Ultra-rare Gene-based Therapy (URGenT) Network Clinical Trials Program is sponsored by National Institute of Neurological Disorders and Stroke (NINDS), NIH. This opportunity supports mission-aligned projects and measurable outcomes.

Expired PAR-25-326: Ultra-Rare Gene-based Therapy (URGenT) Network Resource Access (X01, Clinical Trial Not Allowed) This notice has expired. For NIH, in limited situations, applications may be accepted on a case-by-case basis for a short period after expiration to accommodate NIH late or continuous submission policies . Contact the eRA Service Desk for any submission issues.

Check the NIH Guide for active opportunities and notices. Department of Health and Human Services Part 1.

Overview Information Participating Organization(s) National Institutes of Health ( NIH ) Components of Participating Organizations National Institute of Neurological Disorders and Funding Opportunity Title Ultra-Rare Gene-based Therapy (URGenT) Network Resource Access (X01, Clinical Trial Not Allowed) X01 Resource Access Award March 12, 2026 - Notice of Change: Early Expiration of PAR-25-326 Ultra-Rare Gene-based Therapy (URGenT) Network Resource Access (X01, Clinical Trial Not Allowed).

See Notice NOT-NS-26-032 . March 31, 2025 - This funding opportunity was updated to align with agency priorities. Carefully reread the full funding opportunity and make any needed adjustments to your application prior to submission.

April 4, 2024 - Overview of Grant Application and Review Changes for Due Dates on or after January 25, 2025. See Notice NOT-OD-24-084 . August 31, 2022 - Implementation Changes for Genomic Data Sharing Plans Included with Applications Due on or after January 25, 2023.

See Notice NOT-OD-22-198 . August 5, 2022 - Implementation Details for the NIH Data Management and Sharing Policy. See Notice NOT-OD-22-189 .

Funding Opportunity Number (FON) Companion Funding Opportunity Research Project (Cooperative Agreements) See Section III. 3. Additional Information on Eligibility .

Assistance Listing Number(s) Funding Opportunity Purpose The purpose of this NOFO 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 and other IND-enabling activities .

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

Open Date (Earliest Submission Date) February 9, 2025 - May 31, 2025 June 1, 2025 - September 30, 2025 October 1, 2025 - January 31, 2026 February 1, 2026 - May 31, 2026 June 1, 2026 - September 30, 2026 October 1, 2026 - January 31, 2027 February 1, 2027 - May 31, 2027 June 1, 2027 - September 30, 2027 October 1, 2027 - January 31, 2028 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. 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.

AIDS Application Due Date(s) July 2025, November 2025, March 2026, July 2026, November 2026, March 2027, July 2027, November 2027, March 2028 October 2025; January 2026; May 2026; October 2026; January 2027; May 2027; October 2027; January 2028, May 2028 December 2025, April 2026, July 2026, December 2026, April 2027, July 2027, December 2027, April 2028, July 2028 New Date March 12, 2026 per issuance of NOT-NS-26-032 .

(Original Expiration Date: February 01, 2028 ) Required Application Instructions It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide , except where instructed to do otherwise (in this NOFO or in a Notice from NIH Guide for Grants and Contracts ).

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

Applications that do not comply with these instructions may be delayed or not accepted for review. Part 1. Overview Information Part 2.

Full Text of Announcement Section I. 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 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. 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 NOFO 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.

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 its reissues, and seeks applications proposing to conduct formal IND-enabling activities and clinical trial planning activities.

Another path described in this NOFO 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, knockdown expression, or edit 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)-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 Biologics Regulatory Affairs and Regulatory Operations 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, and biodistribution and ADME studies Qualification/validation of bioassays for use in nonclinical or clinical studies 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.

Examples of planning activities that can be supported include, but are not limited to: 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 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 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 NOFO Applications that include any the following activities will be considered non-responsive and will not be reviewed: Ultra-rare diseases studies for diseases or disorders outside the mission of NINDS 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 recipient 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 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. See Section VIII.

Other Information for award authorities and regulations. Section II. Award Information Other: A mechanism that is not a grant or cooperative agreement.

Examples include access to research resources or pre-applications. Application Types Allowed The OER Glossary and the How to Apply - Application Guide provides details on these application types. Only those application types listed here are allowed for this NOFO.

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

Eligibility Information All organizations administering an eligible parent award may apply for a supplement under this NOFO.

Higher Education Institutions Public/State Controlled Institutions of Higher Education Private Institutions of Higher Education Nonprofits Other Than Institutions of Higher Education Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education) Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education) For-Profit Organizations (Other than Small Businesses) City or Township Governments Special District Governments Indian/Native American Tribal Governments (Federally Recognized) Indian/Native American Tribal Governments (Other than Federally Recognized) Eligible Agencies of the Federal Government U.S. Territory or Possession Independent School Districts Public Housing Authorities/Indian Housing Authorities Native American Tribal Organizations (other than Federally recognized tribal governments) Faith-based or Community-based Organizations Applications Involving the NIH Intramural Research Program The requests by NIH intramural scientists will be limited to the incremental costs required for participation.

As such, these requests will not include any salary and related fringe benefits for career, career conditional or other Federal employees (civilian or uniformed service) with permanent appointments under existing position ceilings or any costs related to administrative or facilities support (equivalent to Facilities and Administrative or F&A costs).

These costs may include salary for staff to be specifically hired under a temporary appointment for the project, consultant costs, equipment, supplies, travel, and other items typically listed under Other Expenses. Applicants should indicate the number of person-months devoted to the project, even if no funds are requested for salary and fringe benefits. If selected, appropriate funding will be provided by the NIH Intramural Program.

Intellectual property will be managed in accord with established policy of NIH in compliance with Executive Order 10096, as amended, 45 CFR Part 7; patent rights for inventions developed in NIH facilities are NIH property unless NIH waives its rights. Should an extramural application include the collaboration with an intramural scientist, no funds for the support of the intramural scientist may be requested in the application.

The intramural scientist may submit a separate request for intramural funding as described above. 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 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 NIH Grants Policy Statement Section 2. 3.

9. 2 Electronically Submitted Applications for additional information. System for Award Management (SAM) – Applicants must complete and maintain an active registration, which requires renewal at least annually .

The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code. 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. Eligible Individuals (Program Director/Principal Investigator) Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with their organization to develop an application for support.

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

Applications that are out of compliance with these instructions may be delayed or not accepted for review. All page limitations described in the 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 12 pages.

Instructions for Application Submission The following section supplements the instructions found in the How to Apply – Application Guide and should be used for preparing an application to this NOFO. All instructions in the How to Apply - 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 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. SF424(R&R) Senior/Key Person Profile All instructions in the How to Apply - Application Guide must be followed. All instructions in the How to Apply - Application Guide must be followed.

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.

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

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