Department of Health and Human Services

Part 1. Overview Information

Participating Organization(s)

National Institutes of Health (NIH)

Components of Participating Organizations

National Institute of Neurological Disorders and Stroke (NINDS)

Funding Opportunity Title
Ultra-Rare Gene-based Therapy (URGenT) Network Resource Access (X01, Clinical Trial Not Allowed)
Activity Code

X01 Resource Access Award

Announcement Type
New
Related Notices
  • December 8, 2021 - Notice of Correction to Due Dates for PAR-22-028, "Ultra-Rare Gene-based Therapy (URGenT) Network Resource Access (X01, Clinical Trial Not Allowed)". See Notice NOT-NS-22-048
Funding Opportunity Announcement (FOA) Number
PAR-22-028
Companion Funding Opportunity
PAR-22-030 , U01 Research Project (Cooperative Agreements)
Assistance Listing Number(s)
93.853
Funding Opportunity Purpose

The purpose of this FOA is to provide investigators with a mechanism to access contract research/medical organizations (CROs/CMOs) and subject matter experts (SMEs) within the NINDS Ultra-Rare Gene-based Therapy (URGenT) Network to support planning, manufacturing, and limited nonclinical therapeutic development efforts.

Key Dates

Posted Date
November 09, 2021
Open Date (Earliest Submission Date)
November 22, 2021
Letter of Intent Due Date(s)

30 days prior to the application submission

Application Due Date(s)

December 22, 2021 - January 31, 2022

February 1, 2022 - May 31, 2022

June 1, 2022 - September 30, 2022

October 1, 2022 - January 31, 2023

February 1, 2023 - May 31, 2023

June 1, 2023 - September 30, 2023

October 1, 2023 - January 31, 2024

February 1, 2024- May 31, 2024

June 1, 2024 - September 31, 2024

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.

AIDS Application Due Date(s)

Not Applicable

Scientific Merit Review

March 2022, July 2022, November 2022, March 2023, July 2023, November 2023, March 2024, July 2024, November 2024

Advisory Council Review

May 2022; October 2022; January 2023; May 2023; October 2023; January 2024; May 2024; October 2024; January 2025

Earliest Start Date

 June 2022, November 2022, February 2023, June 2023, November 2023, February 2024, June 2024, November 2024, February 2025

Expiration Date
October 01, 2024
Due Dates for E.O. 12372

Not Applicable

Required Application Instructions

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

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

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

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

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

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


  4. Table of Contents

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

Background

According to the definition created by Congress in the Orphan Drug Act of 1983 and adopted by the FDA, a rare disease is a condition that affects fewer than 200,000 people in the United States. 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 alters 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 the ultra-rare disease communities and applicable to a broader range of diseases. In addition, this approach aims to facilitate harmonization of efforts when possible and bring therapeutic interventions to individuals more efficiently.

The design of early-phase clinical trials for gene-based therapies for individuals afflicted with ultra-rare disease 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 activities in this X01 is expected to generate supporting data for further advancement of a proposed therapeutic towards clinical trials.

Purpose

NINDS established the URGenT network to support the development, nonclinical, and clinical testing of gene-based or transcript-directed therapeutics for individuals with ultra-rare neurological disorders within the mission of NINDS. The overarching goal of URGenT is to rapidly advance precision therapeutics through manufacturing, nonclinical toxicology testing and other required IND-enabling activities, as well as evaluation in First-in-Human (FIH) clinical studies.

The purpose of this FOA is to provide investigators with a mechanism to access contract research/medical organizations (CROs/CMOs) and subject matter experts (SMEs) within the NINDS URGenT Network to support planning, manufacturing, and limited nonclinical therapeutic development. Contract access is in-kind and at no cost to the investigators.

Scope of the Program

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 into the network is described in PAR-22-030 Translational Efforts to Advance Gene-based Therapies for Ultra-Rare Neurological and Neuromuscular Disorders (U01 - Clinical Trial Optional) and seeks applications proposing to conduct formal IND-enabling activities and clinical trial planning activities. Another path described in this FOA allows direct access to resources for applicants proposing to conduct planning activities and 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.

This Ultra-Rare Gene-based Therapy (URGenT) Network Resource Access (Clinical Trial Not Allowed) X01 encourages proposals from investigators for access to NINDS contract resources to assist in the planning, manufacturing, and nonclinical development activities that may be required before submitting an IND package to the FDA. Prior to requesting a pre-IND meeting with the FDA, the successful applicant will work with URGenT SMEs to determine what kind of feedback is needed and identify potential issues within existing or future research plans, protocols, or existing data. Only after potential issues are identified clearly can a plan to frame the discussion with the FDA be determined. This planning will lead to specific, focused questions for the FDA and help to identify considerations for future nonclinical and clinical therapeutic development activities.

Since a single ultra-rare disease may be caused by many different genetic variants, some of which may be unique to a very small numbers of individuals, 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 and transcript-directed therapeutic modalities are potentially amenable to the development of precision gene-based or transcript-directed 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. Alternatively, cell therapies involving ex vivo gene targeting may offer another therapeutic approach.

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)-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.

Leveraging NINDS Contract Research Resources

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

URGenT SME consultants will support successful applicants with strategic therapeutic development plans and assisting with preparation for a formal pre-IND meeting and/or submission of a pre-IND meeting package to the FDA. Once the investigator gathers characterization information, nonclinical data, and available clinical data, URGenT SME consultants can also assist with planning and preparation activities associated with the preparation of the IND package.

The SME consulting services may include support in disciplines such as:

  • Biologics Chemistry, Manufacturing and Controls (CMC)
  • Nonclinical/Preclinical, including Pharmacokinetics (PK), Pharmacodynamics (PD), and Toxicology
  • Bioassay Development
  • Biologics Regulatory Affairs and Regulatory Operations
  • Medical Writing
  • Biostatistics
  • Quality Assurance

URGenT nonclinical CROs/CMOs can support successful applicants by providing manufacturing, GLP toxicology, and other limited nonclinical resources for IND package submission.

The nonclinical CRO/CMO contract resources may include support in areas such as:

  • Technology-transfer, small-scale GLP lot or cGMP clinical lot manufacturing
  • GLP toxicology studies, PK/PD studies, ADME studies
  • Qualification/validation of bioassays for use in nonclinical or clinical studies

Entry Requirements

Proposals that have rational proof of concept (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.

  • 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 establishes the feasibility and rationale for the use of the investigational candidate as evidenced by a pharmacologically effective dose range using appropriate assays.
  • The Program Director/Principal Investigator (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 intends to conduct a formal pre-IND meeting with FDA but needs to plan and/or generate limited additional data before preparing and submitting the pre-IND meeting data package.
  • The PD/PI intends to submit an IND package to the FDA but needs to address recommendations with planning and/or limited additional data resulting from the formal pre-IND meeting.

Access to URGenT Contract Resources

For each project provided access to the network, the NINDS will assemble a customized Multi-disciplinary Project Team (MPT). The MPT will include members of the PD/PI's team, additional SME consultants, and NIH staff. 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.

Each successful X01 applicant should expect to receive support for planning and/or implementation activities that will utilize the resources of and facilitate access to the contract resources of the NINDS URGenT Network.

The goal of the planning process is to develop a sufficiently detailed project development plan that will identify gaps and/or needs to support future regulatory interactions (e.g., pre-IND meetings and IND package). Implementation is expected to include activities to generate data or obtain information as identified before a pre-IND meeting is conducted and/or an IND package is submitted.

Applications to this X01 should be limited to activities that can be completed within 2 years.

Planning

Examples of planning activities that can be supported include, but are not limited to:

  • Formation of a MPT
  • Access to SMEs to assess feasibility and perform a gap-analysis of data and study requirements before a pre-IND meeting is conducted
  • Development of a product development plan, including Target Product Profile (TPP) and considerations for future nonclinical and clinical study requirements
  • Development of a regulatory strategy and establishment of objectives for a pre-IND meeting
  • Determination of scope and timeline of studies to be executed by NINDS URGenT CRO/CMO resources
  • Development of a regulatory strategy and establishment of objectives to prepare and submit a well-designed, well-executed IND package based on guidance received from FDA

Implementation

Examples of implementation activities that can be supported include, but are not limited to:

  • Manufacturing - process development, engineering lot and/or GLP manufacturing
  • Confirmatory studies to demonstrate pharmacological activity and safety of the investigational clinical candidate
  • Additional studies (in vitro and/or in vivo) to support initial dosing estimates using the therapeutic clinical candidate
  • Bioassay development, e.g., potency assays, assays to measure the immune response to the therapeutic, etc., to be used to monitor safety and/or target engagement or biodistribution during clinical studies
  • Establishment of optimal route of delivery, timing of product administration, and/or dosing schedule(s)
  • Request and completion of a formal pre-IND meeting with the relevant division of the FDA
  • Preparation and submission of an IND package

Scope Limitations

Access to the resources available within the NINDS URGenT Network via an X01 is not intended to be a complete drug development program. Furthermore, obtaining access to SMEs and/or CROs/CMOs does not guarantee a successful therapy development plan nor imply a successful application for funding to other NIH programs.
 

Applications Not Responsive to this FOA

Applications that include any the following activities will be considered non-responsive and will not be reviewed:

  • Development of in vitro screening assays and/or animal models
  • Basic research of disease mechanisms or therapeutic mechanism of action studies
  • Lead optimization studies before selecting a clinical therapeutic candidate
  • Early stage discovery research, such as target identification and validation
  • Clinical research and clinical trials involving human subjects


 

Intellectual Property Rights and Confidentiality

This program is structured so that the awardee institution retains their assignment of 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 awardee 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.

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

Section II. Award Information

Funding Instrument

Other: A mechanism that is not a grant or cooperative agreement. Examples include access to research resources or pre-applications.

Application Types Allowed
New
Resubmission

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

Clinical Trial?

Not Allowed: Only accepting applications that do not propose clinical trials.

Need help determining whether you are doing a clinical trial?

Funds Available and Anticipated Number of Awards

Funds are not awarded via the X01 mechanism. The total number of approvals for access is dependent on the number of meritorious applications and the capacity of the URGenT Network.

Award Budget

Not Applicable; funds are not awarded via the X01 mechanism.

Award Project Period

The scope of the proposed project should determine the project period. The maximum project period is two years.

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

Section III. Eligibility Information

1. Eligible Applicants

Eligible Organizations

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Local Governments

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

Federal Governments

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

Other

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

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

Required Registrations

Applicant organizations

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

  • 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.
  • 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.

2. Cost Sharing

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

3. Additional Information on Eligibility

Number of Applications

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

The NIH will not accept duplicate or highly overlapping applications under review at the same time.  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.

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.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-1779
Email: chris.boshoff@nih.gov

Page Limitations

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

For this specific FOA, the Research Strategy section is limited to 12 pages.

Instructions for Application Submission

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

SF424(R&R) Cover

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

Total Federal Funds Requested: Enter $0.

Total Federal & Non-Federal Funds: Enter $0.

Estimated Program Income: Enter $0.

SF424(R&R) Project/Performance Site Locations

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

SF424(R&R) Other Project Information

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

SF424(R&R) Senior/Key Person Profile

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

R&R Budget

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

Not Applicable

R&R Subaward Budget

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

Not Applicable

PHS 398 Cover Page Supplement

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

PHS 398 Research Plan

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

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

The relevant background to justify the request, the clinical significance, the importance of the research/development project, the innovation of the project, and how completion of the requested service will set the stage for the next well-planned objective leading towards submission of an IND package and/or future clinical trials

    • Briefly describe the current state of knowledge of the etiology, clinical characteristics, and current and projected severity and/or prevalence of the proposed disease indication.
    • Discuss the benefits of the treatment compared with current therapy options and their limitations.
    • Describe the expected risk/benefit ratio of the candidate therapeutic under development.
    • Describe the identified patient and/or patient population for the proposed therapeutic intervention.
    • Describe any existing patient advocacy or support groups and/or an existing patient registry.
    • Explain how the project offers a novel approach to treating the proposed disease indication.
    • Briefly comment on the plan to conduct the clinical trial as well as a plan to monitor patients and carry out appropriate follow up after completion of the clinical trial.
    • Briefly describe the natural history of the condition and state of knowledge of rate of progression or periodicity of signs and/or symptoms.
    • Describe the current state of clinical trial readiness. What clinical outcome assessment measures and biomarkers are available for this condition and what is their state of analytical and clinical validation?

In addition, please provide a clear description of all available preliminary data to support the proposed request. Preliminary data must include a full description of the scientific rigor that produced the preliminary data such as blinding, randomization, predetermined samples sizes, appropriate statistical analysis, sex as a biological variable, and authentication of reagents.

  • The dose determination strategy with data from initial dosing studies
  • Preliminary toxicity/safety studies, immunology concerns/considerations and/or established risk analysis
  • Detailed outline of any additional nonclinical studies planned
  • All available POC data

Approach: Describe all activities, services, and defined deliverables requested with justifications and expected impact(s). For applications requesting limited nonclinical studies, provide an abbreviated research plan and timeline for the request and provide well-defined milestones for success.

Activities and/or service requests:

    • SMEs input to provide regulatory advice and support to conduct a pre-IND meeting with FDA
    • SMEs input to provide regulatory advice and preparation of an IND package to the FDA
    • Optimization and/or confirmatory studies using clinical therapeutic candidate requested after regulatory consultation.

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.

Intellectual Property: If applying from an academic institution, include a letter of support from the technology transfer official who will be managing intellectual property 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 intellectual property (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 SF424 (R&R) Application Guide.

  • All applications should address a Data Sharing Plan.
Appendix:
Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

The following modifications apply:

If any FDA meetings have been held, documentation of meeting outcomes, agreements, disagreements, and action items should be summarized and included as an Appendix document. These meetings can include pre-IND meetings and, earlier in development, INitial Targeted Engagement for Regulatory Advice on CBER producTs (INTERACT) meetings. Early, nonbinding regulatory advice can be obtained from the FDA through an INTERACT meeting, which can be used to discuss issues such as a product’s early preclinical program, and/or through a pre-IND meeting prior to submission of the IND.

PHS Human Subjects and Clinical Trials Information

When involving human subjects research, clinical research, and/or NIH-defined clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

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

Study Record: PHS Human Subjects and Clinical Trials Information

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

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).All instructions in the SF424 (R&R) Application Guide must be followed.

Do not enter a delayed onset study.

PHS Assignment Request Form

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

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

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

4. Submission Dates and Times

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

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

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

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

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

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

Pre-award costs are allowable only as described in the NIH Grants Policy Statement.

7. Other Submission Requirements and Information

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

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

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

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.

The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

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

Post Submission Materials

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

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.  

For this particular announcement, note the following:
 

The X01 Resource Access Program invites eligible institutions to seek access to NIH research resources, which are specified in each X01 FOA.  This includes programs where institutions will request access to submit to the resource (e.g., high throughput screening assays) as well as programs where access to a specific NIH research resource is needed to conduct certain research.  Important factors in the peer review of X01 applications are the need for, and potential benefit of, gaining access to the resource, specifications for any assays proposed, timelines for completion and plans for follow-on studies.

  • Applications will be received and reviewed on a rolling basis. Applications will undergo a modified, two-step review process that will involve evaluation by NIH staff and individual external experts followed by peer review
  • The market size for the candidate therapeutic should not be considered in assessing the significance of a project.
  • Evaluation of the approach should focus on the clinical rationale, potential of the clinical candidate, potential patient benefit, competitive landscape (novelty), and strengths/weaknesses of activities/services requested by the PD/PI.
Overall Impact

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

Review Criteria

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

For this announcement, the following review criteria will be used:

  • Is the requested resource likely to lead to significant advances of the candidate towards IND submission and future clinical evaluation?
  • For a given well-reasoned and designed strategy, are the following included:
    • Milestones for success
    • Timeline
    • Objectives
    • A plan for future clinical studies
  • Is there sufficient reason to believe that use of the NINDS URGenT resources is appropriate for the proposed project?
  • How well does the project leverage resources of and ensure collaboration with the URGenT Network?
  • Are the proposal objectives stated clearly?
  • Is the timeline for developing, implementing, and completing the activities appropriate?
  • Does the application have a clear statement of the question(s) that the proposed work will address and its importance?
  • Does the application provide sufficient scientific rationale and clinical need for the requested resources?
  • Are the expertise and experience of the PD(s)/PI(s), collaborators, and other proposed researchers appropriate for the work they intend to conduct themselves with the therapeutic products or studies derived from use of NIH resources?
  • Has the applicant demonstrated sufficient and convincing evidence (i.e., supported by POC data from published literature and/or PI/PD-generated preliminary data) to support the proposed activities for the therapeutic candidate?
  • How rigorous were the experiments used to obtain the POC data? Are blinding, randomization, predetermined sample sizes, appropriate statistical analysis, SBV and authentication of reagents described?
  • Does the applicant have a sufficiently outlined plan to advance this proposal towards patient use? Does the plan include a discussion of the accessible and eligible patient population (i.e., the target candidates for treatment, the number of eligible patients with the genetic variant) and other feasibility considerations, including recruitment potential, follow-up requirements, and data quality?

Protections for Human Subjects

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

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

Inclusion of Women, Minorities, and Individuals Across the Lifespan

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

Vertebrate Animals

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

Biohazards

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

Resubmissions

For Resubmissions, the reviewers 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

Not applicable.

Additional Review Considerations

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

Applications from Foreign Organizations

Not Applicable.

Select Agent Research

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

Resource Sharing Plans

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: (1) Data Sharing Plan; (2) Sharing Model Organisms; and (3)  Genomic Data Sharing Plan (GDS).

Authentication of Key Biological and/or Chemical Resources:

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

Budget and Period of Support

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

2. Review and Selection Process

X01 applications will undergo a modified, two-step review process. The first step will involve the assessment of a project’s program fit and overall feasibility of accessing the resources. The second step will be peer review of the scientific and/or technical merit of applications. Reviewers will have expertise that spans multiple areas, such as pharmacokinetics, biological mechanisms, pharmaceutical industry development, gene-based therapy development, ultra-rare disease(s), and relevant scientific and clinical expertise. Access to consultants for planning stage projects that require input to devise future development plans may be made available to meritorious applications after the first review. These reviews are essential to ensuring selection of applications that best meet the requirements and mission of the program using established criteria (above) and to providing assurance to the public that the evaluation and selection process was impartial and fair. To achieve this result, NIH conducts reviews using standard practices that follow ethical standards applied to all extramural research. Conflicts of interest, prejudices, biases, or predispositions will be appropriately managed during the review process.

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

Applications will be assigned to NINDS. Following initial review, recommended applications may receive a second level of review by the National Advisory Neurological Diseases and Stroke (NANDS) Council. The following will be considered in making funding decisions:

  • Scientific and technical merit of the proposed project as determined by peer review.
  • Available capacity of the network at the time of review and impact of the requested study on resources available to support other projects.
  • Availability of funds.
  • Relevance of the proposed project to program priorities.

3. Anticipated Announcement and Award Dates

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

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

Section VI. Award Administration Information

1. Award Notices

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

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

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

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

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

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Recipients, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights laws that prohibit discrimination on the basis of race, color, national origin, disability, age and, in some circumstances, religion, conscience, and sex. This includes ensuring programs are accessible to persons with limited English proficiency. The HHS Office for Civil Rights provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-providers/provider-obligations/index.html and http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html.

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

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

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

Cooperative Agreement Terms and Conditions of Award

Not Applicable

3. Reporting

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

A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

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

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

Section VII. Agency Contacts

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

Application Submission Contacts

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

Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-945-7573

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

Scientific/Research Contact(s)

Chris Boshoff, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-1779
Email: chris.boshoff@nih.gov

Mario H. Skiadopoulos, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-1779
Email: mario.skiadopoulos@nih.gov

Peer Review Contact(s)

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

Financial/Grants Management Contact(s)

Chief Grants Management Officer 
National Institute of Neurological Disorders and Stroke (NINDS) 
Email: ChiefGrantsManagementOfficer@ninds.nih.gov 

Section VIII. Other Information

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

Authority and Regulations

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

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