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.

IMPORTANT: Per NOT-OD-24-086 updated application forms (FORMS-I) will be used for this opportunity. The updated forms are not yet available and will be posted 30 calendar days or more prior to the first application due date. Once posted, you will be able to access the forms using one of the following submission options:

1. NIH ASSIST
2. An institutional system-to-system (S2S) solution
3. Grants.gov Workspace

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 exploratory Phase 1 and Phase 2 clinical trials to the National Institute of Neurological Disorders and Stroke (NINDS). These trials must address questions within the mission and research interests of the NINDS. They may include studies of drugs and biologics, feasibility and preliminary efficacy studies of devices, and early studies of surgical, behavioral, or rehabilitation therapies. All Phase 1 exploratory trials must contribute to the justification for and provide some of the data required to inform a Phase 2 trial that may also be performed as part of the current grant application if the Phase 1 study is successful. This NOFO uses the UG3/UH3 mechanism.

NINDS, as part of 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 (https://www.ninds.nih.gov/Funding/grant_policy). For example, the biological rationale for the proposed experiments must be based on rigorous and robust supporting data, which means that data should be collected via methods that minimize the risk of bias and be reported in a transparent manner. 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.

For a drug, biologic or device that has not completed a Phase 1/Early Feasibility Trial

The UG3 mechanism will be used to plan and execute the Phase 1 studies. If Phase 1 studies (or their equivalent for devices) are successful, or the study is ready to begin a Phase 2 trial, the UG3 will also include the planning phase of a Phase 2 trial. If the Phase 1 clinical trials are to be conducted by contract research organizations (CRO), then multiple potentially qualified vendors should be proposed. If an NIH contractor is not being used as the CRO, the applicant should provide details about the capabilities of the proposed CRO and its experience in running clinical trials of the kind proposed. The UH3 mechanism might support additional Phase 1-level studies but is primarily intended to support the execution of the Phase 2 clinical trial. Transition to the UH3 will depend on successfully reaching agreed-upon milestones and go/no-go criteria.

Applicants should take note of the following special requirements and considerations:

(1) Scope of this NOFO: NIH defines a clinical trial as "a research study in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes."

Note the following:

• For purposes of this NOFO, the proposed study should be intended to clinically develop interventions to prevent or treat a neurological disorder.
• Biomarker questions that are secondary aims are considered responsive. .

Projects within scope of this NOFO typically will include:

• Evaluation of safety and pharmacokinetics of novel therapeutics in healthy volunteers or in some cases, the target population;
• Projects directed at a Phase I trial that will be able to reference prior GLP toxicology studies (e.g., repeat dose toxicology in rodent and large animal, genotoxicology, hERG and safety pharmacology) in their IND filings (note: if those studies are required to enable a first in human study then applicants should refer to https://grants.nih.gov/grants/guide/pa-files/PAR-20-122.html and companion NOFOs for this type of work);
• Manufacture of required GMP, drug substance/product needed for the proposed clinical trials;
• Simulation studies that will support the design of Phase 2 trials;
• Preparation of protocols, and acquisition of regulatory approvals;
• Evaluation and optimization of dose, formulation, safety, tolerability, or pharmacokinetics of an intervention to enable FDA required (cite guidance or provide documentation from FDA with their specific request) activities for start of Phase 2 in healthy volunteers, or the target population;
• Evaluation of whether an intervention produces sufficient evidence of short-term activity (e.g., biomarker activity, target engagement, dose-response trends, pharmacodynamic response) in a human “proof of concept” trial;
• Selection or ranking of the best of two or more potential interventions or dosing regimens to be evaluated in a subsequent trial, based on tolerability, biological activity, or preliminary clinical efficacy (e.g., futility trials);
• For devices: establishment of proof-of-principle and optimization of techniques, operation, and usability of a device that will inform the final device design decisions, preliminary efficacy and estimation of the magnitude of treatment effect.

Under this NOFO Phase 1 and Phase 2 clinical trials are supported, and applications should aim to generate data that inform further clinical development of the proposed intervention. The earliest studies should be designed to provide important initial information regarding the intervention (e.g., safety, tolerability, dosing). Phase 1 studies may include randomization and blinding and should yield data that allow a clear go/no-go decision (typically based on safety/tolerability data) regarding whether the intervention should proceed to a Phase 2 clinical trial.

Interventions that have already completed all Phase 1 studies and are ready for Phase 2 studies are also supported by this NOFO.

(2) Devices: NINDS recognizes that devices can differ greatly in terms of basic form and function, physiological bases for therapy, degree of invasiveness, etc. 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 to discuss these issues and determine the suitability of their project for this funding mechanism.

(3) Efficacy: This NOFO is not intended to support the conduct of a clinical trial where the primary aim is to establish or confirm definitive efficacy (although under certain circumstances, early studies of preliminary efficacy can be a secondary aim). While an exploratory clinical trial may examine clinical outcomes or biomarker outcomes as measures of "preliminary efficacy" as a secondary aim, it is important that it not be an underpowered efficacy trial. Applications to implement definitive efficacy trials (e.g., Phase 3 trials of drugs/biologics or Pivotal device trials) should be submitted to PAR-21-237 (https://grants.nih.gov/grants/guide/pa-files/PAR-21-237.html), NINDS Efficacy Clinical Trials.

In general, a phase 2 trial within the scope of this NOFO is considered to be one in which the Phase 1 trials (or, for devices, their equivalent) have been successfully completed separately or is proposed to be completed during the UG3 phase and possibly part of the UH3 phase of the current application. The Phase 2 trial will then proceed as part of the UH3 phase, and in general, will have fewer than one hundred patients enrolled. The aim of Phase 2 is to provide additional safety data, to refine the research questions, to look for a signal of efficacy, and to generate data that will inform the design a Phase 3 trial.

(4) Effect Size: A drug or biologic trial will not be considered for funding under this NOFO when its primary objective is to estimate intervention effect size to be used in power calculations for a future efficacy clinical trial. Effect size estimates based on small or short-term studies are often unreliable. Power for an efficacy trial should be based on the smallest clinically meaningful effect size, which is often determined by surveying physicians or patients, or by comparison to the effect produced by existing interventions.

(5) Secondary Aims: Issues of study feasibility and refinement of study procedures may be addressed as secondary aims in an exploratory clinical trial (i.e., Phase 2), but not as the primary aim. Examples of such secondary aims include:

• Determining the optimal outcome measure (endpoint), its variability, and/or the optimal timing of outcome evaluations in the context of the intervention.
• Collecting information on the utility of questionnaires, rating scales, or biomarkers.
• Developing and refining data collection procedures.
• Optimizing the administration of the study intervention.
• Developing and refining standardized methods of assessing outcome.
• Optimizing methods for identifying, recruiting, and retaining study participants.

(6) Multiple Trials: There may be several questions to be answered before a phase 3 efficacy trial can be designed and conducted. The proposed study is not required to address all potential questions, but the applicant should clearly detail the overall clinical development plan for the intervention, which could involve more than one exploratory trial.

(7) Study Rationale: The rationale for a clinical trial must be based on (i) an unmet medical need; (ii) a plausible biological mechanism; and (iii) robust supporting data, e.g., from non-clinical (in vivo and/or in vitro data) studies or preliminary clinical studies demonstrating that there is an adequate scientific foundation to justify the proposed trial. The scientific premise for the trial should be based on preclinical and/or clinical data from rigorously performed studies (see https://grants.nih.gov/grants/guide/notice-files/NOT-OD-15-103.html). If previous research does not meet the rigor criteria outlined to an acceptable degree, applicants should address how the current study design addresses the deficiencies.

(8) Innovative Designs: The use of innovative and efficient study designs is encouraged, such as adaptive dose-finding designs, designs incorporating plans for sample size recalculation, preliminary efficacy for devices, and futility designs. Applications for Phase 1 trials in the patient population are encouraged when appropriate (e.g., certain rare diseases), as are applications that will encompass both Phase 1 and Phase 2 studies (early proof of mechanism or proof of concept). Applications for Phase 3 trials should be submitted under PAR-21-237 or its reissue, NINDS Efficacy Clinical Trials.

For medical devices, traditional feasibility study designs may include, for example, single-arm studies, on-off interventions (patients as their own controls), device-device comparisons, device-drug comparisons, comparisons to historical controls, comparisons to performance criteria/goals, adaptive designs, and Bayesian designs.

(9) Innovative Technologies: Applicants are encouraged to consider utilizing (at least experimentally) digital/mobile/sensor technologies and web-based systems to facilitate data collection (including data collection in a continual, contextual, real-world setting rather than through a traditional milestone-based approach), as well as to enhance protocol adherence.

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

(11) Applications proposing Ancillary studies (that are not clinical trials) to ongoing NINDS funded clinical trials should apply to PA-20-185.

If the ancillary study proposed is a clinical trial, then the NINDS Division of Clinical Research (DCR) should be consulted to decide to which NOFO it should respond.

(12) Biomarkers: Applications are encouraged that evaluate preliminary efficacy based on early signals of activity on biomarkers or clinical endpoints, or that mechanistically test the activity of an intervention in terms of its presumed target(s). However, this NOFO is not appropriate for applications primarily intended to discover or validate biomarkers. See https://grants.nih.gov/grants/guide/pa-files/PAR-22-089.html for Biomarker funding opportunities.

(13) 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 of the nervous system, 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 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 subjects. 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, and reporting.

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

(15) Relationships with Patient Groups: Applicants are strongly encouraged to establish relationships with patient groups and solicit their input on recruitment, the clinical meaningfulness of the question under study, the relevance of the proposed clinical outcomes, and approaches to minimizing the burden on study subjects.Specific patient groups that will potentially be targeted should be listed as well as action plan of how this relationship will be established. 

(16) IRB documentation: IRB approval of the protocol and informed consent is not required at the time of application submission but is required prior to any human studies. As such, NINDS encourages investigators to begin these processes as early as possible. NINDS also will require documentation of any other necessary regulatory approvals (e.g., Recombinant DNA Advisory Committee) prior to funding.

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

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

(18) Consultation with NINDS: Applicants are strongly encouraged to consult with NINDS Program staff in the Division of Clinical Research as plans for an application are being developed (see Section VII, Agency Contacts) no later than 12 weeks 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, which is subject to peer review. NINDS Program staff are also available to discuss strategies for recruitment and inclusion of women and minorities.

(19) Period of support: The mechanism used to support this funding opportunity announcement is a cooperative agreement (UG3/UH3) mechanism with two phases. The initial milestone-driven planning phase (UG3) for Phase 1 studies and Phase 2 planning may last up to two years, with possible transition to the second phase (UH3), for a total of up to 5 years of support.

Only UG3 projects that have met scientific milestones and feasibility requirements will be approved to transition to the UH3 phase. The UG3/UH3 application must be submitted as a single application at the time of the initial application. The UG3 phase will permit both scientific and operational planning activities. The UH3 phase of the award will support the clinical trial of the drug, biologic, device, or behavior intervention (and if needed, additional scientific studies).

The UG3 Phase may not exceed 2 years.

The UH3 Phase may not exceed 4 years.

(20) If the follow-on (Phase 2) trial will be a multi-site trial, the applicant should contact the relevant NINDS program staff as plans for an application are being developed (see Section VII, Agency Contacts), and no later than 12 weeks prior to the anticipated application submission date. NINDS staff will evaluate whether the NINDS StrokeNet or NeuroNEXT networks are appropriate for both phases of the trial (1 and 2) and the applicant will be directed to the appropriate NOFO after NINDS approval (StrokeNet PAR-18-561; NeuroNEXT PAR-16-155). 

Applications Not Responsive to this NOFO

Applications proposing the following topics will be considered non-responsive to this NOFO, and will not be reviewed.

• For Phase 1 studies, please note that synthetic route selection and drug product form work is not envisioned under this NOFO. Please refer to https://grants.nih.gov/grants/guide/pa-files/PAR-20-122.html and companion NOFOs for this type of work.
• 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, are not permitted within the clinical trial application in response to this NOFO. Such studies will be considered not-responsive.
• An application involving a clinical experiment that is not directly intended to develop a preventative or therapeutic intervention will be considered not responsive.
• Examples that are not responsive may include an experiment where the objective is to elucidate the pathogenesis of the disease or identify potential therapeutic targets for future exploratory trials.
• Studies involving only Basic Experimental Studies Involving Humans (BESH) are not responsive.
• Phase 3 clinical trials will be considered not responsive.

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

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

Section II. Award Information

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

Section III. Eligibility Information

1. Eligible Applicants

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Local Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized).

Federal Government

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

Other

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

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. 

Applicant Organizations

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

• System for Award Management (SAM) – Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
  • NATO Commercial and Government Entity (NCAGE) Code – Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
  • Unique Entity Identifier (UEI) - A UEI is issued as part of the SAM.gov registration process. The same UEI must be used for all registrations, as well as on the grant application.
• eRA Commons - Once the unique organization identifier is established, organizations can register with eRA Commons in tandem with completing their Grants.gov registration; all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov – Applicants must have an active SAM registration in order to complete the Grants.gov registration.

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

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

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with their organization to develop an application for support. Individuals from diverse backgrounds, including underrepresented racial and ethnic groups, individuals with disabilities, and women are always encouraged to apply for NIH support. See, Reminder: Notice of NIH's Encouragement of Applications Supporting Individuals from Underrepresented Ethnic and Racial Groups as well as Individuals with Disabilities, NOT-OD-22-019.

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. 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:

Jeremy Brown, MD
Email: jeremy.brown@nih.gov and  Exploratory_NINDS@NINDS.NIH.gov  

Page Limitations

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

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

SF424(R&R) Cover

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

SF424(R&R) Project/Performance Site Locations

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

SF424(R&R) Other Project Information

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

Other Attachments:

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:

Research Plan:

Significance and Biological Relevance: Describe the significance of the proposed Phase 1 (or their equivalent for devices and behavioral interventions) and Phase 2 clinical trials in the context of the status of therapeutics for the disease and the costs and benefits of the proposed study intervention. Discuss how the trial will test the hypotheses proposed and how the results of the trial (positive or negative) will advance the field. Summarize plans for future clinical development of the intervention in the event the exploratory trial yields promising results and explain why the proposed exploratory trial is necessary to inform the design of a subsequent clinical trial for efficacy. Describe how proposed intervention will likely be an improvement over existing therapies.

Preliminary Studies: Present the major findings of the preclinical and clinical studies that led to the proposed exploratory trial. Ensure that the data supporting the proposed trial meet the NIH scientific rigor guidelines (see https://grants.nih.gov/grants/guide/notice-files/NOT-OD-15-103.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.

Approach: The proposed research plan should include a detailed description of the proposed UG3 and UH3 activities as described above. For all clinical trials, the rationale for the trial design, population(s) and hypotheses being tested, and control groups must be described. Potential biases and/or challenges in the study design and protocol should be identified and addressed. For exploratory (typically Phase I or II) clinical trials, the proposed study design should enable the rigorous assessment of outcomes focused on dosing, target engagement, safety, or other appropriate measures.

NINDS urges investigators to follow the NIH guidance for rigor and transparency in grant applications (https://grants.nih.gov/policy/reproducibility/guidance.htm) and additionally recommends the research practices described at https://www.ninds.nih.gov/Funding/grant_policy. This will ensure that robust experiments are designed, potential experimenter biases are minimized, results and analyses are transparently reported, and results are interpreted carefully. These recommended research practices include, where applicable, expressing clear rationale for the chosen model(s) and primary/secondary endpoint(s), describing tools and parameters clearly, blinding, randomizing, ensuring adequate sample size, pre-specifying inclusion/exclusion criteria, appropriately handling missing data and outliers, implementing appropriate controls, preplanning analyses, and using appropriate quantitative techniques. It is also strongly recommended to indicate clearly the exploratory vs. confirmatory components of the study, consider study limitations, and plan for transparent reporting of all methods, analyses, and results so that other investigators can evaluate the quality of the work and potentially perform replications.

Evidence that relevant stakeholders (e.g., potential subjects, referring and treating physicians, patient groups) have equipoise, view the question to be important and consider the study design to be acceptable.
A discussion of potential biases and/or challenges in the protocol and how they will be addressed.
All trials regardless of stage should have clear go/no-go criteria for proceeding with a subsequent clinical trial(s).

Letters of Support: Please provide a page listing the names and institutions of all providers of 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 patients were included as partners in the concept development and design of the trial.

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

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:

• 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.
• For guidance on these plans please visit the NIH Resources page.

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

2.3a Inclusion of Individuals Across the Lifespan
Applicants must include a plan to enroll individuals across the lifespan. Considerations that may contribute to successful inclusion are appropriate site selection, patient-or community-engagement for the major elements of the projects, use of focus groups to address barriers to inclusion, etc.

2.4 Inclusion of Women and Minorities

Applicants must include a plan to enroll women and underrepresented minorities (as appropriate). The plan must also consider translation of all the study-related documents to enroll participants from communities that do not speak English. Considerations that may contribute to successful inclusion are appropriate site selection, patient- or community-engagement for the major elements of the project, use of focus groups that include URMs to address barriers to inclusion, etc.

2.5 Recruitment and Retention Plan

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

Applicants should survey all the potential clinical sites to ensure that recruitment targets can be met considering the proposed inclusion/exclusion criteria. 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 (if applicable)?
• 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?
• Does this site have experience enrolling and following with participants with limited English proficiency?
• What plans are there to enroll from diverse populations?

2.7 Study Timeline

Applicants should provide detailed study performance and timeline objectives. The proposed milestones must include achievable goals for each stage of the study timeline within the UG3/UH3 project.

Proposed milestones should be clear and quantitative and need to be included for the entire UG3/UH3 proposal. For trials that extend beyond the five-year funding period, milestones should be included for the entire trial. This information will be used for planning purposes and to support the rationale for the full trial but does not indicate continued funding after beyond the initial funding cycle. Regulatory milestones (e.g., related to FDA) also may need to be included. Milestones and timelines will be refined and finalized in consultation with Program staff at the time of 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, 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 https://www.ninds.nih.gov/Funding/grant_policy.

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.

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 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.

In addition, applicants should strive to increase the diversity of their teams. Research shows that diverse teams working together and capitalizing on innovative ideas and distinct perspectives outperform homogeneous teams. Scientists from diverse backgrounds and life experiences bring different perspectives, creativity, and individual enterprise to address complex scientific problems. There are many benefits that flow from a diverse NIH-supported scientific workforce, including: fostering scientific innovation, enhancing global competitiveness, contributing to robust learning environments, improving the quality of the research, advancing the likelihood that underserved or health disparity populations participate in, and benefit from health research, and enhancing public trust. Please see NIH NOT-OD-20-031 (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-20-031.html) for details.

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)  
• PROMIS (http://www.healthmeasures.net/explore-measurement-systems/promis) .

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.

For trials at any stage, state the go/no-go criteria that will be used to decide whether to proceed with a subsequent clinical trial.

4.3 Statistical Design and Power

Applicants should provide a Statistical Analysis Plan (SAP), 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, subject eligibility criteria, etc., sufficient details about the simulations should be provided in the SAP. It is particularly important to discuss the range of conditions that were considered in the simulation and why this range was considered appropriate, how robust the findings were across the range of conditions considered, and how the study will adjust for any design deficiencies (e.g., bias, loss of power) the simulations revealed.

4.5 Will the study use an FDA-regulated intervention?

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

For first in human studies or in which a clinical site has not yet been identified, and an IND has not yet been filed, the applicant must demonstrate that the project will be ready to submit an IND before the beginning of the UH3 phase.

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 provide such FDA documentation either as post-submission material or prior to the UH3 phase. Some examples of specific scenarios:

(a) The protocol has been submitted under an open IND and the IND is not under full or partial hold:. Under this scenario, applicants must provide documentation such as a "may proceed" email or letter from the FDA. (Funding will be restricted until the IND has received FDA approval.)

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

(c) The protocol has been submitted under an IND and is on full or partial hold: Under this scenario applicants must provide full documentation from the FDA on the reasons for the hold and the FDA recommendations. Applicants should discuss how they intend to address the hold issues and when they believe they will have FDA approval to proceed with trial implementation.

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

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

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

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.

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.

Applicants who are unable to provide the IRB and/or FDA Communications at the time of application submission may provide them as post-submission materials as described further below. Prior to transitioning to the UH3 phase, awardees who do not have an exemption from the FDA must provide any additional FDA correspondence regarding the status of the protocol to the NINDS, especially if the trial has been placed under full or partial hold.

Delayed Onset Study

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

PHS Assignment Request Form

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

Foreign Organizations

Foreign (non-U.S.) institutions must follow policies described in the NIH Grants Policy Statement, and procedures for foreign institutions 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. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

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

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

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

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

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

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

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

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

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

Important reminders:

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

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

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by components of participating organizations, NIH. Applications that are incomplete, non-compliant and//or nonresponsive will be withdrawn and 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.

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

Review Criteria

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

Factor 1: Importance of the Research

Significance

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

Innovation

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

Specific to this NOFO:

• Assess if the intervention is ready for the stage of clinical development proposed.
• Evaluate how necessary the data from the proposed exploratory clinical trial are to inform the next steps in the clinical development of the intervention 
• Assess how convincing the evidence is that equipoise exists in the medical and patient communities.

Factor 2. Rigor and Feasibility

Approach

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

Rigor:

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

Feasibility:

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

Specific to this NOFO:

• Assess whether the stage of development of the intervention is appropriate for the studies proposed, how well the proposed studies fit the separate goals of the UG3 and UH3 phases and whether the application clearly indicates the exploratory vs. confirmatory components of the proposed studies.
• Evaluate whether the proposed research specifically addresses the following (including but not limited to): clear description of the i) chosen primary/secondary endpoint(s) and their appropriateness, ii) blinding and randomization procedures, iii) pre-specified inclusion/exclusion criteria, iv) appropriate handling of missing data and outliers, as well as v) any pre-planned analyses.
• Evaluate whether the proposed intervention arms as well as dosage and duration of therapy are well justified and if the proposed study design enables the rigorous assessment of outcomes focused on dosing, target engagement, safety, or other appropriate measures.
• Evaluate (as applicable) whether the necessary therapeutic agent(s) and placebo or device(s) are available in sufficient quantity and quality to conduct the study. If the agent(s) will need to be manufactured, does the application demonstrate good manufacturing practices (GMP) guidelines in procuring the same.
• Assess the appropriateness of the go/no-go criteria (these may be separate from the project milestones) especially those related to safety/tolerability, for progressing from the UG3 to the UH3 stage and for proceeding with a subsequent efficacy clinical trial(s) beyond the current proposal. Evaluate how well the application outlines specific plans for clinical development of the intervention beyond this study.
• If an FDA-regulated intervention will be studied, assess if the application documents FDA approval of plans to proceed with implementing the proposed trial. If regulatory documentation is pending, assess if steps are underway to obtain FDA approval, (including evaluating any preliminary correspondence from the FDA). If the trial is on full or partial hold, evaluate if the application clearly documents that the hold issues are readily addressable.
• Evaluate how well the application demonstrates evidence of involvement of patient groups in study design and recruitment plans.
• Evaluate how well the community engagement strategies (preferably bi-directional) describe plans to include populations known to experience health disparities.
• Evaluate if planned statistical methods and analyses are consistent with the proposed aims.
• Assess if the procedures for standardization and quality control of data are adequate at clinical site(s) or at center laboratories, as applicable.
• Assess whether the plans to monitor adherence to the trial protocol and data collection guidelines are appropriate.

Factor 3. Expertise and Resources

Investigator(s)

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

Environment

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

Specific to this NOFO:

• Evaluate how well the project leverages the use of existing NIH tools and other resources (e.g., CTSAs, practice-based research networks, electronic medical records, administrative database, or patient registries), including partnership with existing research networks, as appropriate.
• Where there is involvement of multiple sites/centers, assess how well the individual sites or centers are able to:
  • enroll the proposed number of eligible subjects,
  • adhere to the protocol,
  • collect and transmit data in an accurate and timely fashion,   and
  • operate within the proposed organizational structure.

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

Protections for Human Subjects

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

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

Vertebrate Animals

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

Biohazards

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

Resubmissions

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

Renewals

Not applicable.

Revisions

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

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

Authentication of Key Biological and/or Chemical Resources:

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

Budget and Period of Support

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

2. Review and Selection Process

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

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

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

. Applications will compete for available funds with all other recommended applications submitted in response to this NOFO. Following initial peer review, recommended applications will receive a second level of review by the National Advisory Neurological Disorders and Stroke Council . The following will be considered in making funding decisions:

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

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

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

3. Anticipated Announcement and Award Dates

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

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

Section VI. Award Administration Information

1. Award Notices

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

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

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

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

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

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

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

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

2. Administrative and National Policy Requirements

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

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

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

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

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

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

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

• The Program Director/Principal Investigator will have the primary responsibility to define research objectives and approaches and to plan, conduct, analyze and publish results, interpretation and conclusions of their studies and for providing overall scientific and administrative leadership for the research project.
• The PD/PI will oversee all aspects of the organization and execution of the studies outlined in the application and approved by NINDS after peer review.
• Recipients have primary and lead responsibilities for the project as a whole, including any modification of study design, conduct of the study, quality control, data analysis and interpretation, preparation of publications, and collaboration with other investigators, unless otherwise provided for in these terms or by action of the primary leadership committee.
• Recipients will be responsible for putting all study materials and procedure manuals into the public domain. Recipients are expected to publish and publicly disseminate results, data and other products of the study, concordant with governance policies and protocols. Publications and oral presentations of work performed under this agreement will require appropriate acknowledgment of support by the NINDS/NIH.
• Recipients will be responsible for obtaining prior written approval of the NINDS Grants Management Specialist in consultation with the NINDS Program Officer for any change in any of the key personnel identified in the Notice of Grant Award.
• Recipients(s) will retain custody of and have primary rights to the data and software developed under these awards, subject to Government policies regarding rights of access consistent with current DHHS, PHS, and NIH policies.

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

• An agency program official or program director will be responsible for the normal scientific and will work with the recipients to 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 the process.
• 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.
• If applicable, a third NINDS Program Official from the Office of Clinical Research may serve as the NINDS liaison to a NINDS appointed 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.

The NINDS Program Staff will:

• 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 have 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 recipient'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.

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.

Areas of Joint Responsibility include:

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

Dispute Resolution:

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

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

4. Reporting

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

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

Section VII. Agency Contacts

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

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

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

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: GrantsInfo@nih.gov (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: support@grants.gov

Jeremy Brown MD
National Institute for Neurological Diorders and Stroke (NINDS)
jeremy.brown@nih.gov and  Exploratory_NINDS@NINDS.NIH.gov  

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

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.