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

NINDS Efficacy and Exploratory Clinical Trials (UG3/UH3 - Clinical Trial Required) is sponsored by National Institute of Neurological Disorders and Stroke (NINDS). This Notice of Funding Opportunity (NOFO) encourages applications for investigator-initiated clinical trials that address questions within the mission and research interests of the NINDS.

Expired PAR-21-237: NINDS Efficacy Clinical Trials (UG3/UH3 Clinical Trial Required) This notice has expired. Check the NIH Guide for active opportunities and notices. 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 Funding Opportunity Title NINDS Efficacy Clinical Trials (UG3/UH3 Clinical Trial Required) UG3 / UH3 Exploratory/Developmental Phased Award Cooperative Agreement Notices of Special Interest associated with this funding opportunity January 12, 2024 - Notice of Change: Extension of PAR-21-237.

See Notice NOT-NS-24-033 .

NOT-OD-23-012 Reminder: FORMS-H Grant Application Forms and Instructions Must be Used for Due Dates On or After January 25, 2023 - New Grant Application Instructions Now Available NOT-OD-22-190 - Adjustments to NIH and AHRQ Grant Application Due Dates Between September 22 and September 30, 2022 February 8, 2022 - Notice of Correction to PAR-21-237 "NINDS Efficacy Clinical Trials (UG3/UH3 Clinical Trial Required)".

See Notice NOT-NS-22-060 . October 28, 2021 - Reminder: FORMS-G Grant Application Forms & Instructions Must be Used for Due Dates On or After January 25, 2022 - New Grant Application Instructions Now Available. See Notice NOT-OD-22-018 .

September 13, 2021 - Updates to the Non-Discrimination Legal Requirements for NIH Recipients. See Notice August 5, 2021 - New NIH "FORMS-G" Grant Application Forms and Instructions Coming for Due Dates on or after January 25, 2022. August 5, 2021 - Update: Notification of Upcoming Change in Federal-wide Unique Entity Identifier Requirements.

See Notice NOT-OD-21-170 April 20, 2021 - Expanding Requirement for eRA Commons IDs to All Senior/Key Personnel. See Notice NOT-OD-21-109 May 26, 2021 - Temporary Extension of Eligibility for the NINDS F32 Award Due the COVID-19 Pandemic. See Notice NOT-NS-21-071 .

Funding Opportunity Announcement (FOA) Number Companion Funding Opportunity See Section III. 3. Additional Information on Eligibility .

Assistance Listing Number(s) Funding Opportunity Purpose The purpose of this Funding Opportunity Announcement (FOA) is to encourage grant applications for investigator-initiated efficacy clinical trials to the National Institute of Neurological Disorders and Stroke (NINDS).

The trials must address questions within the mission and research interests of the NINDS and may evaluate drugs, biologics, and devices, as well as surgical, behavioral and rehabilitation therapies. Information about the mission and research interests of the NINDS can be found at the NINDS website ( https://www. ninds.

nih. gov/ ). Open Date (Earliest Submission Date) Letter of Intent Due Date(s) The following table includes NIH standard due dates marked with an asterisk.

Application Due Dates Review and Award Cycles New Renewal / Resubmission / Revision (as allowed) AIDS Scientific Merit Review Advisory Council Review Earliest Start Date June 25, 2021 July 26, 2021 September 07, 2021 * November 2021 January 2022 April 2022 October 13, 2021 November 12, 2021 January 07, 2022 * March 2022 May 2022 July 2022 February 09, 2022 March 09, 2022 May 07, 2022 * July 2022 October 2022 December 2022 June 09, 2022 July 08, 2022 September 07, 2022 * November 2022 January 2023 April 2023 October 11, 2022 November 10, 2022 January 07, 2023 * March 2023 May 2023 July 2023 February 09, 2023 March 09, 2023 May 07, 2023 * July 2023 October 2023 December 2023 June 09, 2023 July 10, 2023 September 07, 2023 * November 2023 January 2024 April 2024 October 10, 2023 November 09, 2023 January 07, 2024 * March 2024 May 2024 July 2024 February 09, 2024 March 11, 2024 May 07, 2024 * July 2024 October 2024 December 2024 June 9, 2024 July 9, 2024 September 10, 2024 November 2024 January 2025 April 2025 October 9, 2024 November 8, 2024 January 8, 2025 March 2025 May 2025 July 2025 All applications are due by 5:00 PM local time of applicant organization.

All types of non-AIDS applications allowed for this funding opportunity announcement are due on the listed date(s). 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. New Date January 9, 2025 per issuance of NOT-NS-24-033 .

(Original Expiration Date: May 08, 2024 ) 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.

Part 1. Overview Information Part 2. Full Text of Announcement Section I.

Funding Opportunity Description Section II. Award Information Section III. Eligibility Information Section IV.

Application and Submission Information Section V. Application Review Information Section VI. Award Administration Information Section VII.

Agency Contacts Section VIII. Other Information Part 2. Full Text of Announcement Section I.

Funding Opportunity Description The purpose of this Funding Opportunity Announcement (FOA) is to encourage grant applications for investigator-initiated efficacy clinical trials to the National Institute of Neurological Disorders and Stroke (NINDS).

The trials must address questions within the mission and research interests of the NINDS and may include studies of drugs, biologics, and devices, as well as behavioral or other types of interventions meant to prevent or treat disorders of the nervous system within the NINDS mission. This FOA uses the UG3/UH3 mechanism. Only projects that provide satisfactory progress in the UG3 phase may move to the UH3 phase.

(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 prevent or treat a neurological disorder.

An application involving a clinical experiment that is not directly intended to develop a preventative or therapeutic intervention is not suitable for this FOA. This would include, for instance, an experiment where the objective is to elucidate the pathogenesis of the disease or to identify potential therapeutic targets for future trials.

Under this FOA NINDS will accept renewal applications to request additional years or funds to complete the original scientific aims of the efficacy clinical trial. This FOA will only support Phase 3 or Phase 4 clinical trials conducted to provide a definitive answer regarding the safety and efficacy of an intervention or to compare the effectiveness of two or more interventions.

The proposed research must address a scientifically important question, provide valuable information to the existing knowledge base, and have public health relevance. The trial design should ensure that high quality, complete data regarding the primary outcome will be collected in the most efficient manner in terms of time, resources, and burden to subjects.

Secondary outcomes should be included only when they are anticipated to provide important supportive or explanatory data. The necessity of each secondary endpoint must be justified in light of cost and burden. Pragmatic trials requiring minimal data collection and low cost per subject are encouraged.

This FOA 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.

(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 the Scientific/Research staff as early as possible to discuss these issues and determine the suitability of their project for this funding mechanism.

(3) StrokeNet : NINDS has a network called StrokeNet specifically designed to implement multicenter efficacy trials in stroke prevention, treatment and rehabilitation (see http://www. nihstrokenet. org/ ).

NINDS requires that all large stroke trials using five or more sites be considered for StrokeNet. Only under exceptional circumstances will NINDS consider funding such trials outside of the StrokeNet program (see https://grants. nih.

gov/grants/guide/notice-files/NOT-NS-14-043. html ). An important advantage of StrokeNet is that it can provide clinical, statistical and logistical expertise in developing study protocols as well as a standing national network of experienced clinical sites prepared to enroll study participants.

(4) SIREN : NINDS supports the SIREN network which performs clinical trials that impact the care of the patient with a neurological emergency other than stroke in the pre-hospital or emergency department setting. NINDS requires that all such trials be first considered for the SIREN network, though the study PI may come from outside of the network.

The study PI will work with the SIREN network to write the protocol and lead the operations committee for the trial.

(5) 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 that demonstrate 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. (6) Project Stages : The implementation of an efficacy clinical trial should be divided into two stages stages that include the activities listed below.

The first stage will be supported under the UG3 mechanism. Only studies that have satisfactorily met all of the milestones of the UG3 phase will be allowed to proceed to the full clinical trial.

Development of data management system, case report forms and data dictionaries, incorporating applicable NINDS Common Data Elements (CDEs) and other NIH-funded CDE Projects (e.g. PhenX Toolkit ); Development of tools for data and quality management; Enrollment, retention, plans to minimize losses to follow-up, and acceptable attrition rates; Development of recruitment and retention strategies Finalization of protocol, manual of procedures, consent forms, and data management plan; Finalization of statistical analysis plan (including interim analyses, if appropriate); Finalization of the study data sharing plan Protocol approval from Data and Safety Monitoring Board; Initiation of contracts and training of clinical site personnel (NINDS expects the initiation of all study sites to occur in the start-up stage; if a large number of sites is needed, a plan that describes how additional sites will be added after the initiation of the study should be included); Initiation of processes for including proposed international clinical sites, if applicable; Plans for site activation, execution of contracts and training of additional clinical sites, including any international sites, if applicable.

Enroll at least one patient from each site. Complete enrollment and follow-up of all subjects Minimize losses to follow-up Register results with www. clinicaltrials.

gov as per FDAAA 801 requirements: https://clinicaltrials.

gov/ct2/manage-recs/fdaaa Submit the primary publication within one year of completion of subject followup Provide a complete, cleaned, and de-identified dataset and any supporting documentation (including but not limited to the study protocol, statistical analysis plan, and data dictionary) required for the analysis of the data within one year of the primary publication or within 18 months of the last study visit of the last subject, whichever occurs first.

See the NIH guidelines on sharing research data (https://grants. nih. gov/grants/policy/data_sharing/) and the NINDS Procedures for Submitting Datasets ( https://www.

ninds. nih. gov/Current-Research/Research-Funded-NINDS/Clinical-Research/Archived-Clinical-Research-Datasets ).

Adaptive Designs : The use of innovative and efficient study designs is encouraged, such as adaptive dose-finding designs, designs incorporating plans for sample size recalculation, and futility designs.

Ancillary studies : 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.

Applicants are advised to discuss their ideas with Scientific/Research staff for direction on an appropriate funding mechanism. 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 efficacy trials in other disorders of the nervous system, and innovative trial designs, including crossover designs and adaptive designs, can be appropriately considered.

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. Applicants proposing studies to support a licensing application should contact the FDA to gain concurrence on the trial design.

Applicants are also advised to contact NINDS Scientific/Research contacts early in the planning process. 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.

IRB documentation : IRB approval of the protocol and informed consent is not required at the time of application submission, but it is required prior to funding. 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.

NIH Resources : As appropriate, applicants are encouraged to make use of the following resources for clinical research including: PROMIS ( http://www. healthmeasures. net/explore-measurement-systems/promis ); and NINDS Common Data Elements ( https://www.

commondataelements. ninds. nih.

gov/#page=Default ). Clinical and Translational Science Award (CTSA) program ( https://ctsacentral. org/ ); NeuroQOL ( http://www.

healthmeasures. net/explore-measurement-systems/neuro-qol ); NIH Toolbox ( http://www. healthmeasures.

net/explore-measurement-systems/nih-toolbox ); (12 ) 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.

(13) Consultation with NINDS : Applicants are encouraged to consult with NINDS Scientific/Research 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 (with the exception of the first receipt 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. Scientific/Research contacts are also available to discuss strategies for recruitment and inclusion of women and minorities.

Enrollment must comply with the NIH Policy and Guidelines on The Inclusion of Women and Minorities as Subjects in Clinical Research (https://grants. nih. gov/policy/inclusion/women-and-minorities/guidelines.

htm) and Inclusion Across the Lifespan(https://grants. nih. gov/policy/inclusion/lifespan.

htm ) Funding period : The grant mechanism used to support this funding announcement is a cooperative agreement (UG3/UH3) mechanism with two phases. The initial milestone-driven planning phase (UG3) will last for up to one year, with possible transition to the clinical phase, as outlined below. 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. 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 or device.

The UG3 Phase may not exceed 1 years The UH3 Phase may not exceed 4 years The total length of the project may not exceed 5 years See Section VIII. Other Information for award authorities and regulations. Section II.

Award Information 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 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.

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.

Application budgets are not limited but need to reflect the actual needs of the proposed project. The scope of the proposed project should determine the project period. The maximum project period is 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 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 (Other than Small Businesses) City or Township Governments Special District Governments Indian/Native American Tribal Governments (Federally Recognized) Indian/Native American Tribal Governments (Other than Federally Recognized) Eligible Agencies of the Federal Government U.S. Territory or Possession 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 Non-domestic (non-U.S.) Entities (Foreign Institutions) Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.

Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply. Foreign components, as defined in the NIH Grants Policy Statement , are allowed. Applicant organizations 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.

Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. 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.

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. eRA Commons - Applicants must have an active DUNS number to register in eRA Commons. Organizations can register with the eRA Commons as they are working through their SAM or Grants.

gov registration, but 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 DUNS number and 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.

This FOA does not require cost sharing as defined in the NIH Grants Policy Statement. 3. Additional Information on Eligibility 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. 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 NOT-OD-11-101 ). 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. All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed.

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

For due dates on or before January 24, 2023, the Data Sharing Plan and Genomic Data Sharing Plan GDS) will continue to be attached in the Resource Sharing Plan attachment in FORMS-G application forms packages. 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. 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.

The clinical trial must be directed by PD(s)/PI(s) with experience in the conduct of clinical trials and expertise in the disease area. Such experience must be documented in the biosketch, including timely submission of primary publications from previous trials, ideally within one year of completion of subject follow-up.

The application should also indicate the prior experience of other study team members in clinical trial design and implementation. All instructions in the SF424 (R&R) Application Guide must be followed. All instructions in the SF424 (R&R) Application Guide must be followed.

Costs must be budgeted on a per-subject or per-procedure basis. Applicants should provide a breakdown of the total per subject costs as part of the budget justification and should indicate how the cost for an item or procedure was determined. Applicants should budget for preparing a clean, de-identified dataset and data dictionary for submission to the NINDS.

NINDS will serve as a repository for de-identified datasets. Applicants should budget for the services of a Medical Safety Monitor (who should be independent of the study investigators) to provide timely reviews of Serious Adverse Events (SAEs).

Additionally, applicants should expect an annual one-day, in-person meeting of the NINDS-appointed Data and Safety Monitoring Board and should budget to allow up to 6 persons from the investigator team to attend. The travel expenses of DSMB members and the meeting room rental will be handled by NINDS.

If some trial costs are to be borne by sources other than NIH, these contributions must be presented in detail in the budget justification. These costs borne by third parties do not constitute cost-sharing as defined in the current NIH Grants Policy Statement and should not be presented as part of the requested budget.

The release of funds will be milestone-driven, according to milestones pre-specified in the Notice of Grant Award 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.

Note: Effective for due dates on or after January 25, 2023, the Data Management and Sharing Plan will be attached in the Other Plan(s) attachment in FORMS-H and subsequent application forms packages. For due dates on or before January 24, 2023, the Data Sharing Plan and Genomic Data Sharing Plan GDS) will continue to be attached in the Resource Sharing Plan attachment in FORMS-G application forms packages.

All applicants planning research (funded or conducted in whole or in part by NIH) that results in the generation of scientific data are required to comply with the instructions for the Data Management and Sharing Plan. All applications, regardless of the amount of direct costs requested for any one year, must address a Data Management and Sharing Plan.

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions: Significance and Biological Relevance : Describe the significance of the proposed efficacy clinical trial 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. Preliminary Studies : Present the major findings of the preclinical and clinical studies that led to the proposed efficacy clinical trial. Ensure that the data supporting the proposed trial meet the NIH scientific rigor guidelines ( 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 mechanistic studies, summarize and reference the results from these studies. If preclinical data (e.g. animal studies) do not meet the rigor guidelines, the applicant should discuss the limitations of those data and any plans to address those gaps in knowledge through the current study design.

Approach : The summary of the proposed research should include: 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.

Note that in order to increase the value of its funded research, NINDS will serve as a repository for de-identified datasets. The expectation is that a complete de-identified dataset containing all variables collected in the trial and a data dictionary will be submitted to NINDS for data sharing within an agreed upon timeframe, ideally within one year of publication of the primary outcome paper.

Please refer to the NINDS website for details ( https://www. ninds. nih.

gov/Current-Research/Research-Funded-NINDS/Clinical-Research ). 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.

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