Department of Health and Human Services

Part 1. Overview Information

Participating Organization(s)

National Institutes of Health (NIH)

Components of Participating Organizations

National Institute of Neurological Disorders and Stroke (NINDS)

Funding Opportunity Title
NINDS Exploratory Clinical Trials (UG3/UH3 Clinical Trial Required)
Activity Code

UG3/UH3 Exploratory/Developmental Phased Award Cooperative Agreement

Announcement Type
Reissue of PAR-21-236
Related Notices
  • NOT-OD-22-190 - Adjustments to NIH and AHRQ Grant Application Due Dates Between September 22 and September 30, 2022
  • July 28, 2022 - Notice of Correction to Announcement Type for "PAR-22-142: NINDS Exploratory Clinical Trials (UG3/UH3 Clinical Trial Required)". See Notice NOT-NS-22-120
Funding Opportunity Announcement (FOA) Number
PAR-22-142
Companion Funding Opportunity
None
Assistance Listing Number(s)
93.853
Funding Opportunity Purpose

The purpose of this Funding Opportunity Announcement (FOA) 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 or 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 future Phase 2 trial that may also be performed as part of the current grant application, should the results of the Phase 1 studies be encouraging. This FOA uses the UG3/UH3 mechanism.

Key Dates

Posted Date
April 18, 2022
Open Date (Earliest Submission Date)
May 22, 2022
Letter of Intent Due Date(s)

30 days prior to application due date.

Application Due Dates Review and Award Cycles
New Renewal / Resubmission / Revision (as allowed) AIDS Scientific Merit Review Advisory Council Review Earliest Start Date
June 22, 2022 July 22, 2022 Not Applicable November 2022 January 2023 April 2023
October 07, 2022 November 10, 2022 Not Applicable March 2023 May 2023 July 2023
February 08, 2023 March 08, 2023 Not Applicable July 2023 October 2023 December 2023
June 13, 2023 July 13, 2023 Not Applicable November 2023 January 2024 April 2024
October 10, 2023 November 09, 2023 Not Applicable March 2024 May 2024 July 2024
February 08, 2024 March 08, 2024 Not Applicable July 2024 October 2024 December 2024
June 10, 2024 July 10, 2024 Not Applicable November 2024 January 2025 April 2025
October 08, 2024 November 08, 2024 Not Applicable March 2025 May 2025 July 2025
February 10, 2025 March 10, 2025 Not Applicable July 2025 October 2025 December 2025

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.

Expiration Date
March 11, 2025
Due Dates for E.O. 12372

Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in the Research (R) Instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from NIH Guide for Grants and Contracts).

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

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

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

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

  3. Use Grants.gov Workspace to prepare and submit your application and eRA Commons to track your application.


  4. Table of Contents

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

Purpose

The purpose of this Funding Opportunity Announcement (FOA) 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 future Phase 2 trial that may also be performed as part of the current grant application if the Phase 1 study is successful. This FOA 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 FOA: 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 FOA, 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 FOA 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 FOAs 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 II 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 FOA 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 FOA.

(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) EPPIC-Net: NINDS supports EPPIC-NET (Early Phase Pain Investigation Clinical Network) that seeks to enhance the treatment of acute and chronic pain and reduce reliance on opioids by accelerating early-phase clinical trials of non-addictive treatments for pain. When appropriate, it is strongly preferred that early phase trials of potential therapeutics for various pain conditions be performed within EPPIC-NET. Therefore, before applying to this exploratory clinical trials FOA, applicants should follow the instructions on the website below to obtain feedback on the suitability of their trial for the EPPIC-NET program (see https://www.ninds.nih.gov/Current-Research/Trans-Agency-Activities/NINDS-Role-HEAL-Initiative/NINDS-Role-HEAL-Initiative-EPPIC).

(4) Efficacy: This FOA 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 appear to 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 FOA is considered to be one in which the Phase 1 trials (or, for devices, their equivalent) have been successfully completed during the UG3 phase and possibly part of the UH3 phase. 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.

(5) Effect Size: A drug or biologic trial will not be considered for funding under this FOA 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.

(6) 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.

(7) 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.

(8) 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.

(9) 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, 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.

(10) 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.

(11) 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.

(12) 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 FOA it should respond.

(13) 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 FOA 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.

(14) 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.

(15) 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.

(16) 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.

(17) 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.

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

(19) 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.

(20) 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 1studies and Phase 2planning maylast 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 2years.

The UH3 Phase may not exceed 4 years.

(21) 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 FOA after NINDS approval (StrokeNet PAR-18-561; NeuroNEXT PAR-16-155).

The total length of the project (UG3 phase plus UH3 phase) may not exceed 5 years.

Applications Not Responsive to this FOA

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

  • For Phase I study enablement, please note that synthetic route selection, drug product form work is not envisioned under this FOA. Please refer to https://grants.nih.gov/grants/guide/pa-files/PAR-20-122.html and companion FOAs 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 FOA. 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.

Section II. Award Information

Funding Instrument

Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, NIH scientific or program staff will assist, guide, coordinate, or participate in project activities. See Section VI.2 for additional information about the substantial involvement for this FOA.

Application Types Allowed
New
Resubmission
Revision

The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types. Only those application types listed here are allowed for this FOA.

Clinical Trial?

Required: Only accepting applications that propose clinical trial(s).

Funds Available and Anticipated Number of Awards

The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications.

Award Budget
Application budgets are not limited but need to reflect the actual needs of the proposed project.
Award Project Period

The maximum request cannot exceed 5 years.  

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

Section III. Eligibility Information

1. Eligible Applicants

Eligible Organizations

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Local Governments

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

Federal Government

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

Other

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

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

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

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

Required Registrations

Applicant organizations

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

  • System for Award Management (SAM) – Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
    • NATO Commercial and Government Entity (NCAGE) Code – Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
    • Unique Entity Identifier (UEI)- A UEI is issued as part of the SAM.gov registration process. SAM registrations prior to fall 2021 were updated to include a UEI. For applications due on or after January 25, 2022, the UEI must be provided on the application forms (e.g., FORMS-G); the same UEI must be used for all registrations, as well as on the grant application.
    • Dun and Bradstreet Universal Numbering System (DUNS) – Organization registrations prior to April 2022 require applicants to obtain a DUNS prior to registering in SAM. By April 2022, the federal government will stop using the DUNS number as an entity identifier and will transition to the Unique Entity Identifier (UEI) issued by SAM. Prior to April 2022, after obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
  • eRA Commons - Once the unique organization identifier (DUNS prior to April 2022; UEI after April 2022) is established, organizations can register with eRA Commons in tandem with completing their full SAM and 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. 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.

Eligible Individuals (Program Director/Principal Investigator)

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

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

2. Cost Sharing

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

3. Additional Information on Eligibility

Number of Applications

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

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

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

Section IV. Application and Submission Information

1. Requesting an Application Package

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

2. Content and Form of Application Submission

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

Letter of Intent

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

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

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

The letter of intent should be sent to:

Jeremy Brown, MD
Email: jeremy.brown@nih.gov

Page Limitations

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

Instructions for Application Submission

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

SF424(R&R) Cover

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

SF424(R&R) Project/Performance Site Locations

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

SF424(R&R) Other Project Information

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

SF424(R&R) Senior/Key Person Profile

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

R&R Budget

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

R&R Subaward Budget

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

PHS 398 Cover Page Supplement

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

PHS 398 Research Plan

All instructions in the SF424 (R&R) 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 SF424 (R&R) Application Guide, with the following modification: All studies must be registered in clinicaltrials.gov before enrollment of the first patient. The final results must be reported in clinicaltrials.gov according to current NIH guidelines.

All applications, regardless of the amount of direct costs requested for any one year, must address a Data Sharing Plan.

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

The following modifications also apply:

  • All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.
  • Generally, Resource Sharing Plans are expected, but they are not applicable for this FOA.
Appendix:
Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.
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 SF424 (R&R) Application Guide, with the following additional instructions:

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

Study Record: PHS Human Subjects and Clinical Trials Information

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

Section 2 - Study Population Characteristics

2.3a 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 a Data Management Plan including the methods and systems for data collection and quality control, and for ensuring data confidentiality and privacy, and the process for locking the final dataset and providing for data sharing. Describe the plans, if any, to use non- traditional data collection approaches (e.g., digital/mobile/sensor technologies and web-based systems) and why these are appropriate.

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

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 homogenous 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:

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 within six months of the start of funding of the UH3 phase.

Any correspondence from FDA must be included in the application. 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. If this is not possible, the study must be IND ready within six months of the start of the UH3 funding or the proposed clinical trial start date during UG3. (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 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.

The study must have one of the above prior to the release of clinical trial study funds.

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

PHS Assignment Request Form

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

Foreign Institutions

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

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

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

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 Policy on Late Application Submission.

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

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

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

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.

7. Other Submission Requirements and Information

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

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

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

Important reminders:

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

The applicant organization must ensure that the unique entity identifier (DUNS number or UEI as required) provided on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness 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.

Use of Common Data Elements in NIH-funded Research

Many NIH ICs encourage the use of common data elements (CDEs) in basic, clinical, and applied research, patient registries, and other human participants research to facilitate broader and more effective use of data and advance research across studies. CDEs are data elements that have been identified and defined for use in multiple data sets across different studies. Investigators are encouraged to consult the NIH CDE Repository and describe in their applications any use they will make of NIH-supported CDEs in their projects, when applicable. Use of CDEs can facilitate data sharing and standardization to improve data quality and enable data integration from multiple studies and sources, including electronic health records. NIH ICs have identified CDEs for many clinical domains (e.g., neurological diseases), types of studies (e.g. genome-wide association studies (GWAS)), types of outcomes (e.g., patient-reported outcomes), and patient registries (e.g., the Global Rare Diseases Patient Registry and Data Repository). NIH has established a “Common Data Element (CDE) Repository Resource Portal" (http://cde.nih.gov/) to assist investigators in identifying NIH-supported CDEs when developing protocols, case report forms, and other instruments for data collection. The Portal provides guidance about and access to NIH-supported CDE initiatives and other tools and resources for the appropriate use of CDEs and data standards in NIH-funded research.

Post Submission Materials

Applicants are required to follow the instructions for post-submission materials, as described in the policy. Any instructions provided here are in addition to the instructions 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.

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

Overall Impact

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

Scored Review Criteria

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

Significance

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

How essential is the proposed exploratory trial to inform the design and implementation of subsequent steps in the evaluation of the intervention? Is there a strong scientific premise for the project? What reasonable justification is provided in the application to suggest that the proposed intervention is likely to be an improvement over existing therapies?

Does the application adequately describe whether prior research that serves as the key support for the proposed project employed rigorous practices such as minimization of potential experimenter biases, robust experimental designs, transparent reporting of results and analyses, and careful interpretation? How does the application address ambiguity, weaknesses, or limitations in rigor of the prior research, if applicable? What information is available on the translatability of the preclinical data models and rigor of those studies?

How well will the current study design address those gaps in knowledge?
How convincing is the evidence that equipoise exists in the medical and patient communities and that the intervention is ready for clinical development?

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

Investigator(s)

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

Specific to this FOA

Have sufficient efforts been made to build a diverse team of investigators, including PI/PDs and team members that are underrepresented in the biomedical workforce (defined in NIH NOT-OD-20-031).

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

Innovation

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

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

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of individuals of all ages (including children and older adults), justified in terms of the scientific goals and research strategy proposed?

Specific to this FOA

How well designed is the study for the particular intervention's stage of development? How well do the proposed studies fit the different UG3 and UH3 phases of funding?

Are the necessary therapeutic agent(s)( drug products and drug substance)  and placebo (if applicable) or device available in sufficient quantity and quality to begin the study? If the agent(s) will need to be manufactured, has the PI demonstrated that the project is following good manufacturing practices (GMP) guidelines in procuring the active pharmaceutical ingredients?

Where applicable, are all protocols, bioassays and workflows in place to begin the proposed study?

Does the applicant adequately explain the goals of each of the stages (UG3 and UH3), and how they will be achieved?

How appropriate are the go/no-go criteria (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? How well does the application outline specific plans for clinical development of the intervention beyond this proposal?

Does the proposed research incorporate adequate methodological rigor where applicable, including, but not limited to, clear rationale for the chosen model(s) and primary/secondary endpoint(s), clear descriptions of tools and parameters, blinding, randomization, adequate sample size, pre-specified inclusion/exclusion criteria, appropriate handling of missing data and outliers, appropriate controls, preplanned analyses, and appropriate quantitative techniques? Do the applicants clearly indicate 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?

For clinical trials, is the scientific rationale of the proposed study based on well-designed, rigorous, and transparent previous preclinical and/or clinical research? Were any gaps in the rigor, robustness, or transparency of prior research identified, and, if so, how well were they addressed? Does the applicant describe potential biases and/or challenges in the study design or protocol and how they will be addressed? Is the proposed study design justified and appropriate, adequately controlled, and powered to address primary and secondary outcome variable(s)/endpoints? If applicable, will those variables/endpoints be clear, informative, and relevant to the population and hypothesis being tested? Are the study population(s) (i.e., gender, age, demographic group), proposed intervention arms and/or dosage, and duration of the trial appropriate and well justified? Is there a compelling rationale for the chosen subjects, endpoints, and statistical methods? For exploratory (typically Phase I or II) clinical trials, does the proposed study design enable the rigorous assessment of outcomes focused on dosing, target engagement, safety, or other appropriate measures?

If an FDA-regulated intervention will be studied: Does the application document FDA approval plans to proceed with implementing this trial? If the trial is not already approved, what steps are underway to obtain FDA approval, (including any correspondence from the FDA)? If the trial is on full or partial hold, does the application make clear that the hold issues are readily addressable?

How well does the application show evidence of involvement of patient groups in study design and recruitment plans?

Does the applicant describe the planned distribution of subjects by sex/gender, race, and ethnicity for each proposed study? Is there a description of the planned distribution using the Planned Enrollment Report format? If there is no report, does the applicant provide sufficient information to understand the planned distribution of subjects by sex/gender, race, and ethnicity?

Is there a description of the planned distribution using the Planned or Cumulative Enrollment Report format? Or, Is there an explanation if the sex/gender, racial, and/or ethnic composition of existing dataset is unknown? If so, Is there a description of the sex/gender, racial, and ethnic composition for the population base of the existing dataset(s), if known?

How well are the community engagement strategies described to include populations known to experience health disparities? Are there plans to create a community advisory board? Will there be bi-directional community engagement?

When applicable, do the milestones include measurable outcomes that will be collected using rigorous and transparent experimental approaches, including 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?

How well does the Data Sharing Plan provide a summary of the shared data, a description of the data standards, a plan for the data archiving, and a timeline for data submission to the archive and sharing data with the research community?

When considering Overall Impact, reviewers should focus primarily on the potential for significant impact of the intervention(s) being tested, and not where they are in the Clinical Trial pipeline.

Does the application adequately address the following, if applicable

Study Design

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

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

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

Data Management and Statistical Analysis

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

Environment

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

Specific to this FOA

How well does the project leverage the use of existing NIH tools and other resources, including partnership with existing research networks?

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

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

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

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

Additional Review Criteria

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

Study Timeline


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

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

Protections for Human Subjects

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

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

Inclusion of Women, Minorities, and Individuals Across the Lifespan

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

Vertebrate Animals

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

Biohazards

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

Resubmissions

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

Renewals

Not applicable.

Revisions

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

Additional Review Considerations

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

Applications from Foreign Organizations

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

Select Agent Research

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

Resource Sharing Plans

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

Authentication of Key Biological and/or Chemical Resources:

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

Budget and Period of Support

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

2. Review and Selection Process

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

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

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

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. 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.

3. Anticipated Announcement and Award Dates

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

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

Section VI. Award Administration Information

1. Award Notices

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

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

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

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

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

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

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

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

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

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Recipients, and Activities, including of note, but not limited to:

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

Should the applicant organization successfully compete for an award, recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights laws that prohibit discrimination on the basis of race, color, national origin, disability, age and, in some circumstances, religion, conscience, and sex (including gender identify, sexual orientation, and pregnancy). This includes ensuring programs are accessible to persons with limited English proficiency and persons with disabilities. The HHS Office for Civil Rights provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-providers/provider-obligations/index.html and https://www.hhs.gov/civil-rights/for-individuals/nondiscrimination/index.html

HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research. For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA.

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

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

Cooperative Agreement Terms and Conditions of Award

Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Parts 75 and 2 CFR Part 200, and other HHS, PHS and NIH grant administration policies. 

The administrative and funding instrument used for this program will be the cooperative agreement, and "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 award recipients in a partnership role; it is not to assume direction, prime responsibility or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the recipients for the project as a whole, although specific tasks and activities may be shared among the recipients and the 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 reporting recruitment data to the NINDS Recruitment Planning & Monitoring System (RPMS).
  • 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 acknowledgement 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 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. 

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

An NINDS Project Scientist will have substantial programmatic involvement that is above and beyond the typical stewardship role in other awards, as described below.  In addition to the Project Scientist, an NINDS Administrative Program Director will be responsible for programmatic stewardship of the award and will be named in the award notice.  This stewardship will include detailed monitoring of trial progress and milestones as described below.  A third NINDS Program Official from the Office of Clinical Research will serve as the NINDS liaison to the NINDS appointed Data and Safety Monitoring Board.

The NINDS Project Scientist 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:

  • The NINDS Project Scientist will serve on the primary leadership committee. In addition, the Project Scientist, or other NINDS Program Officials, may serve on other study committees regarding recruitment, intervention, follow-up, quality control, protocol adherence, assessment of problems affecting the study and potential changes in the protocol, interim data and safety monitoring, final data analysis and interpretation, preparation of publications, and development of solutions to major problems such as insufficient participant enrollment. The NINDS Project Scientist will have voting membership on the primary leadership committee and its subcommittees.
  • Each full member will have one vote. Recipient members of the Steering Committee will be required to accept and implement policies approved by the Steering Committee.

Dispute Resolution:

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

Continuation of Funding:

The award and administrative continuation of funding are subject to milestones to be specified in the notice of grant award according to NINDS policies (see NINDS policy for continuation of Phase 3 clinical trials (NOT-NS-10-009). The Terms and Conditions will include site activation and recruitment milestones, accrual goals for women and minorities (as appropriate) and any other identified requirements for completion of the approved research. 

As with any award, continuation is conditional upon satisfactory progress, even during the period recommended for support. If recruitment falls significantly below the projected milestones at any time, the NINDS may consider ending support and implementing a phase-out of the award. The NINDS retains the option to obtain periodic external peer review of progress

3. Reporting

When multiple years are involved, recipients will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement. NIH FOAs outline intended research goals and objectives. Post award, NIH will review and measure performance based on the details and outcomes that are shared within the RPPR, as described at 45 CFR Part 75.301 and 2 CFR Part 200.301.

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

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

Section VII. Agency Contacts

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

Application Submission Contacts

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: http://grants.nih.gov/support/ (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: 301-637-3015

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: support@grants.gov

Scientific/Research Contact(s)

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

Peer Review Contact(s)

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

Financial/Grants Management Contact(s)

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.

Authority and Regulations

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75.

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