encouraged.

Application Development

Applicants should make note of the following:

General Considerations

(1) Consultation with NINDS: NINDS Program staff in the Division of Clinical Research are available for consultation as plans for an application are being developed (see Section VII, Agency Contacts) prior to the anticipated application submission date. This early contact will provide an opportunity to clarify NINDS policies and guidelines as well as to discuss how to develop an appropriate project timeline and milestone plan. NINDS Program staff are also available to discuss strategies for recruitment and Inclusion Policies for Human Subjects . 

(2) Rigor and transparency: NINDS, as part of the NIH, strives for rigor and transparency in all research it funds. For this reason, NINDS explicitly emphasizes the NIH application instructions related to rigor and transparency (https://grants.nih.gov/policy/reproducibility/guidance.htm) and provides additional guidance to the scientific community (NIH Grants Policy Statement | Grants & Funding).  If previously published or preliminary studies do not meet these standards, applicants should address how the current study design addresses the deficiencies in rigor and transparency. Proposed experiments should likewise be designed in a manner that minimizes the risk of bias and ensures the validity of experimental results.

(3) Rationale: The major findings of the studies, whether preclinical and/or clinical, that are offered in support of the proposed clinical trial should provide a compelling justification for the phase of study and that the proposed intervention will be effective. Data from preclinical and pilot studies that demonstrate the need for, and the feasibility of the trial should be presented when available.  Preclinical data (such as from animal studies) that do not sufficiently meet the rigor guidelines or are not sufficiently associated with the human condition may be inadequate to support the rationale for the study.

(4) Clinical Development Plan: For early and middle phase trial proposals, the clinical development plan describes the overall strategy for advancing the proposed intervention. Such plans may include one or more subsequent exploratory trials and outline the progression of development toward a confirmatory trial. The development pathway may incorporate predefined go/no-go decision points that inform progression between stages and advancement toward confirmatory evaluation.

Trial Design and Innovation

(1) Pragmatic Trials: The NINDS  recognizes the value of proposals that are able to evaluate the effectiveness of interventions in real-world circumstances, as appropriate. These pragmatic trials typically yield results that are more broadly applicable, often require less data collection, and incur lower per patient costs when compared to randomized control trials.

(2) Innovative Designs: Innovative and efficient study designs may include adaptive dose-finding designs, designs incorporating plans for sample size recalculation, preliminary efficacy for devices, umbrella or basket trial designs, and futility designs. Traditional feasibility study designs may include, for example, single-arm studies, cross-over designs, device-device comparisons, device-drug comparisons, comparisons to historical controls, comparisons to performance criteria/goals, adaptive designs, and Bayesian designs.

(3) Innovative and Mobile Technologies: Digital/mobile/sensor technologies, health tools and web-based systems can facilitate data collection (including data collection in a continual, contextual, real-world, etc.), as well as to enhance protocol adherence on the part of research participants and study site staff.

Intervention and Disease Considerations 

(1) Devices: This NOFO supports medical device feasibility and pivotal studies. 

• Feasibility studies should focus on acquiring preliminary safety and effectiveness information on a near-final or final device design to adequately plan a Pivotal study. 
• Pivotal studies are definitive studies during which evidence is gathered to support the safety and effectiveness evaluation of the medical device for its intended use. 

Due to the broad scope of possible medical devices and the varied nature of the regulatory path, investigators considering applications to evaluate devices are strongly encouraged to contact NIH Program staff as early as possible in the development of their application to receive guidance on the best options and pathways for submitting their grant.

(2) Behavioral Interventions or Rehabilitation Strategies: Applications seeking to develop behavioral interventions to prevent, treat or manage neurological conditions are welcome. When applicable, such applications can use the UG3 phase for safety/tolerability/feasibility studies that will inform further testing in a larger trial in the UH3 phase once initial milestone-driven planning phase (UG3) is completed successfully.

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

(4) Rare Diseases: Trials in rare diseases are encouraged, particularly in conditions for which definitive outcome measures and prior data from natural history studies are available. It is recognized that available patient pools may not be adequate to meet the sample size requirements typically seen in trials in more common disorders, and innovative trial designs, including crossover designs and adaptive designs, can be appropriately considered. Additionally, an assessment of clinical efficacy as a secondary outcome may be warranted for early/middle phase trials in rare diseases where the available patient pool may not make a definitive efficacy trial feasible. Regardless of the design, it is especially important to ensure that the study design and statistical analysis plans will meet the stated objectives and allow for the most efficient evaluation of the limited participants. The application should clearly demonstrate recruitment feasibility at the participating sites and applicants are encouraged to fully engage patient advocacy groups or similar representatives of the affected disease community in study design, execution, recruitment plans and reporting.

Existing NINDS Clinical Trial Networks

The NINDS currently supports three independent clinical trial networks focused on different neurological disorders, neurological disease stages, and/or clinical trial phases. It is highly advised that applicants research these networks and consult with NINDS Program Directors before beginning the development of clinical trial applications to be considered for funding through the NINDS and before submission to this NOFO.

StrokeNet: The NIH StrokeNet is specifically designed to implement multicenter trials in stroke prevention, treatment, and rehabilitation. NINDS requires that all multisite stroke trials be considered for StrokeNet. Multisite trials are generally considered needing more than 3 clinical enrolling sites to recruit the participants. Only under exceptional circumstances will NINDS consider funding such stroke trials outside of StrokeNet. 

NeuroNEXT: The NINDS's NeuroNext network provides a robust, standardized, and accessible infrastructure to facilitate the rapid development and implementation of sound, phase 2 clinical trial protocols for non-stroke, neurological disorders affecting adult and/or pediatric populations.

SIREN: The NINDS's  SIREN Network performs clinical trials that impact the care of the patient with a non-stroke neurological emergency in the pre-hospital or emergency department setting. NINDS requires that all such trials be first considered for the SIREN network.

Award Structure and Requirements

This NOFO will utilize a bi-phasic, milestone-driven, cooperative agreement (UG3/UH3) mechanism. The UG3 phase is intended to be used primarily for planning, start-up, and establishing feasibility of the trial over the course of a year, but can be planned for up to 2 years, if necessary. If and when the respective UG3 milestones stated in the notice of award are met, the project may then transition to the UH3 phase for full implementation of the study. The UH3 phase may be planned for up to 6 years, but the total duration of both phases cannot exceed 7 years. Importantly, the justification for needing more than 5 years total will only be approved for exceptionally well justified situations, such as needing longer primary outcome follow-up (e.g., 2 or more years) or enrollment of a rare disease population. This is especially true for early or middle phase exploratory trials, where a 5-year total project period should be sufficient to complete the trial.

Milestones and objectives for both the UG3 and UH3 phases are included and clearly described in the application.

Project milestones will be crafted in conjunction with the applicant. Continuation of funding and subsequent notices of award are subject to milestones to be specified in the Notice of Award.

Award Phases

UG3 Stage

The UG3 phase will support start-up feasibility phase to initiate enrollment in the clinical trial. Note specifically, the UG3 is not appropriate for completing preclinical R&D activities.  All necessary regulatory approvals not already provided, including FDA "may proceed" letter, if applicable, as well as provision of the necessary drugs, devices or other resources, should be obtained by the end of the UG3 award and prior to beginning enrollment to allow for the successful execution of the proposed clinical trial in the UH3 phase. It is expected that enrollment in the study will begin by the end of the UG3 phase or sooner.

Activities in the UG3 phase may include the following:

1. Development of data management system, case report forms and data dictionaries, incorporating applicable NINDS Common Data Elements (CDEs) and other NIH-funded data collection Projects (e.g., PhenX Toolkit);
2. Development of tools for data and quality management
3. Development of recruitment and retention strategies
4. Development of plans to minimize losses to followup and determination of acceptable attrition rates
5. Finalization of the manual of procedures, consent forms, and data management plan;
6. Finalization of statistical analysis plan (including interim analyses, if appropriate);
7. Finalization of the study data sharing plan;
8. Obtaining appropriate regulatory approvals including IRB approval and when applicable, FDA approval;
9. Acquisition of the drugs, biologics or devices needed to conduct the trial along with preparing the control, etc.;
10. 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);
11. Plans for site activation, execution of contracts and training of additional clinical sites;
12. Opening site enrollment with at least one patient enrolled into the trial.

Applications testing behavioral interventions or rehabilitation strategies may use the UG3 phase for safety/tolerability/feasibility studies that will inform further testing in a larger trial in the UH3 phase once the initial milestone-driven planning phase (UG3) is completed successfully.

UH3 Stage

The UH3 Phase will be used to complete the clinical trial.  Subject to NINDS funding availability and scientific priorities, UH3 awards will be made after administrative review with particular attention to the extent to which agreed upon milestones have been met. If the UH3 phase of the grant is funded, UH3 milestones and/or enrollment milestones will be closely monitored during each project year with discretion from NINDS to terminate a trial that fails to demonstrate sufficient progress toward completing the project.

Milestones

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

This NOFO will support applications that include a series of annual milestones for completion of the study (UH3 phase) and provide contingency plans to proactively confront potential delays or disturbances in meeting the milestones. NINDS staff in collaboration with the recipient will closely monitor progress at all stages, including milestones, accrual, and safety. If, at any time, recruitment falls significantly below the projected milestones for recruitment, NINDS may consider ending support and negotiating a phase-out of the award. Continuation of the award is conditional upon satisfactory progress in meeting milestones and subject to the availability of funds.

Applications Not Responsive to this NOFO

The following types of applications are not responsive to this NOFO and will not be reviewed or considered for funding:

• Studies of synthetic route selection and drug product development.
• Ancillary studies, defined as research undertaken to address scientific questions relevant to the parent study and that require access to data or records from the parent study, and/or involve collection of additional data, specimens, or records.
• An application involving a clinical experiment that is not directly intended to develop a preventative or therapeutic intervention.
• Studies where the objective is to elucidate the pathogenesis of the disease or identify potential therapeutic targets for future exploratory trials.
• Device development and feasibility studies focused on early clinical evaluation of devices to provide proof of principle and initial clinical safety data while device design and operations are still in development are not allowed.
• Pre-clinical Research and Development activities.
• Studies involving only Basic Experimental Studies Involving Humans (BESH).
• Studies designed as biomarker discovery/validation as the primary aim are not allowed.

• Applications that propose research objectives that are not aligned with the mission of the participating ICs

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

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

Section II. Award Information

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

Section III. Eligibility Information

1. Eligible Applicants

Higher Education Institutions - Includes all types

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

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 Governments

• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

Other

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

Foreign Organizations/International Collaborations

Non-domestic (non-U.S.) Entities (Foreign Organizations) 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.

NIH will no longer issue awards (i.e., new, renewal, or non-competing continuation) to domestic or foreign entities that involve foreign subawards/subcontracts. All NIH-funded research involving foreign subawards/subcontracts must be submitted in response to a NOFO that is specifically designated for funded international collaborations. See NIH Grants Policy Statement 16.8 Collaborative International Research Awards.

Applications involving foreign subawards/subcontracts submitted in response to this NOFO will be deemed noncompliant and will not be considered for funding. This policy applies to all monetary international collaborations resulting in foreign subawards/subcontracts, however, it does not preclude unfunded international collaborations or foreign components, funding for foreign consultants, or procurement of unique equipment or supplies from foreign vendors.

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the How to Apply- Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. Failure to complete registrations in advance of a due date is not a valid reason for a late submission, please reference the NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications for additional information.

• 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. Foreign organizations must obtain a NATO Commercial and Government Entity (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 registrations; 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. Obtaining an eRA Commons account can take up to 2 weeks.

All PD(s)/PI(s) must be registered with ORCID. The personal profile associated with the PD(s)/PI(s) eRA Commons account must be linked to a valid ORCID ID. For more information on linking an ORCID ID to an eRA Commons personal profile see the ORCID topic in our eRA Commons online help.

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with their organization to develop an application for support.

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

2. Cost Sharing

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

3. Additional Information on Eligibility

Number of Applications

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

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

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

Section IV. Application and Submission Information

1. Requesting an Application Package

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

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide except where instructed in this notice of funding opportunity to do otherwise (in this NOFO, in a policy notice, or other notice from NIH Guide for Grants and Contracts). Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

Page Limitations

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

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

SF424(R&R) Cover

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

SF424(R&R) Project/Performance Site Locations

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

SF424(R&R) Other Project Information

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

SF424(R&R) Senior/Key Person Profile

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

R&R Budget

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

R&R Subaward Budget

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

PHS 398 Cover Page Supplement

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

PHS 398 Research Plan

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

The following criteria must be addressed:

Specific Aims: Describe the potential impact of the proposed research. The hypotheses and specific aims of the research must be clearly and concisely stated. The primary and secondary outcomes to be measured must be defined. Justify the inclusion of secondary aims by describing the importance of supportive or explanatory data.

Research Strategy

Significance and Biological Relevance: Concisely state the need, rationale, timeliness, and scientific relevance of the proposed study in the context of the status of therapeutics for the disease and the costs and benefits of the proposed study intervention. It is particularly important that there be a discussion about how the trial will test the hypotheses proposed and how the results of the trial (positive or negative) will advance the field. The application must present an overview of the state of the science, the current status of the therapeutics for the disease, and relevance of the study. The applicant should also identify other (industry or academic) current or planned studies that potentially overlap with the proposed research and describe how proposed intervention will likely be an improvement over existing therapies. The timeliness of the proposed study should be discussed in the application.

Prior Studies and Rationale for Development: Describe the full body of evidence being used to support the proposed study and comment on the justification for moving forward with this proposed clinical study. Proposed clinical studies must anchor their rationale in (1) an unmet medical need; (2) a plausible biological mechanism, as well as (3) preclinical (in vitro and/or in vivo) data and/or (4) early clinical data. Their individual weight should be carefully assessed in the specific context of the application at hand; the applicant is not required to provide support from all four areas. Applicants should specifically address the rigor of any animal studies being used as support (https://grants.nih.gov/grants/guide/notice-files/NOT-NS-11-023.html).  If the proposed trial plans to study the intervention(s) based upon preclinical mechanism studies, summarize and reference the results from these studies. Applicants must describe the rigor, robustness, and transparency of supporting data that are being used to justify the proposed trial and address any gaps identified.  Data from preclinical and pilot studies that demonstrate the need for, and the feasibility of the trial should be presented when available. Applications for trials of drugs or biologics should provide compelling scientific evidence that the investigational agent and dose proposed for study will reach/act upon the designated target or that its mechanism of action is such that it is expected to be of benefit in ameliorating a specific aspect of the disease.

Approach: Provide a concise summary of the protocol including the items listed below. Information that is required as part of the PHS Human Subjects and Clinical Trials Information Form need not be described in detail in this section; specific details can be referenced to the attached full protocol or the PHS Human Subjects and Clinical Trials Information Form.

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

• A description and rationale for the selected study design.
• Rationale for selecting the study population (as described in section 2 of the PHS Human Subjects and Clinical Trials Information form) and why it is an appropriate group to answer the question under study.
• Rationale for selection of the intervention(s) to be tested and study outcomes and endpoints.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 expected to provide important supportive or explanatory data.
• For confirmatory definitive Phase 3 and comparative effectiveness trials, a discussion of the evidence regarding whether clinically important sex and race/ethnicity differences in the intervention effect are to be expected and plans for valid design and analysis. (see instructions for Section 2.4)
• A description of all assessments, including clinical, laboratory, physiological, behavioral, patient-centered, or other outcomes addressing the primary and secondary research questions. Use of patient reported outcomes, including those available through PROMIS and NeuroQoL, as well as non-traditional data collection approaches (e.g., telephone, mobile devices or web-based systems) should be considered.
• A discussion of potential scientific biases and/or challenges in the protocol and how they will be addressed.
• Evidence that relevant stakeholders (e.g., potential participants, referring and treating physicians, patient groups) have equipoise, view the question to be important and consider the study design to be acceptable.
• A discussion of how the study investigators will be kept blinded to treatment group-specific data during the course of the clinical trial, if applicable.

For an exploratory trial (e.g., a drug, device, biologic, rehab intervention, etc.), specific plans for the next steps of the therapy's development (such as a future efficacy trial) and proposed go/no-go criteria must be clearly stated. For applications proposing to conduct a seamless Phase 2/3 trial, where data from subjects in Phase 2 are included in the analysis of Phase 3, a transition plan from the Phase 2 component to the Phase 3 component should be described and trial termination plans should be defined in the event that the results of Phase 2 do not support continuation to Phase 3.

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

Briefly describe the milestones that will be met in the UG3 and UH3 phases to address the specific aims and ensure the successful completion of the clinical trial and dissemination of its results.

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

Examples of UG3 Milestones:

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

Examples of UH3 Milestones:

• Enrollment of 25%, 50%, 75% and 100% of the projected recruitment for all study participants, in accordance with the Inclusion Policies for Human Subjects.
• Study closure and completion plans
• Collection of data related to primary and secondary endpoints and database lock
• Completion of final study report
• Submission of primary manuscript to peer-reviewed scientific journal(s) and dissemination of results
• Reporting of results in ClinicalTrials.gov
• Submission of final public use dataset 

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

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

If CTSA resources will be utilized, include letter of support from each site CTSA program officer concurring with the specific plan for using these resources. If some trial costs are to be borne by sources other than NIH, include documentation of this support signed by individuals who have the authority to make a commitment on behalf of the organization they represent. This may include, for instance, an agreement by a pharmaceutical company to donate study drug and placebo.

Applicants are encouraged to include letters or other supporting documentation from patient organizations, professional organizations or treating physicians to show that patients and physicians believe the study question to be relevant, that equipoise exists, and that potential study participants (or their caretakers) were included as partners in the concept development and design of the trial.

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

The following modifications also apply:

• Generally, Resource Sharing Plans are expected, but they are not applicable for this NOFO.

 Other Plan(s): 

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

• A Data Management and Sharing Plan (DMS Plan) is required for any NIH-funded or conducted research that will generate scientific data. Applicants must submit the DMS Plan at the time of application using the NIH DMS Plan Format Page. The DMS Plan must address the elements in the structured format. Where the DMS Plan Format Page requires a "Yes or No" response, no additional narrative is allowed. 

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

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

PHS Human Subjects and Clinical Trials Information

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

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

Study Record: PHS Human Subjects and Clinical Trials Information

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

Section 2. Study Population Characteristics

Considerations that may contribute to successful inclusion are appropriate site selection, patient-or community-engagement for the major elements of the projects, and the use of focus groups to address barriers to inclusion.

2.7 Study Timeline

Applicants should provide detailed study performance and timeline objectives. The proposed milestones must include achievable goals for both stages (UG3/UH3) of the project as applicable:

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

Proposed milestones should be clear and quantitative and need to be included for the entire UG3/UH3 proposal. For trials expected to continue beyond the five-year funding period, milestones should be outlined for the entire duration of the trial. This information will be used for planning purposes and to support the rationale for the full trial but does not indicate continued funding beyond the initial funding cycle. Regulatory milestones, if needed, (e.g., related to FDA) should also be included.

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

When applicable, milestone reports should describe how measurable outcomes will be collected using rigorous and transparent experimental approaches. These approaches include, but are not limited to, randomization, masking/blinding, use of statistically adequate sample sizes with biologically relevant effect sizes, minimization of potential bias, independent replication, and adequate reporting of experimental details and results as described at NIH Grants Policy Statement | Grants & Funding.

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://grants.nih.gov/policy-and-compliance/policy-topics/human-subjects/policies-and-regulations/data-safety) when developing their DSMP.

3.5 Overall Structure of the Study Team

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

Describe the composition and role of any advisory committees.
Discuss the responsibilities, oversight and coordination of any centers or cores. Describe any subcontracts or service agreements for personnel or facilities.

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
• NeuroQOL  
• NIH Toolbox 
• PROMIS 
• BioSEND  

If applicable, include a statement regarding how the NCATS Clinical and Translational Science Award (CTSA) program 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.

Where applicable, (for example, for behavioral or rehabilitation trials as explained in Section I of the NOFO), state the go/no-go criteria of the UG3 stage that will be used to decide whether to proceed with a subsequent clinical trial in the UH3 phase.

4.3 Statistical Design and Power

Applicants should provide a Statistical Analysis Plan (SAP) consistent with the proposed aims, including details on the analyses specified in the study protocol, including a description of how the statistical analysis of the primary, secondary and other endpoints will be performed, how the sample size was determined, how missing data will be handled, plans for interim analyses for safety, efficacy and futility, plans for recalculation of the sample size midway through the trial (if applicable), and other measures to ensure rigor and transparency of the analysis. 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, accounting for the impact of non-compliance, missing data, participant eligibility criteria, etc., sufficient details about the simulations should be provided in the SAP. It is particularly important to discuss the range of conditions that were considered in the simulation and why this range was considered appropriate, how robust the findings were across the range of conditions considered, and how the study will adjust for any design deficiencies (e.g., bias, loss of power) the simulations revealed.

4.5 Will the study use an FDA-regulated intervention?

Enrollment of participants into the trial is contingent on FDA approval. If the trial will use an FDA regulated drug or device, the applicant must demonstrate that the project will be ready to submit an IND (Investigational New Drug)/IDE (Investigational Device Exemption) when submitting the application.

Any correspondence from FDA should be included in the application, if available at the time of submission. If there has not been correspondence with FDA at the time the application is submitted, then for studies where the intervention is a drug, biologic, or device, applicants must obtain an FDA "may proceed" letter in the UG3 award period to allow for the successful launch and enrollment of participants into the proposed clinical trial.  Projects failing to obtain regulatory approval will not be approved to transition into the UH3 phase of the award.

If the protocol is exempt from an IND or IDE, the applicant must provide a copy of the exemption letter or risk determination letter from the IRB or FDA.

Prior to transitioning to the UH3 phase, recipients who do not have an exemption from the FDA must provide any additional FDA correspondence regarding the status of the protocol to the NINDS, especially if the trial has been placed under full or partial hold.

Section 5. Other Clinical Trial-Related Attachments

5.1 Other Clinical Trial-related Attachments

Describe any preclinical toxicology, drug formulation or manufacturing required including timelines.

Delayed Onset Study

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

PHS Assignment Request Form

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

Foreign Organizations

Foreign (non-U.S.) organizations must follow policies described in the NIH Grants Policy Statement, and procedures for foreign organizations described throughout the How to Apply- Application Guide.

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

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

4. Submission Dates and Times

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

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

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

Information on the submission process and a definition of on-time submission are provided in the How to Apply-Application Guide.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

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

Pre-award costs are allowable only as described in the NIH Grants Policy Statement Section 7.9.1 Selected Items of Cost.

Applications must be submitted electronically following the instructions described in the  How to Apply – Application Guide. Paper applications will not be accepted.

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

For assistance with your electronic application or for more information on the electronic submission process, visit How to Apply – Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile form. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this NOFO for information on registration requirements.

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

See more tips for avoiding common errors.

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

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

Send written disclosures to the NIH Chief Grants Management Officer listed on the Notice of Award for the IC that funded the award and to the HHS Office of Inspector Grant Self Disclosure Program at grantdisclosures@oig.hhs.gov.

Post Submission Materials

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 nonsignificant 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 (Optional - 10 pages max):

Applicants should include a summary (1-page max) of interactions with the FDA, supported by the following associated and attached documentation):

• approved minutes from all pre-submission meetings
• notice of IND or IDE 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 drug, biologic, device (or other intervention) review, or outcome.

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.

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 scored review criteria and additional review criteria (as applicable for the project proposed). An application does not need to be strong in all categories to be judged likely to have a major scientific impact.

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

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

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.

2. Review and Selection Process

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

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

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

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

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

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement Section 2.5.1. Just-in-Time Procedures. This request is not a Notice of Award nor should it be construed to be an indicator of possible funding.

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

3. Anticipated Announcement and Award Dates

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

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

Section VI. Award Administration Information

1. Award Notices

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

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

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

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

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

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

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

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

2. Administrative and National Policy Requirements

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

• The rules listed at 2 CFR Part 200, Uniform Administrative Requirements, Cost Principles, and Audit Requirements for Federal Awards.
• All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the terms and conditions in the Notice of Award (NoA). The NoA includes the requirements of this NOFO. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Recipients, and Activities.

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

By applying for or accepting federal funds from HHS, recipients certify compliance with all federal antidiscrimination laws and these requirements and that complying with those laws is a material condition of receiving federal funding streams. Recipients are responsible for ensuring subrecipients, contractors, and partners also comply.

Applicants and recipients are strongly encouraged to refer to the NIH Director's Statement of Priorities, entitled "Advancing NIH's Mission Through a Unified Strategy." 

Recipients are responsible for ensuring that their activities comply with all applicable federal regulations. Pursuant to 2 CFR 200.340, by accepting an NIH award, the recipient agrees that continued funding for the award is contingent upon the availability of appropriated funds, recipient satisfactory performance, compliance with the Terms and Conditions of the award, and may also otherwise be terminated, to the extent authorized by law, if the agency determines that the award no longer effectuates the program goals or agency priorities, in line with 2 CFR 200.340(a)(4).

Pursuant to the Cybersecurity Act of 2015, Div. N, § 405, Pub. Law 114-113, 6 USC § 1533(d), the HHS Secretary has established a common set of voluntary, consensus-based, and industry-led guidelines, best practices, methodologies, procedures, and processes.

Successful recipients under this NOFO agree that:

When recipients, subrecipients, or third-party entities have:

• ongoing and consistent access to HHS owned or operated information or operational technology systems; and
• receive, maintain, transmit, store, access, exchange, process, or utilize personal identifiable information (PII) or personal health information (PHI) obtained from the awarding HHS agency for the purposes of executing the award.

Cybersecurity plans and procedures must at minimum include the following:

• Develop cybersecurity plans and procedures, modeled after the NIST Cybersecurity framework, to protect HHS systems and data:
  • Identify:
    • Develop an inventory of all assets and accounts with access to HHS owned and operated information or operational technology systems or which obtain PII or PHI for the purposes of the award.
  • Protect:
    • Limit access to HHS owned and operated systems to only those in need of access to complete reward activities.
    • Require all staff to complete annual cybersecurity and privacy awareness training. Visit 405(d): Knowledge on Demand (hhs.gov) to obtain free trainings, if needed.
    • Enable multifactor authentication for all employees, subrecipients, and third-party entities to access HHS owned and operated information or operational technology systems.
    • Regularly backup sensitive data and test backups.
  • Detect:
    • Install anti-virus or anti-malware software on all devices, servers, and accounts used to connect to HHS owned and operated systems.
  • Respond:
    • Develop an incident response plan. See Incident-Response-Plan-Basics_508c.pdf (cisa.gov) to learn about developing incident response plans.
    • Have cybersecurity incident reporting procedures that ensure the relevant HHS awarding agencies are notified of a cybersecurity incident within 48 hours of discovery. A cybersecurity incident is defined as an unplanned interruption to a technology service or reduction in the quality of a technology service, or an occurrence that actually or potentially jeopardizes the confidentiality, integrity, or availability of an information system or the information the system processes, stores, or transmits.
  • Recover:
    • Investigate incidents and plug any security gaps identified. 

All activities proposed in your application and budget narrative must align with applicable law, including but not limited to statutes, executive orders, federal regulations and applicable judicial holdings.  Accordingly, discretionary awards shall not be used to fund, promote, encourage, subsidize, or facilitate; racial preferences or other forms of racial discrimination by the recipient, including activities where race or intentional proxies for race will be used as a selection criterion for employment or program participation; denial by the recipient of the sex binary in humans, or the belief that sex is a chosen or mutable characteristic; illegal immigration; or any other initiatives that compromise public safety.  If an application does not align, the application will not receive funding to the extent permitted by law and applicable court orders.

For applications involving substance abuse, the application must not support harm reduction. Please see Updated Funding Guidance for Recipients on Supplies and Services.

For applications involving funding Medication-Assisted Treatment (MAT) or medications for opioid use disorder (MOUD), this funding should be used to provide comprehensive treatment and recovery support services rather than medication-only models for opioid use disorder. Services should include medications, where clinically indicated, in conjunction with psychosocial and other treatment and recovery support services. Funding can also be used to support individualized tapering and discontinuation of medications when clinically indicated. Please see Updated Funding Guidance for Recipients on  MAT/MOUD.

As of October 1, 2025, HHS has adopted 2 CFR Part 200, with some modifications included in 2 CFR Part 300. These regulations replace those in 45 CFR Part 75. However, for NIH, under the Consolidated Appropriations Act for FY 2026, (P.L. 119-75, Division B, Title II, Sec. 224), the provisions relating to indirect costs in 45 CFR 75 continue to apply to NIH awards. Consistent with the statute, NIH will not apply updated thresholds outlined within 2 CFR Part 200, at this time.

In administering programs under this and all funding announcements, NIH prioritizes: 

• Research involving rigorous scientific methods, including for studies related to children and adolescents, where NIH is committed to approaches that reflect the highest standards of clinical care and child safety. 
• Biological and physiological integrity: Recognizing the relevance of biological sex to health outcomes, NIH encourages applicants to account for sex-based health factors in program design, data collection, and service delivery where scientifically appropriate.
• NIH will implement these priorities consistent with applicable laws, regulations, court orders, and all required administrative procedures. Applicants are encouraged to describe how their proposed programs align with these priorities in their project narratives. Funded activities must advance NIH's vision of protecting and improving the health and well-being of Americans. The particular focus is on those who are medically vulnerable, or live in areas with limited access to care. NIH's duty is to serve wisely, effectively, and with measurable results that justify every taxpayer dollar invested. 

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (HHS) grant administration regulations at 2 CFR Part 200, and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the recipients is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the recipients for the project as a whole, although specific tasks and activities may be shared among the recipients and NIH as defined below.

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

• Recipients will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies.
• Defining research objectives and approaches.
• Planning, conducting, analyzing, and publishing results, interpretations, and conclusion of their studies and providing overall scientific and administrative leadership for the Research Project.
• Supervising the clinical study with consistent emphasis on collaborative interactions between investigators, advisory and steering committees, and NINDS representatives.
• Acquiring an IND/IDE from the FDA if an investigational agent or device is to be used,
• Acting as a member of the study Steering Committee for the duration of the study with possible participation in steering groups for planning, quality control, publications etc.

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

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

• An NINDS Project Scientist working with the investigators will develop milestones for the study that will be established prior to the award of the grant based on recommendations from the primary review group. Failure to meet the agreed upon milestones may result in reduced funding or early termination of the cooperative agreement. NINDS retains the option to obtain periodic external peer review of progress.
• The NINDS Project Scientist will function as one of several co-investigators, collaborating and interacting as necessary with the PI in accomplishing the overall goals of the Research Program.
• The NINDS Project Scientist may provide technical assistance to, recipients in performing project activities, e.g., development of research protocols; data collection, analyses, and interpretations; re-establishment of objectives during the course of a project; selection of contractors or sub-recipients under the assistance award; the selection of key project personnel other than principal investigators of projects or sub-projects; coordinate amongst award recipients or NIH to leverage resources and prevent duplication of effort; and participation in the presentation of research results, including publications from the project.
• The NINDS Project Scientist will oversee the adequacy of adverse event management and reporting by the study team and may make recommendations to support patient safety.
• If applicable, a third NINDS Program Official, from the Division of Clinical Research, may serve as the NINDS liaison to the Data and Safety Monitoring Board (DSMB).
• If the proposed trial should require that FDA issue an IND/IDE, the NINDS Project Scientist and/or Program Official(s) will be present at any meetings held with the FDA related to this NIH-funded protocol and will be provided copies of any regulatory correspondence with the FDA.
• In addition to the Project Scientist, an NINDS Administrative Program Official will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.

NINDS will make an award (UG3) to start up the trial and establish performance feasibility.  Feasibility milestones will be defined at the start of each trial and will be monitored closely by the NINDS Program Official and, if applicable, the NINDS-appointed Data and Safety Monitoring Board (DSMB).  Continuation of the award past this feasibility period (transition to UH3) will be contingent upon a demonstrated ability to meet milestones indicating that the trial can be implemented as planned.

Recipients who do not accomplish the negotiated milestones shall submit a milestone report no later than 2 months following the missed milestone, which will include a discussion of why the milestones were not met in the agreed upon timeframe and propose an action plan to increase recruitment to agreed upon levels. The recruitment action plan shall include: amended milestones, plans/timeframe to achieve the amended milestones and any additional required items. The plan must be approved and signed by the Institutional Officials and the PI/PD(s) listed on the awards prior to submission.

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

If the study is no longer feasible by the NINDS or the recipient, the investigator will be required to submit a close-out plan to NINDS within 2 months.

Areas of Joint Responsibility include:

Steering Committee

• The Steering Committee has primary responsibility for developing the common research protocol, adverse event management procedures, reviewing progress, monitoring patient accrual, coordinating data management, and cooperating on the publication of results. Major scientific decisions regarding the core data will be determined by the Steering Committee.
• The Steering Committee will be composed of all Program Director(s)/Principal Investigator(s), and co-investigator(s), the NINDS Project Scientist, and the Program Official. The NINDS Project Scientist will have voting membership on the Steering Committee, and as appropriate, its subcommittees. The NINDS voting member will have one vote to represent NIH in support of the project. The frequency of Steering Committee meetings will be dictated by a vote of the members of the Steering Committee.

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between recipients and NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual recipient. This special dispute resolution procedure does not alter the recipient's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and HHS regulation 45 CFR Part 16.

A Data Management and Sharing Plan (DMS Plan) is required for any NIH-funded or conducted research that will generate scientific data. Applicants must submit the DMS Plan at the time of application using the NIH DMS Plan Format Page. The DMS Plan must address the elements in the structured format. Where the DMS Plan Format Page requires a "Yes or No" response, no additional narrative is allowed. 

4. Reporting

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

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

Section VII. Agency Contacts

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

eRA Service Desk - Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten submission by the due date, and post-submission issues.

Grants.gov Support Center - Questions regarding Grants.gov registration and services (e.g., Workspace, subscriptions).

National Institute for Neurological Disorders and Stroke (NINDS)
Email: Exploratory_Efficacy_Trials@ninds.nih.gov 

Examine your eRA Commons account for review assignment and contact information (information appears two weeks after the submission due date).

Chief Grants Management Officer
National Institute of Neurological Disorders and Stroke (NINDS)
Email: ChiefGrantsManagementOfficer@ninds.nih.gov

Section VIII. Other Information

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

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 2 CFR Part 200.