Part 1. Overview Information

Key Dates

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

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

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

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

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

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

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



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

This Notice Of Funding Opportunity (NOFO) is part of the NINDS Ultra-Rare Gene-based Therapy (URGenT) network. The mission of URGenT is to support and facilitate the development of gene-based or transcript-directed therapeutic agents with compelling proof-of-concept (POC) data towards First-in-Human (FIH) clinical trials for individuals suffering from severely debilitating or life-threatening ultra-rare neurological diseases. Specifically, this NOFO will support projects ready to complete Investigational New Drug (IND)-enabling studies and initiate clinical trial planning activities. Successful projects ending with an IND cleared by FDA will be eligible to apply for funding to conduct a FIH clinical trial supported by URGenT network resources.

Applicants must have identified and characterized a clinical therapeutic candidate as supported by robust POC data for the intended therapeutic approach and specific disease. The objective of this program is to support activities, such as process development and cGMP manufacturing, bioassay development, IND-enabling safety/toxicology and biodistribution studies, and pharmacodynamic and pharmacokinetic (PK/PD) studies, to support the development of a clinical protocol, clinical end-point assay development, assembly of a research IND application, and clinical trial planning and preparedness activities. This is a milestone-driven cooperative agreement program involving participation of NIH program staff and external subject matter experts (SMEs) in the development of the project plan and monitoring of research progress.

Background

In the United States, a rare disease is defined as a condition that affects fewer than 200,000 people in the United States, based on the definition created by Congress in the Orphan Drug Act of 1983 and adopted by the FDA. Ultra-rare diseases affect substantially fewer people, less than or equal to 6,000; in the U.S., this equates to as few or fewer than one in 50,000 people. Approximately 95% of rare diseases, including ultra-rare diseases, have no FDA-approved therapeutic available and an estimated 80% of rare diseases have an identified genetic origin. These rare diseases are often due to pathogenic variants in a single gene that alter gene product function. Many rare and ultra-rare diseases are caused by different pathogenic variants, some of which may be unique to a single individual or to a very small number of individuals. Cumulatively, these diseases represent a large unmet medical need as there are few available effective treatments and limited commercial incentive for therapeutic development.

The NINDS Ultra-Rare Gene-based Therapy (URGenT) network addresses challenges within ultra-rare disease communities by facilitating and supporting the development of tailored therapeutic interventions using established precision medicine platforms for the treatment of individuals diagnosed with a debilitating and often fatal, ultra-rare neurological and/or neuromuscular disease. Due to the urgency of these individuals’ conditions, rapid intervention in the clinical course of disease is critical. Therefore, the selection of a viable therapeutic approach will require the ability to customize the design, testing, and delivery of these interventions.

URGenT is poised to leverage nonclinical and manufacturing data from one project to another to enable the continuous reassessment of best development practices and clinical outcomes data. This would make a platform approach to therapeutic development more accessible to ultra-rare disease communities and applicable to a broader range of diseases. In addition, this approach aims to facilitate regulatory harmonization when possible and bring therapeutic interventions to individuals sooner.

The design of early-phase clinical trials for gene-based or transcript-directed therapies for ultra-rare patient populations often differs from the design of clinical trials for other types of therapies and relies upon unique collaborations to be successful. Successful completion of the funded project is expected to lead into a clinical trial, which will be supported by mechanisms targeted to URGenT U01 award recipients through limited competition.

Research Scope

URGenT provides multiple pathways into the network for studies that propose to utilize URGenT infrastructure and resources, culminating in submission of an IND package to the FDA and preparation for a subsequent application to conduct a FIH clinical trial. One path allows direct access to resources, PAR-25-326 Ultra-Rare Gene-based Therapy (URGenT) Network Resource Access (Clinical Trial Not Allowed)(X01), for applicants proposing to conduct planning activities and/or limited nonclinical development studies with a clinical candidate therapeutic to generate additional data (as needed) before a pre-Investigational New Drug (IND) meeting or submission of an IND application. Another path into the network is described in this NOFO and seeks applications proposing to conduct formal IND-enabling activities and clinical trial planning activities. This program will support nonclinical IND-enabling development activities, such as cGMP manufacturing and safety/toxicology studies, of a clinical therapeutic that will lead to the assembly and submission of a research IND application. Proposals may also include support for the initiation of clinical trial planning activities.

PD(s)/PI(s) who have obtained a cleared IND application through the URGenT network, will also have the opportunity to submit applications for conducting a Clinical Trial through the Other Transaction funding mechanism (OTA-24-011 and OTA-24-012). Funded clinical trials could be conducted within the Network of Excellence in Neuroscience Clinical Trials (NeuroNEXT). Investigators who already have a cleared IND may apply directly to OTA-24-011.

Since a single ultra-rare disease may be caused by many different pathogenic variants, some of which may be unique to a very small numbers of patients, the selection of a viable therapeutic approach will require the ability to customize the design, testing, and delivery of these interventions. The following gene-based or transcript-directed therapeutic modalities are potentially amenable to the development of precision therapeutic approaches:

Oligonucleotide-based approaches

Oligonucleotides offer the potential to treat many genetic diseases by either ameliorating splicing pathogenic variants, promoting exon skipping, or targeting dominantly acting transcripts. Oligonucleotide-based interventions for neurological diseases include but are not limited to antisense oligonucleotides (ASOs), small interfering RNAs (siRNA) or short hairpin RNAs (shRNA).

Viral vector-based approaches

Viral-based therapeutics (e.g., Adeno-Associated Viruses (AAVs)) and other potential vector and/or delivery vehicles, containing the correct gene construct, may be used as an in vivo therapeutic approach to replace or knockdown expression of a disease-causing gene.

Cell therapy-based approaches

Gene-modified cell-based therapies may be used for an ex-vivo therapeutic approach. Only gene targeting cell therapies will be considered for this program.

Genome editing-based approaches

Several platform technologies such as Zinc Finger Nucleases (ZFNs), Transcription Activator-like Effector-based Nucleases (TALENs) and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-CRISPR-associated protein systems have emerged as promising approaches to correct disease-causing pathogenic variants.

Other gene-based therapeutic approaches

Small-molecule drugs that can selectively bind RNA and modulate pre-mRNA splicing have potential as a treatment strategy for human genetic diseases. Therefore, these nucleic acid targeted small molecules have therapeutic potential in the treatment of some ultra-rare neurological and neuromuscular diseases.

Structure

Applications submitted in response to this NOFO will utilize a milestone-driven cooperative agreement (U01) mechanism to conduct nonclinical IND-enabling studies, file a research IND, and prepare for a clinical trial. Applications are expected to address objectives for both the nonclinical and clinical trial preparedness milestones and are strongly encouraged to use project management principles as appropriate.

The nonclinical and clinical trial planning milestones combined are generally expected to be completed in not more than 3 years.

For each project provided access to the network, the NINDS will assemble a customized Multi-disciplinary Project Team (MPT). The MPT will include NINDS Program Staff plus members of the Program Director/Principal Investigator’s (PD/PI) team and additional SME consultants. The MPT will establish an overall strategy for the project with milestones, including a plan and timeline, and will develop and coordinate activities across different URGenT contract resources.

Leveraging NINDS Contract Research Resources

URGenT will provide successful applicants with access to therapeutic development resources and SME consultants. These NINDS contract resources will assist investigators to rapidly advance patient-customized therapeutics through manufacturing, nonclinical toxicology testing, and evaluation in clinical studies. A list of current URGenT resources can be found at  http://www.ninds.nih.gov/Current-Research/Research-Funded-NINDS/Translational-Research/urgent-network.

Entry Requirements

Applicants that have rational POC data obtained through scientifically rigorous experimentation for a viable gene-based or transcript-directed therapeutic clinical candidate for a specified ultra-rare disease patient population that supports nonclinical and clinical development are encouraged to apply.

• A patient or patient population has been identified with an ultra-rare neurological or neuromuscular syndrome due to a defined pathogenic variant.
• A sufficient understanding of the pathogenic variant exists and is the basis of the proposed therapeutic approach that will allow for a plausible intervention strategy in the specified patient population.
• The POC data demonstrated scientific rigor and established the feasibility and rationale for the use of the gene-based therapeutic candidate, as evidenced by an effective dose range using appropriate assays.
• The PD/PI has identified a gene-based or transcript-directed therapeutic clinical candidate supported by a substantial body of in vivo and/or in vitro data demonstrating that testing of the efficacy and preliminary safety of the candidate therapeutic in one or more model systems can mimic the planned clinical trial scenario.
• The PD/PI has scheduled a Pre-IND meeting or has held formal pre-IND discussions with the relevant FDA division regarding a future regulatory path and other requirements needed by the submission date of the application.
• The PD/PI is able to provide an outline of the future clinical trial, detailing aspects such as the proposed study design, study duration, study population, primary outcomes and safety measures, and data analysis methods. 

This NOFO encourages applications proposing plans for nonclinical development in parallel with clinical trial planning activities, including, but not limited to: 

• Manufacturing (i.e., technology transfer, process development, analytical methods development, small-scale, engineering runs, and clinical scale cGMP manufacturing of the biological therapeutic at a CMO to be used for IND-enabling studies and FIH clinical trial).
• Qualification and/or validation of any bioassays required for IND-enabling nonclinical and clinical studies.
• Non-clinical and non-interventional clinical studies and to support, for example, drug efficacy biomarker qualification and/or validation.
• IND-enabling efficacy studies with intended clinical product.
• IND-enabling biodistribution, safety, and toxicology testing in relevant animal model(s) for proposed indication in compliance with Good Laboratory Practices (GLP).
• Assessment of off-target effects as appropriate for the type of intervention under development
• Evaluation utility of efficacy biomarkers associated with the therapeutic target or disease.
• Completion of all clinical trial planning activities necessary for implementation of future clinical trial, including but not limited to IRB approval.
• Preparation and submission of an IND package to FDA.

Milestones

Because therapeutics development is inherently high risk, it is expected that there may be attrition as projects progress. Clear Go/No-Go milestones will be established by the MPT. The MPT will establish an overall strategy for the project with milestones, including a plan and timeline, to develop and coordinate activities across different URGenT contract resources.

These milestones will be based upon a template outline of achievements necessary to progress through therapeutic development but will be tailored to the specific therapeutic and its intended disease indication. Successful continuation of projects will be contingent upon:

• Successful achievement of the milestones
• Overall feasibility of project advancement, considering data that may not have been captured in the milestones
• Additional resources needed
• Ethical considerations

Clinical Trial Information

For applications proposing a clinical trial, note the following definitions and restrictions for this funding announcement:

• NIH defines clinical trials are research studies 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. For this funding announcement, only the following types of clinical trials will be supported:
  • Mechanistic trials, defined as studies designed to understand a biological or behavioral process, the pathophysiology of a disease, or the mechanism of action of an intervention (i.e., HOW an intervention works, but not IF it works or is safe).
  •  
• Clinical trials that seek to answer specific questions about safety, tolerability, clinical efficacy, effectiveness, clinical management, and/or implementation of pharmacologic, behavioral, biologic, surgical, or device (invasive or non-invasive) interventions, preventive, therapeutic, and services interventions will not be supported under this Translational Efforts to Advance Gene-based Therapies for Ultra-Rare Neurological and Neuromuscular Disorders (U01) NOFO. Safety and efficacy trials as part of the URGenT network could be supported through a separate funding mechanism including but not limited to the NeuroNEXT network. Please refer to the Ultra-rare Gene-based Therapy (URGenT) Clinical Trials Conducted within NeuroNEXT Research Opportunity Announcement (ROA) OTA-24-011 and OTA-24-012.  
• For further clarification on how NIH defines the different types of clinical trials, please refer to the following resources:
  • NOT-OD-15-015: Notice of Revised NIH Definition of “Clinical Trial”
  • NIH's Definition of a Clinical Trial
  • Decision Tree for NIH Clinical Trial DefinitionNIH Definition of Clinical Trial Case Studies

Applicants are strongly advised to consult with NINDS Scientific/Research staff prior to submitting an application with human subjects to determine the appropriate funding opportunity.
 

Applications Not Responsive to this NOFO:

Nonresponsive applications include those that involve any of the following activities:

• Ultra-rare diseases studies for diseases or disorders outside the mission of NINDS
• Screening to identify and/or optimize lead therapeutic agents
• Nonclinical studies of disease mechanism or therapeutic mechanism of action studies
• Animal model development
• Development of diagnostics or diagnostic devices
• Research focused entirely on biomarkers and/or clinical endpoint development
• Early-stage projects without significant POC data that have not identified a lead clinical candidate ready for IND-directed development
• Clinical trials that seek to answer specific questions about safety, tolerability, clinical efficacy, effectiveness, clinical management, and/or implementation of pharmacologic, behavioral, biologic, surgical, or device (invasive or non-invasive) interventions, preventive, therapeutic, and services interventions

Nonresponsive applications will be administratively withdrawn prior to review.
 

Intellectual Property Rights and Confidentiality

This program is structured so that the recipient institution retains their assignment of intellectual property (IP) rights and gains assignment of IP rights from the URGenT contractors (and thereby control the patent prosecution and licensing negotiations) for candidate therapeutics developed in this network. It is expected that the recipient institution will take responsibility for patent filings and maintenance and licensing efforts toward eventual commercialization. The PD/PI is expected to work closely with technology transfer/business development officials at his or her institution to ensure that royalty agreements, patent filings, and all other necessary IP arrangements are completed in a timely manner and that commercialization plans are developed and updated over the course of the project. Award recipients will be encouraged to identify and foster relationships with potential licensing and commercialization partners early in the drug development process, consistent with the goals of URGenT.

All SMEs will treat information as confidential and not disclose data or their assessments to third parties.

Consultation

Applicants to this NOFO are strongly encouraged to consult with the Scientific/Research staff for the area of science for which they are planning to develop an application. Early contact, at least six (6) weeks prior to the next application receipt date is strongly encouraged as it provides an opportunity for NINDS staff to discuss the scope, goals, and resources needed of the project and to provide guidance to applicants.

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

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

Section II. Award Information

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

Section III. Eligibility Information

1. Eligible Applicants

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Local Governments

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

Federal Government

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

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations

Non-domestic (non-U.S.) Entities (Foreign Organizations) are not eligible to apply.

Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.

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

Applicant Organizations

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

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

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

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

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with their organization to develop an application for support. Individuals from diverse backgrounds, including underrepresented racial and ethnic groups, individuals with disabilities, and women are always encouraged to apply for NIH support. See, Reminder: Notice of NIH's Encouragement of Applications Supporting Individuals from Underrepresented Ethnic and Racial Groups as well as Individuals with Disabilities, NOT-OD-22-019 and Notice of NIH's Interest in Diversity, NOT-OD-20-031.

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

2. Cost Sharing

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

3. Additional Information on Eligibility

Number of Applications

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

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

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

Section IV. Application and Submission Information

1. Requesting an Application Package

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

2. Content and Form of Application Submission

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

Letter of Intent

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

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

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

The letter of intent should be sent to:

Chris Boshoff, Ph.D.
Program Director
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-1779
Email: [email protected]

Page Limitations

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

For this specific NOFO, the Research Strategy section is limited to 30 pages.

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

SF424(R&R) Cover

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

SF424(R&R) Project/Performance Site Locations

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

SF424(R&R) Other Project Information

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

Other Attachments:

Additional Required Pre-IND Meeting Minutes Documents:

As part of the application submission, applicants are required to include any available minutes from pre-IND meetings with the FDA. These minutes should be submitted under the "Other Attachments" section of the application. This requirement is essential to provide context on prior discussions with regulatory authorities and to assess the alignment of the proposed research with regulatory feedback.

Please ensure that the minutes are detailed and reflect all points of discussion and any recommendations or concerns raised. Please make sure that these points have been addressed in the proposed research plan. Please upload the document as “Other Attachments_Pre-IND Meeting Minutes_Contact PI Name”. 

If the minutes from the pre-IND meeting with the FDA are not available at the time of submission, please explain any FDA feedback received and provide the minutes as soon as they are available (refer to Post-Submission Material in this section). 

Intellectual Property Documentation: 

In alignment with the intellectual property rights and confidentiality provisions of this program, applicants are required to submit relevant, comprehensive intellectual property documentation as part of their application. This includes:

1. Details of Existing IP: Information on any existing patents, patent applications, or other IP filings related to the proposed research.
2. Plans for IP Management: A description of the plans for patent filings, maintenance, and licensing, including how these efforts will be managed and coordinated with technology transfer or business development officials.
3. Commercialization Strategy: An outline of the commercialization plans, including strategies for fostering relationships with potential licensing and commercialization partners.

This information is crucial for evaluating the potential for commercialization, ensuring that IP issues are appropriately addressed, and evaluating the applicant’s readiness to manage IP and commercialization efforts effectively throughout the project. Please include a summary of the IP status and any agreements or licenses that may impact the project, along with a copy of any pertinent documents and ensure that they are named as “Other Attachments_IP Documentation_Contact PI Name”.

Other Attachments:

SF424(R&R) Senior/Key Person Profile

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

The proposed nonclinical activities and clinical trial planning activities must be directed by PD(s)/PI(s), or including a co-PD/PI, with experience in the conduct of studies leading up to IND submissions and clinical trials for individuals with ultra-rare disorders. Such experience must be documented in the biosketch, including timely submission of primary publications from previous studies and/or clinical trials. The application should also indicate the prior experience of other study team members.

R&R or Modular Budget

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

R&R Subaward Budget

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

PHS 398 Cover Page Supplement

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

PHS 398 Research Plan

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

Preliminary Studies: Present the major findings of the nonclinical studies that led to the pre-IND meeting with the relevant FDA division. Ensure that the data supporting the proposed study meets the NIH scientific rigor guidelines (NOT-OD-15-103) . If nonclinical data (e.g., animal studies) do not meet the rigor guidelines, the applicant should discuss the limitations of the data and any plans to address those gaps in knowledge through the current study design.

Discuss the potential biases and/or challenges in the feasibility of the study and how they will be addressed.

Specific Aims: The Specific Aims section should include Aims delineated for both the nonclinical and clinical trial planning activities of the project.

Research Strategy: The Research Strategy must include the entire scope of the project and provide a clear description of requested activities and/or services including:

• Clinical Impact (Significance)
• Biological Rationale and Profile of the Therapeutic Modality (Significance)
• Early or Late Strategy (Approach)
• Milestones
• Innovation
• Intellectual Property

Clinical Impact (Significance):

Applicants should include a brief statement of the therapeutic hypothesis that includes: the projected patient reduction of symptoms, slowing disease progression, side effects, dose administration and regimen, and sustainability of effect.

Provide a Target Product Profile (TPP) that summarizes the minimal/ideal profile of the final product and shows the ultimate goals of the proposed drug development effort, such as disease indication, patient population, delivery mode, treatment duration, treatment regimen, and standards for clinical efficacy. See examples: https://neuroscienceblueprint.nih.gov/sites/default/files/documents/Example_TPP_508C.pdf

Discuss how the therapy would be an improvement over currently available therapies. Describe the target clinical population and how treatment would be most efficacious at different stages of disease (therapeutic window).

Biological Rationale and Profile of the Therapeutic Agent (Significance):

Applicants should summarize the evidence that validates the drug target from cellular or animal models and/or related clinical studies, provide a brief summary of the rationale for the selection of the target, the level of agreement in the field regarding the target's role in disease pathogenesis, and clinical relevance of the target.

Provide the evidence that altering target activity as proposed will give desirable clinical outcomes.

Describe possible clinical trial endpoints and the availability of analytical methods. Indicate if biomarkers are available in animal models and humans to detect whether the therapy engages the target.

Applicants should discuss the disease-relevance of in vitro or in vivo models that are proposed or that have been used and whether the endpoints measured, and levels of activity observed are likely to be clinically relevant.

Studies using animal models presented to justify the choice of therapeutic target or gene-based therapeutic must be sufficiently powered, controlled, and replicated to lend a high degree of confidence in the results. Supporting preclinical data should be gathered and reported in compliance with NIH guidance on rigor and reproducibility (https://grants.nih.gov/reproducibility/index.htm#guidance).

Demonstrate that the therapeutic candidate proposed is expected to alter the activity of the putative target as intended and/or produces desired outcomes in disease models, with sufficient detail to allow reviewers to evaluate the rigor of the experimental design. Explain the choice of models, assays, and endpoints for these studies.

Demonstrate that the proposed development candidate has clinically relevant in vivo or in vitro activity, when delivered by the clinically intended route of administration, at exposure levels that can likely be achieved clinically with the proposed human dosing regimen.

Describe the in vivo (animal model) efficacy study design in detail, including the power analysis and associated assumptions for the determination of sample size, statistical handling of the data (such as criteria for data inclusion or exclusion), procedures used for blinding and randomization, and whether studies were replicated and consideration of sex as a biological variable (SBV) and the authentication of reagents.

Testing Strategy (Approach):

Indicate which activities will be conducted by the PD/PI and associated personnel and which activities will be conducted through NINDS resources.

Discuss plans to incorporate any translatable, clinically relevant biomarkers into preclinical and clinical development plan.

Include an outline that lays out each step in the critical path of the project.

Include a table with yearly milestones and quantitative successes (Go-No Go criteria).

Describe plans for data analysis and interpretation of outcomes, including what effect size would be considered minimally acceptable and clinically relevant (i.e., what constitutes a go/no-go decision for advancement into FIH Clinical trial).

Explain how the project offers an approach to treating the patient population as proposed in the Target Product Profile (TPP).

Explain how the anticipated clinical testing of the therapeutic compound will be addressed including aspects such as the proposed study design, study duration, study population, primary outcomes and safety measures, and data analysis methods.

Intellectual Property:

Applicants should describe any constraints of which they are aware that could impede their use of compounds, assays, or models for research purposes and/or clinical development (e.g., certain restrictions under transfer or sharing agreements, applicants' previous or present intellectual property filings and publications, compounds with similar structures that are under patent and/or on the market, etc.) and how these issues would be addressed. If the applicant has filed pertinent patents, the applicant should indicate filing dates, the type of patent, and application status.

No IP will be held by NINDS or any of its contractors or consultants.

Letters of Support: If collaborations have been established, include letters of collaboration in the application that document the role of each collaborator. Letters should be combined into a single PDF and uploaded via the Letters of Support attachment.

• If applying from an academic institution, include a letter of support from the technology transfer official who will be managing IP and licensing associated with this project and agreement to share confidentially with NIH details of any licensing agreements related to the proposed program relevant to determining feasibility of commercialization for the proposed disease area.
• If research will be performed at more than one institution, include a letter of support from each institution clarifying how IP will be shared or otherwise managed across the institutions, to ensure that the IP remains unencumbered, consistent with achieving the goals of the project.

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:

• 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.

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

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

PHS Human Subjects and Clinical Trials Information

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

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

Study Record: PHS Human Subjects and Clinical Trials Information

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

Delayed Onset Study

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

Do not enter a delayed onset study.

PHS Assignment Request Form

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

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

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

4. Submission Dates and Times

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

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

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

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

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

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

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

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

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

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

Important reminders:

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

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

See more tips for avoiding common errors.

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

Requests of $500,000 or more for direct costs in any year

Applicants requesting $500,000 or more in direct costs in any year (excluding consortium F&A) must contact a Scientific/Research Contact at least 6 weeks before submitting the application and follow the Policy on the Acceptance for Review of Unsolicited Applications that Request $500,000 or More in Direct Costs as described in the SF424 (R&R) Application Guide.

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

Send written disclosures to the NIH Chief Grants Management Officer listed on the Notice of Award for the IC that funded the award and to the HHS Office of Inspector Grant Self Disclosure Program at [email protected].

Post Submission Materials

Applicants are required to follow the instructions for post-submission materials, as described in the policy

In addition, NINDS will accept regulatory meeting minutes and transcripts, patents, and late-breaking data.

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.

For this particular announcement, note the following:

Reviewers will focus on the overall impact of the study which will also include the evaluation of the supporting data, experimental design, and all the review criteria described below.

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed). An application does not need to be strong in all categories to be judged likely to have a major scientific impact.

Review Criteria

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

Factor 1: Importance of the Research

Significance

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

Innovation

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

Specific to this NOFO:

• Evaluate whether the application addresses the strength of the POC data (in vitro and/or in vivo models) supporting the choice of the therapeutic modality and patient population for the identified genetic disease.
• Evaluate whether the current understanding of the pathogenic variant and its consequences is adequate to form the basis for the proposed therapeutic approach.
• Evaluate whether target selection, its role in disease pathogenesis, and its clinical relevance have been convincingly addressed in the application.
• If the nonclinical data (e.g., animal studies) do not meet the rigor guidelines, evaluate how well the application discusses the limitations of such data.
• Evaluate the likelihood that completion of the research objectives will lead to a therapy (e.g., if there is a clear path into the clinic).
• For applications involving clinical studies or clinical trial planning focused on clinical or public health endpoints, evaluate whether the intervention would lead to a change in clinical practice, community behaviors, or health care policy.

Factor 2. Rigor and Feasibility

Approach

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

Rigor:

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

Feasibility:

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

Specific to this NOFO:

• Evaluate if the eligible patient population can be identified based on the pathogenic variant and other common disease characteristics and clinical manifestations.
• Evaluate whether rigorous testing methodologies, e.g., biomarker assays, are available and proposed for assessing the safety and efficacy outcomes of the therapeutic for IND-enabling and subsequent clinical trials.
• Evaluate if the route of administration and initial dose selection are well-justified and appropriate and if the potential side effects are explained in enough detail to determine the project’s potential risk/benefit profile adequately.
• Evaluate if the proposed therapeutic candidate is expected to alter the activity of the putative target as intended, produce the desired outcomes in the disease models, such as ameliorating symptoms, and/or delay disease onset.
• Evaluate if the FDA has provided guidance through a pre-IND meeting and whether the proposed studies match that guidance.
• Evaluate whether it is feasible to scale up the synthesis/manufacture of the proposed development candidate to levels required for proposed IND-enabling studies and future clinical trials.
• Evaluate whether the proposed development plan includes all the appropriate studies and realistic timelines for obtaining an IND, with defined milestones and clear go/no-go criteria.
• Evaluate whether the project incorporates efficiencies and utilizes existing resources.
• Evaluate if the proposed studies are appropriate, feasible, and consistent with the proposed TPP and late-stage nonclinical activities.
• Evaluate if the proposed clinical therapeutic candidate is expected to result in measurable clinical outcomes (i.e., disease onset and/or disease progression) and if the candidate would be ready for clinical testing at the conclusion of the proposed activities.
• In addition, for applications involving clinical studies or clinical trial planning activities:
  • Evaluate whether appropriate plans to standardize, assure quality of, and monitor adherence to the trial protocol and data collection and distribution guidelines have been adequately addressed and if there is a plan to obtain the required study agent(s).
  • Evaluate if the methods used to assign participants and deliver interventions are appropriate and if the statistical approach and analysis plan are a good fit for the proposed aims/study design. Evaluate whether the study aims to complete data analysis within the proposed funding period. 

Factor 3. Expertise and Resources

Investigator(s)

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

Environment

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

Specific to this NOFO:

• Investigator(s)
  • For applications involving clinical studies or clinical trial preparation activities, assess if the PD/PI(s) and key personnel have specific/demonstrated expertise in organizing and implementing clinical trials and in study coordination, data management, and statistical design and analysis of clinical trials. 
• Environment
  • Evaluate how the project will benefit from unique features of the scientific environment, subject populations, or collaborative arrangements.
  • Evaluate how the project will leverage the use of existing NIH tools and resources, including partnership(s) with existing research networks.  

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

Protections for Human Subjects

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

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

Vertebrate Animals

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

Biohazards

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

Resubmissions

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

Renewals

Not Applicable. 

Revisions

For Revisions, the committee will consider the appropriateness of the proposed expansion of the scope of the project. If the Revision application relates to a specific line of investigation presented in the original application that was not recommended for approval by the committee, 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.

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

Authentication of Key Biological and/or Chemical Resources:

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

Budget and Period of Support

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

2. Review and Selection Process

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

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

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

Applications will 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 NOFO. Following initial peer review, recommended applications will receive a second level of review by the appropriate national Advisory Council or Board. The following will be considered in making funding decisions:

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

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

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

3. Anticipated Announcement and Award Dates

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

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

Section VI. Award Administration Information

1. Award Notices

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

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

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

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

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

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

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

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

2. Administrative and National Policy Requirements

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

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

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

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

Successful recipients under this NOFO agree that:

Where the award funding involves implementing, acquiring, or upgrading health IT for activities by any funded entity, recipients and subrecipient(s) are required to: Use health IT that meets standards and implementation specifications adopted in 45 CFR part 170, Subpart B, if such standards and implementation specifications can support the activity.  Visit https://www.ecfr.gov/current/title-45/subtitle-A/subchapter-D/part-170/subpart-B to learn more.

Where the award funding involves implementing, acquiring, or upgrading health IT for activities by eligible clinicians in ambulatory settings, or hospitals, eligible under Sections 4101, 4102, and 4201 of the HITECH Act, use health IT certified under the ONC Health IT Certification Program if certified technology can support the activity. Visit https://www.healthit.gov/topic/certification-ehrs/certification-health-it to learn more.

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

Successful recipients under this NOFO agree that:

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

        1) ongoing and consistent access to HHS owned or operated information or operational technology systems; and 

        2) receive, maintain, transmit, store, access, exchange, process, or utilize personal identifiable information (PII) or personal health information (PHI) obtained from the awarding HHS agency for the purposes of executing the award.

Recipients shall develop plans and procedures, modeled after the NIST Cybersecurity framework, to protect HHS systems and data. Please refer to NIH Post-Award Monitoring and Reporting for additional information. 

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

The administrative and funding instrument used for this program will be the cooperative agreement, 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, although specific tasks and activities may be shared among the recipients and the NIH as defined below.

• The PD/PI in collaboration with the MPT will have the primary responsibility to define research objectives and approaches and to plan, conduct, analyze and publish results, interpretations and conclusions of their studies, and for providing overall scientific and administrative leadership for the research project.
• The PD/PI in collaboration with the MPT will oversee all aspects of the organization and execution of the studies outlined in the application and approved by NINDS.
• Recipients have primary and lead responsibilities for the project as a whole, including any modification of study design, the 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 the action of the primary leadership committee.
• Recipients will be responsible for putting all study materials and procedure manuals into the public domain. Recipients are expected to publish and publicly disseminate results, data, and other products of the study, concordant with governance policies and protocols. Publications and oral presentations of work performed under this agreement will require appropriate acknowledgment of support by the NINDS/NIH.
• Recipients will be responsible for obtaining prior written approval of the NINDS Grants Management Specialist in consultation with the NINDS Program Officer for any change in any of the key personnel identified in the Notice of Grant Award.
• Recipients 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:

The Project Coordinator will have substantial programmatic involvement that is above and beyond the typical stewardship role in other awards, as described below. The Project Coordinator, with no role in stewardship of the award, will provide technical assistance, advice, coordination, and other program actions to support the recipients of the cooperative agreement during the conduct of an activity. In addition to the Project Coordinator, an NINDS Administrative Program Officer (PO) will be responsible for normal program stewardship of awards and will sign off on the grant documents and be responsible for the stewardship of the award, including monitoring implementation of the Data Management and Sharing Plan (DMS Plan) and Research Resource Sharing Plan. The PO is named in the award notice.

Joint Responsibilities

The MPT will include NINDS Program Staff plus members of the Program Director/Principal Investigator’s (PD/PI) team and additional SME consultants. The MPT will establish an overall strategy for the project with milestones, including a plan and timeline, and will develop and coordinate activities across different URGenT contract resources.

The MPT 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 recipients and contractors, advising in management and technical performance, or participating in the preparation of publications.
• 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.

Dispute Resolution

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. It will have three members: 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.

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

4. Reporting

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

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

Section VII. Agency Contacts

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

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

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

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: [email protected] (preferred method of contact)
Telephone: 301-480-7075

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: [email protected]

Chris Boshoff, Ph.D.
Program Director
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-1779
Email: [email protected]

Chief, Scientific Review Branch
National Institute of Neurological Disorders and Stroke (NINDS)
Email: [email protected]

Chief Grants Management Officer
National Institute of Neurological Disorders and Stroke (NINDS)
Email: [email protected]

Section VIII. Other Information

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

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