PAR-27-065-Full-Announcement.html

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 Efficacy and Exploratory Clinical Trials (UG3/UH3 - Clinical Trial Required)

Activity Code

UG3/UH3 Exploratory/Developmental Phased Award Cooperative Agreement

Announcement Type

Reissue of

PAR-25-054

Related Notices

Check for any recent Notices of NIH Policy Changes that may impact application requirements.

Funding Opportunity Number (FON)

PAR-27-065

Companion Funding Opportunity

None

Number of Applications

See Section III. 3. Additional Information on Eligibility.

Assistance Listing Number(s)

93.853

Funding Opportunity Purpose

This Notice of Funding Opportunity (NOFO) encourages applications for investigator-initiated 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 and may include studies of small molecules, biologics, devices as well as surgical, behavioral, diet-based, or rehabilitation therapies. Studies addressing neurological diseases and care across the lifespan are highly encouraged. This notice invites both early- and middle-phase exploratory clinical trials as well as later phase confirmatory Phase 3 or comparative effectiveness clinical trials.

Funding Opportunity Goal(s)

To support extramural research funded by the National Institute of Neurological Disorders and Stroke (NINDS) including: basic research that explores the fundamental structure and function of the brain and the nervous system; research to understand the causes and origins of pathological conditions of the nervous system with the goal of preventing these disorders; research on the natural course of neurological disorders; improved methods of disease prevention; new methods of diagnosis and treatment; drug development; development of neural devices; clinical trials; and research training in basic, translational and clinical neuroscience.

Key Dates

Posted Date

August 31, 2026

Open Date (Earliest Submission Date)

September 09, 2026

November 09, 2026

November 09, 2026

Not Applicable

July 2027

February 10, 2027

March 10, 2027

Not Applicable

December 2027

June 10, 2027

July 09, 2027

Not Applicable

April 2028

October 08, 2027

November 08, 2027

Not Applicable

July 2028

February 10, 2028

March 10, 2028

Not Applicable

December 2028

June 09, 2028

July 10, 2028

Not Applicable

April 2029

October 10, 2028

November 09, 2028

Not Applicable

July 2029

February 09, 2029

March 09, 2029

Not Applicable

December 2029

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.

Due Dates for E.O. 12372

Not Applicable

Expiration Date

March 10, 2029

Required Application Instructions

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

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

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

Table of Contents

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

Part 2. Full Text of Announcement

Section I. Notice of Funding Opportunity Description

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

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

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

Types of projects permitted under this NOFO:

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

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

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

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

Application Development Applicants should make note of the following:

General Considerations

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

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

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

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

Trial Design and Innovation

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

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

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

Intervention and Disease Considerations

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

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

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

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

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

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

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

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

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

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

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

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

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

Activities in the UG3 phase may include the following:

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

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

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

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

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

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

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

Section II. Award Information

Funding Instrument

Cooperative Agreement: A financial assistance 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 NOFO.

Application Types Allowed

New

Resubmission

Revision

The OER Glossary and the How to Apply Application Guide provide details on these application types. Only those application types listed here are allowed for this NOFO.

Clinical Trial?

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

Need help determining whether you are doing a clinical trial?

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 UG3 period may not exceed 2 years. The maximum project period of both phases may not exceed 7 years.

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

Section III. Eligibility Information

1. Eligible Applicants

Eligible Organizations

Nonprofits Other Than Institutions of Higher Education

For-Profit Organizations

Local Governments

Federal Governments

Eligible Agencies of the Federal Government

U.S. Territory or Possession

Other

Independent School Districts

Public Housing Authorities/Indian Housing Authorities

Native American Tribal Organizations (other than Federally recognized tribal governments)

Faith-based or Community-based Organizations

Regional Organizations

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

Foreign Organizations/International Collaborations

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

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

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

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

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

Required Registrations

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

System for Award Management (SAM) – Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code. Foreign organizations must obtain a NATO Commercial and Government Entity (NCAGE) Code (in lieu of a CAGE code) in order to register in SAM. Unique Entity Identifier (UEI)- A UEI is issued as part of the SAM.gov registration process. The same UEI must be used for all registrations, as well as on the grant application.

Program Directors/Principal Investigators (PD(s)/PI(s)) All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. Obtaining an eRA Commons account can take up to 2 weeks.

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

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 their organization to develop an application for support.

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

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

3. Additional Information on Eligibility Number of Applications

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

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

A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.

A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.

An application that has substantial overlap with another application pending appeal of initial peer review (see NIH Grants Policy Statement 2.3.9.4 Similar, Essentially Identical, or Identical Applications).

Section IV. Application and Submission Information

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

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

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

Instructions for Application Submission

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

SF424(R&R) Cover All instructions in the How to Apply - Application Guide must be followed.

SF424(R&R) Project/Performance Site Locations All instructions in the How to Apply- Application Guide must be followed.

SF424(R&R) Other Project Information

SF424(R&R) Senior/Key Person Profile

R&R Budget

R&R Subaward Budget

PHS 398 Cover Page Supplement

PHS 398 Research Plan All instructions in the How to Apply - Application Guide must be followed, with the following additional instructions:

The following criteria must be addressed:

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

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

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

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

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

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

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

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

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

Examples of UG3 Milestones:

Examples of UH3 Milestones:

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

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

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

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

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

Other Plan(s):

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

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

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

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

Study Record: PHS Human Subjects and Clinical Trials Information

Section 2. Study Population Characteristics Considerations that may contribute to successful inclusion are appropriate site selection, patient-or community-engagement for the major elements of the projects, and the use of focus groups to address barriers to inclusion.

2.7 Study Timeline

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

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

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

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

Section 3. Protection and Monitoring Plans

3.3 Data and Safety Monitoring Plan

Applicants should refer to the NINDS Guidelines for Data and Safety Monitoring in Clinical Trials (https://grants.nih.gov/policy-and-compliance/policy-topics/human-subjects/policies-and-regulations/data-safety) when developing their DSMP.

3.5 Overall Structure of the Study Team

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

Describe the composition and role of any advisory committees.

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

Section 4. Protocol Synopsis

4.1. Study Design

4.1.a. Detailed Description As applicable, state how the following resources for clinical research will be utilized:

If applicable, include a statement regarding how the NCATS Clinical and Translational Science Award (CTSA) program resources will be leveraged. Describe what CTSA services will be used at each participating CTSA site and how the use of the CTSA impacts the trial budget.

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

4.3 Statistical Design and Power

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

4.5 Will the study use an FDA-regulated intervention?

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

Any correspondence from FDA should be included in the application, if available at the time of submission.