Part 1. Overview Information

Key Dates

It is critical that applicants follow the Multi-Project (M) Instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review,

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

Background

The NIH Somatic Cell Genome Editing (SCGE) Program is funded through the NIH Common Fund, which supports cross-cutting programs that are expected to have exceptionally high impact. All Common Fund initiatives invite investigators to develop bold and innovative approaches to address problems that may seem intractable or to seize new opportunities that offer the potential for transformation of research processes.

The simplicity and broad applicability of targeted and programmable genome editing approaches, including but not limited to those based on CRISPR-Cas9, raise the possibility of a fundamentally new way to treat a variety of genetic diseases. However, many challenges need to be overcome before such techniques could be widely used in the clinic. To maximize the potential of genome editing technology, the SGCE program was developed to accelerate the translation of genome editing technology into clinical applications.

Based on input received from stakeholders from academia, industry, and regulatory agencies, as well as the substantial progress in the field of genome editing since the launch of the first five-year phase of the SCGE program, the second five-year phase of SCGE will focus on translating and accelerating safe and effective genome editing therapeutics into the clinic. Specifically, SCGE Phase 2 will support the following initiatives: 1) Technologies and Assays for Therapeutic Genome Editing INDs; 2) IND-enabling Studies of Somatic Genome Editing Therapeutic Leads; 3) Platform Clinical Trials of Somatic Genome Editing for Multiple Diseases and 4) Somatic Cell Genome Editing Translational Coordination and Dissemination Center.

The SCGE Program will involve collaborative research by a consortium of grantees with differing expertise to develop, optimize and demonstrate improved candidate genome editing therapeutics as treatments for human disease. Recipients from all four SCGE program components will form a consortium, governed by a steering committee of investigators and NIH staff that will develop consensus policies and procedures for Consortium-wide activities such as data and resource sharing. Collectively, these initiatives are intended to substantially expand the number of genetic diseases treated by in vivo genome editing, ultimately allowing this technology to achieve its potential as a therapeutic platform to treat genetic disease.

Program Formation and Governance

The awards funded under this FOA will be cooperative agreements (see Section VI.2. Cooperative Agreement Terms and Conditions of Award). Close interactions among the recipients and NIH will be required to maintain this complex program. The whole SCGE Program governance will rest with the SCGE Program Steering Committee in collaboration with NIH Program Officials, with advice from Program Consultants providing critical scientific and managerial insights, and subject to oversight by the NIH SCGE Working Group. The NIH SCGE Working Group consists of NIH Programmatic Staff from multiple Institutes and Centers of the NIH as well as the Office of the Director. This group will be primarily responsible for the stewardship of the SCGE Program. The SCGE Working Group is co-chaired by the Director of the National Center for Advancing Translational Sciences (NCATS) and the Director of the National Institute for Neurological Disorders and Stroke (NINDS). It reports to the Directors of the Office of Strategic Coordination/Common Fund and the Division of Program Coordination, Planning, and Strategic Initiatives for final funding decisions.

Research Objectives

The goal of this 5-year U19 funding opportunity announcement (FOA) is to facilitate further characterization, optimization, and development of genome editing-based therapeutic lead(s) that show clinical utility and promise for therapeutic development as evidenced by relevant, rigorous, convincing preliminary in vitro and/or in vivo data. The FOA will support activities such as lead selection and optimization, manufacturability, biodistribution, in vivo efficacy and/or target engagement (measurement of target binding or proximal downstream effects) and optimal dosing combined with other properties consistent with the desired clinical application. Once an optimized therapeutic candidate is identified and regulatory advice is obtained through the formal FDA pre-IND meeting process, IND-enabling studies will be supported to file an IND package. Work would include, but is not limited to, activity and safety/toxicology studies to establish initial dosing parameters in humans, development of a clinical protocol, process and clinical assay development, and assembly of an IND application in year five.

To achieve this objective, it is expected applications will include teams of investigators with a wide range of expertise who will join efforts around multiple diseases targeting any disease relevant tissue or cell type(s), including amongst other, in utero therapeutic approaches. Each Program will include a minimum of three interrelated individual Research Projects to optimize existing lead(s) for in vivo genome editing therapeutic interventions. From these proposed Projects, applicants must identify at least one lead or "trailblazer" Project that is considered to be at the most mature stage of product development and is expected to advance a therapeutic clinical candidate to an IND package submission within five years. The other proposed "follower" Projects may enter at earlier stages of development.

An application may include development and maintenance of at least one but not more than three Resource Cores, to provide resources and/or facilities that are essential for the successful execution of the proposed activities of all the Research Projects. A Resource Core is intended to serve the needs of project researchers only and to facilitate economy of effort, space, and equipment. Any proposed Resource Core(s), if justified, are expected to be considered essential to support the Projects and should not duplicate existing institutional resources.

Research Scope

This U19 Program will support lead identification and optimization followed by nonclinical IND-enabling development activities such as cGMP manufacturing and safety/toxicology studies that will result in the assembly and submission of a research IND application to FDA in year five. This is a milestone-driven Cooperative Agreement Program involving participation of NIH program staff in the development of the project plan and monitoring of research progress. Applicants are expected to develop a Target Product Profile (TPP) based on the FDA guidance [https://www.fda.gov/vaccines-blood-biologics/biologics-guidances/cellular-gene-therapy-guidances] for each proposed Project that shows the ultimate goals of the planned therapy development effort, including but not limited to: disease indication, patient population, delivery mode and dosing regimen, treatment duration, and standards for clinical efficacy for each Project.

Applications are invited from an engaged multidisciplinary team with the expertise necessary to execute the entire proposed therapy development plan that will deliver optimized therapeutic candidates and submit at least one IND application to the FDA in year five.

This FOA invites applications from interdisciplinary Research Teams to integrate:

• Identification and optimization of genome editing therapeutic lead(s) using appropriate in vitro and/or animal model(s) to improve in vivo editing efficiency, pharmacokinetic/pharmacodynamic (PK/PD) relationship, biodistribution, dose range, and safety profiles such as off-target effects and/or immune responses for the intended route of administration.
• Optimization of delivery system(s), process development, Chemistry, Manufacturing, and Control (CMC) related activities (e.g., master and working cell banks development, purification development, CMC analytical development, final formulation development, scale-up manufacturing or cGMP manufacturing) intended for IND-enabling safety/toxicology studies.
• Development of a regulatory strategy to facilitate stage-appropriate interactions (e.g. INTERACT and/or pre-IND meetings) and regulatory submissions (e.g. IND package) to the regulatory agency.
• Development of a clinical resource to support preclinical submission planning activities, clinical protocol development, and facilitate future clinical deployment of the proposed therapy.

General U19 Structure for this Funding Opportunity

The Research Programs funded under this FOA will be comprised of multiple components, and include:

Administrative Core: An Administrative Core provides overall management, day-to-day administrative Program coordination, planning, and evaluation of the Program. The PD/PI of the Administrative Core is responsible to administer the implementation of the research plan as outlined in the application to address the short- and long-term objectives of the Program. In this role the PD/PI plays a critical role to facilitate communication among all components within the Program, monitors the progress of the Program, and ensures the effective use and integration of all proposed shared resources. The Administrative Core facilitates and participates with the shared learning and dissemination programs of the Translational Coordination and Dissemination Center (TCDC) to help create a shared learning and training education hub.

As part of this goal, investigators will be expected to provide information to the TCDC about the general approach across research projects to lead identification, optimization, and obtaining the IND to the TCDC, so that information can be disseminated within and outside the consortium.

Resource Core(s): A minimum of one and maximum of three Resource Core(s) may be proposed as a resource to the Multi-Project grant, and the proposed Core(s) must support three or more research Projects. Resource Cores must facilitate and accelerate the pace of discovery via essential support for the aims of proposed research Projects. Examples of relevant cores include safety/toxicology, pharmacokinetics/pharmacodynamics, regulatory support, and CMC/manufacturing. Applicants are expected to address each of these activities through Cores or other established methods.

Research Projects: Each application must propose a minimum of three (3) distinct Projects, each Project targeting the same tissue or cell type that is expected to be amenable to in vivo genome editing therapeutic interventions. At least one Project should be identified as the lead or "trailblazer" Project that is poised to advance a therapeutic clinical candidate to an IND package submission within five years. The other proposed "follower" Projects may enter at earlier stages of development, e.g., lead selection, but all Projects should be on a clear path proposing progressive activities expected to culminate in identifying a clinical candidate within the five years of funding support.

To be eligible for funding through this FOA, the application must include a total of at least three (3), but no more than five (5), distinct Projects. All the proposed Projects should be focused on either the same cell/tissue type and collectively represent an overarching strategy to establish a synergistic therapeutic approach.

All proposed Projects should be based on a strong scientific premise with a sound biological rationale for the intended therapeutic approach.

Specific entry criteria for Lead Project 1:

Each application must include and identify at least one lead "trailblazer" Project that is considered the most advanced in stage of development and meets the following criteria:

Lead Project 1 should include one or more therapeutic lead(s) targeting the in vivo genome editing of a specific target in a defined cell or tissue type to ameliorate the clinical manifestation of a disease. Therapeutic lead(s) should be sufficiently profiled so that the remaining parameters to be optimized can be quantitatively specified and described how each genome editing component is to be manufactured, purified, and tested.

Lead Project 1 should have compelling in vitro and/or in vivo proof of concept (POC) supporting data obtained from rigorous and well-designed experiments. POC data should demonstrate specificity and efficiency of editing targeted and non-targeted cells and demonstrate the functionality of the corrected or expressed gene product.

Lead Project 1 should have the data to demonstrate that the key in vitro and/or in vivo assays are suitable to demonstrate the editing efficiency required to achieve the desired biological activity or therapeutic effect.

Lead Project 1 should demonstrate that the proposed delivery method is appropriate for the intended use as evidenced by the ability to target the tissue or cells of interest and minimize distribution to non-targeted tissues.

Specific entry criteria for follower Project 2 and all subsequent Projects:

Each application must include and identify two or more "follower" Projects that meet the following criteria:

Each follower Project must have a strong biological rationale and preliminary data to support:

1. evidence that the therapeutic lead(s) have the potential to be therapeutically viable
2. evidence to support the robustness of the pharmacodynamic measures using in vitro or in-vivo efficacy models to illustrate how the lead(s) will be optimized and advanced toward further optimization and later stages of development and subsequent IND-enabling studies
3. a clear justification for how these studies are relevant to and part of a well-thought out and clearly defined synergistic therapeutic overall development plan.

Note: Applications consisting of preclinical research alone without a clear and direct pathway to IND-enabling studies will not be supported. The Multidisciplinary Team should establish a desired TPP for each proposed Project that defines the attributes of a successful therapeutic for the intended clinical indication, identify gaps that need to be filled during this funding period, and design the details of the plans and experiments to execute the research strategy. Engaging a team that includes members experienced in the preclinical development and IND submission process will help identify obstacles, strategize solutions and options, plan details of studies, and set a realistic timeline.

Examples of within scope and progressive activities leading towards identification of a clinical candidate and IND-submission that may be proposed include, but are not limited to:

• Lead optimization using in vitro and/or in vivo pharmacology models to assess activity and safety measurements (including pharmacodynamic biomarkers), relationships among pharmacokinetics, target engagement and/or pharmacodynamic measurements, correlations between in vitro and in vivo activities, biodistribution, bioavailability at the site of action e.g., blood-brain-barrier penetration, if applicable.
• Studies to support independent replication, appropriate powering, or an assessment of durability of activity in additional animal models if necessary, to gain a higher level of confidence for translatability of the in vivo genome editing therapeutic to the clinic
• Optimization of production (e.g., expression levels, purification yield, purity, yield of vector or cells)
• Stage-appropriate bioanalytical assay development and optimization in compliance with regulatory requirements. Process development for scale-up manufacturing and development of genome editing component stability indicating assays
• Optimization of delivery systems and/or devices including special formulations (such as liposomes, nanoparticles, etc.) in consideration of the proposed route of administration
• Dose-range finding toxicology studies in species relevant for toxicology or human dose-prediction
• Chemistry, Manufacturing, and Control (CMC) related activities (e.g., master and working banks development, purification development, CMC analytical development, final formulation development, scale-up manufacturing or cGMP manufacturing, and process controls) for drug product manufacture and testing
• Validation of assays for pharmacokinetics, target engagement markers or other assays to monitor safety and activity outcomes, including natural history of the disease, to inform identification of a biologically active dose range to facilitate future clinical trial design and enable human use in the target patient population
• Stage-appropriate interactions with regulatory agency e.g., INTERACT and/or pre-IND meetings
• IND-enabling safety pharmacology and toxicology in relevant animal model(s)
• Preparation and submission of an IND package to FDA

Milestones:

Annual milestones must be proposed to reflect progress of the overall integrated Program.

Specific aims or a list of activities are not considered milestones because they would not provide decision-making goals. The clarity and completeness of the outlined milestones regarding specific goals and feasibility are critical. The milestones proposed will be evaluated by scientific peer review and NIH Program staff may contact the applicant to discuss the proposed milestones and any changes suggested by the scientific review panel or Program Staff. A final set of approved milestones will be specified in the Notice of Award.

Example milestones include:

By the end of year 1, have selected and ranked leads that meet identified therapeutic properties required to deliver highest therapeutic index (ratio of on-target to off-target editing) as evidenced by in vitro and/or in vivo dose-response and gene-editing efficacy models.
By the end of year 2, have generated target product profiles based on pharmacologic, toxicologic, pharmacokinetic, metabolic, and phenotypic outcomes of selected lead candidates.
By the end of year 3, therapeutic candidates optimized with demonstrated efficacy, safety, and manufacturability and pre-IND meetings conducted with FDA.
By the end of year 5, IND package(s) submitted to FDA.

Because target and therapeutic discovery and development are inherently high risk, it is expected that there will be significant attrition of some Projects as Programs progress. NIH program staff and leadership will conduct an annual administrative review of progress toward the milestones. Additional meetings with NIH program staff will be arranged on a frequency appropriate for the development stage of the Project, as determined by NIH. If justified, future year milestones may be revised based on data and information obtained during the previous grant period. The administrative reviews will be based on:

1. Successful achievement of milestones
2. The overall feasibility of Program advancement, considering data that may not have been captured in milestones
3. Ethical considerations

Note: As part of the NIH SCGE Consortium, some applicant-generated animal and/or human samples from genome-editing therapeutic studies are expected to be made available to other Consortium members, and applicants are encouraged to collaborate with other SCGE Consortium members to help evaluate the utility and performance of the assay(s) to further advance the field.

Applications Not Responsive to this FOA

The following applications will be considered non-responsive to this FOA and withdrawn from consideration without review:

• Basic research of disease mechanisms
• Early activities such as target identification
• Development of risk, detection, diagnostic, prognostic, efficacy prediction biomarkers
• Applications lacking milestones
• Stand-alone studies to identify, validate, or qualify a target engagement marker and other bioanalytical assays
• Preclinical research alone without a clear and direct pathway to IND-enabling studies
• Only screening activities to identify new therapeutic leads
• Nonclinical studies of disease mechanism or therapeutic mechanism of action studies
• Nonclinical studies for ex vivo genome editing therapeutic development
• Development of diagnostics or diagnostic devices
• Research focused entirely on biomarkers and/or clinical endpoint development
• Clinical research and clinical trials involving human subjects, except those in scope using human samples to e.g., validate target engagement assays

Pre-application Information Session

A technical assistance teleconference will be held for potential applicants. NIH staff will be available to answer questions related to this and companion FOAs. Time, date, and dial in information for the call will be announced in an NIH Guide Notice and will be posted on the SCGE program website: https://commonfund.nih.gov/editing.

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

Section II. Award Information

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

Section III. Eligibility Information

1. Eligible Applicants

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Local Governments

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

Federal Governments

• Eligible Agencies of the Federal Government, including the NIH Intramural Program
• U.S. Territory or Possession

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

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

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

Applicant organizations

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.

• 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. SAM registrations prior to fall 2021 were updated to include a UEI. For applications due on or after January 25, 2022, the UEI must be provided on the application forms (e.g., FORMS-G); the same UEI must be used for all registrations, as well as on the grant application.
  • Dun and Bradstreet Universal Numbering System (DUNS) Organization registrations prior to April 2022 require applicants to obtain a DUNS prior to registering in SAM. By April 2022, the federal government will stop using the DUNS number as an entity identifier and will transition to the Unique Entity Identifier (UEI) issued by SAM. Prior to April 2022, 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.

• eRA Commons - Once the unique organization identifier (DUNS prior to April 2022; UEI after April 2022) is established, organizations can register with eRA Commons in tandem with completing their full SAM and Grants.gov registrations; all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.

• Grants.gov Applicants must have an active SAM registration in order to complete the Grants.gov registration.

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

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

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with 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, per 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 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 or an institutional system-to-system solution. A button to apply using ASSIST is 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 Multi-Project (M) Instructions in the SF424 (R&R) Application Guide, except where instructed in this funding opportunity announcement to do otherwise and where instructions in the Application Guide are directly related to the Grants.gov downloadable forms currently used with most NIH opportunities. 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 H. Boshoff, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-0664
Email: [email protected]

Page Limitations

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

Instructions for the Submission of Multi-Component Applications

The following section supplements the instructions found in the SF424 (R&R) Application Guide, and should be used for preparing a multi-component application.

The application should consist of the following components:

• Overall: required
• Administrative Core: required, maximum of 1
• Resource Cores: required, minimum of 1 and maximum of 3
• Research Projects: required; minimum of 3 and maximum of 5

Overall Component

When preparing your application, use Component Type Overall .

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

SF424(R&R) Cover (Overall)

Complete entire form.

PHS 398 Cover Page Supplement (Overall)

Note: Human Embryonic Stem Cell lines from other components should be repeated in cell line table in Overall component.

Research & Related Other Project Information (Overall)

Follow standard instructions.

Project/Performance Site Locations (Overall)

Enter primary site only.

A summary of Project/Performance Sites in the Overall section of the assembled application image in eRA Commons compiled from data collected in the other components will be generated upon submission.

Research and Related Senior/Key Person Profile (Overall)

Include only the Project Director/Principal Investigator (PD/PI) and any multi-PDs/PIs (if applicable to this FOA) for the entire application.

A summary of Senior/Key Persons followed by their Biographical Sketches in the Overall section of the assembled application image in eRA Commons will be generated upon submission.

Budget (Overall)

The only budget information included in the Overall component is the Estimated Project Funding section of the SF424 (R&R) Cover.

A budget summary in the Overall section of the assembled application image in eRA Commons compiled from detailed budget data collected in the other components will be generated upon submission.

PHS 398 Research Plan (Overall)

Specific Aims:

Provide a concise description of the Overall Program goals for an impactful and extended scope of work with a 5-plus year horizon. Outline how the approaches and goals of the multiple Research Projects will address the initial up to 5 years of investigative research.

Clearly outline how the research components are interrelated and which research component activities need to be successfully completed before the initiation of other components. Provide well-described, quantifiable, and scientifically justified milestones, which will allow Program Staff to assess progress.

Research Strategy:

The Research Strategy should include a description of the scientific challenges and opportunities being addressed, the integration of the research and resource components, and why these components are essential for accomplishing the overarching goals of the Program. The overall research strategy should be targeted to a broad audience and be concise. This section should lay out a compelling argument for why a team-research approach is needed to approach the aims, and how the synergy between Projects and Cores will interact and inform each other in ways not possible as separate research project grants, and at an economy of scale.

The Overall Research Plan should include:

1. Goals, relevant background, significance, and a description of the impact of the science proposed in relation to the state-of-the-art of the field. This section should also include an explanation of how the work proposed is innovative.
2. An explanation of how the goals of the program will address the promise of genome editing based therapeutics for human genetic based diseases. Describe how the program will be transformative and paradigm-shifting in advancing in the development of in vivo genome editing based therapeutics.
3. A section should address how a team-research plan will allow a multidisciplinary approach necessary to accomplish the goals presented. The necessary expertise of each component should be justified, along with how the value of each component would contribute to the whole. This section should describe the working scientific and logistical design, as well as the resource support components necessary to implement the research.
4. The Overall Research Strategy should include evidence for feasibility and can include general and background preliminary findings from the multiple research and resource components. This section should also present very clear evidence that the research team has been/will be able to work together effectively to accomplish the research proposed in the Projects. Applicants should offer well-reasoned justifications for new and innovative approaches, including discussion of feasibility.
5. A descriptive and graphic timeline must be included in the Research Strategy section for the Overall Program. This section should also include specific proof-of-concept test(s) along with any alternative strategies should any component efforts fail to perform as expected.

Team Management Plan

Provide a plan to demonstrate how the research team will work together effectively to accomplish the research proposal. Describe the leadership approach, governance, and organizational structure of the program. Name a Team Director who has demonstrated ability to organize, direct, and administer a complex research program. Without repeating information in individual biosketches, describe how the team members are well suited to the program, have complementary expertise, are recognized as leaders in their field, have had previous successful collaborations, are diverse, and have interdisciplinary expertise.

Letters of Support:
Statements of individual and Institutional Commitment, as appropriate to the overall application, should be included in this section.

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.

The following modifications also apply:

• All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.
• Applicants should indicate their willingness to abide by all data deposition, quality control metrics, standardization, metadata requirements, data and software release, and public copyright license policies developed by the SCGE Program Steering Committee and approved by NIH staff. A primary goal of the SCGE program is to facilitate discoveries by the broad scientific community, thereby accelerating the translation of genome editing technologies into treatments for human disease. Restrictive licensing terms and sharing practices for SCGE-generated data, tools, and resources could substantially diminish their value and public benefit. Accordingly, recipients should manage data, resources, protocols, tools, and software in a way that achieves this goal. Sharing practices that would hinder, prevent or block access to or use of SCGE program data, tools, and resources for research purposes will be considered to be hindering the goals of the SCGE program. The development of policies, methods, and standards for such sharing is critically important. The NIH expects that the recipients, through the SCGE Program Steering Committee, will develop such policies, methods, and standards in concert with the NIH. These policies, methods, and standards will remain consistent with NIH-wide policies on data and resource sharing.
• Specific Plan for Data Sharing: Consistent with achieving the goals of this program, the NIH expects that information such as collected data, technical protocols, and any other metadata collected under this FOA is to be deposited as appropriate into existing, publicly available data repositories that are easily accessible, and in machine readable format. Where appropriate, applicants should identify such repositories and plans for deposition. For datatypes that lack suitable public repositories, applicants should indicate their willingness to identify an appropriate alternative solution that is consistent with achieving the goals of the program. Data should also be made available as appropriate via the SCGE Phase II Platform that will serve as the central access point for information regarding data, critical tools, protocols and reagents being developed by the SCGE program. If applicable, applicants must abide by the NIH Genomic Data Sharing Policy (https://gds.nih.gov/) and should indicate their agreement to it in the data sharing plan.
• Specific Plan for Protocol, Tool, and Reagent Sharing: As one of the primary goals of this program is to advance research through development, establishment, broad dissemination and use of community resources across the research community, NIH intends that protocols, tools, and reagents generated by the SCGE program be broadly available and distributed at no to minimal cost, and without undue intellectual property constraints, so that they can be as widely used as possible for research purposes by the larger scientific community, while encouraging rapid adoption and commercialization of the technologies for the development of genome editing therapies. For all applications and where otherwise applicable, the applicant should discuss plans for sharing and distribution of non-data resources that will be generated by the proposed project, including animal strains, protocols, biomaterials, and reagents. The SCGE TCDC will work with all SCGE program investigators to collect, curate, and disseminate information regarding tools and reagents being developed by the program and to disseminate this information through the SCGE Toolkit and other sources as appropriate and consistent with achieving the goals of the program.
• Specific Plan for Sharing Software: A software dissemination plan, with appropriate timelines, is expected in applications that are developing software. There is no prescribed single license for software produced in this project; however, reviewers will be asked to evaluate the software sharing and dissemination plan based on its likely impact. A dissemination plan guided by the following principles is thought to promote the largest impact:
  • The software should be freely available to biomedical researchers and educators in the non-profit sector, such as institutions of education, research institutions, and government laboratories.
  • The terms should also permit the dissemination and commercialization of enhanced or customized versions of the software, or incorporation of the software or pieces of it into other software packages.
  • To preserve utility to the community, the software should be transferable such that another individual or team can continue development in the event that the original investigators are unwilling or unable to do so.
  • The terms of software availability should include the ability of researchers outside the project and its collaborating projects to modify the source code and to share modifications with other colleagues. An applicant should take responsibility for creating the original and subsequent official versions of a piece of software.
  • Applicants are asked to propose a plan to manage and disseminate the improvements or customizations of their tools and resources by others. This proposal may include a plan to incorporate the enhancements into the official core software, may involve the creation of an infrastructure for plug-ins, or may describe some other solution.
  • Any software dissemination plans represent a commitment by the institution (and its subcontractors as applicable) to support and abide by the plan.
• Applicants should also be familiar with the NIH statements regarding intellectual property of resources developed with Federal funds (NIH Research Tools Policy (http://grants.nih.gov/grants/intell-property_64FR72090.pdf) and other related NIH sharing policies at http://sharing.nih.gov).

Prior to funding, NIH Program Staff may negotiate modifications to the Sharing Plan with the applicant.

Appendix:

Only limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.

PHS Human Subjects and Clinical Trials Information (Overall)

When involving human subjects research, clinical research, and/or NIH-defined clinical trials 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, there must be at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record within the application. The study record(s) must be included in the component(s) where the work is being done, unless the same study spans multiple components. To avoid the creation of duplicate study records, a single study record with sufficient information for all involved components must be included in the Overall component when the same study spans multiple components.

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.

PHS Assignment Request Form (Overall)

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

Administrative Core

When preparing your application, use Component Type Admin Core.

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

SF424 (R&R) Cover (Admin Core)

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant’s Project
• Proposed Project Start/Ending Dates

PHS 398 Cover Page Supplement (Admin Core)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Admin Core)

Human Subjects: Answer only the Are Human Subjects Involved? and 'Is the Project Exempt from Federal regulations? questions.

Vertebrate Animals: Answer only the Are Vertebrate Animals Used? question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

Project /Performance Site Location(s) (Admin Core)

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

Research & Related Senior/Key Person Profile (Admin Core)

• In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Project Lead and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.

Budget (Admin Core)

Budget forms appropriate for the specific component will be included in the application package.
The Administrative Core Principal Investigator should also budget for two in-person SCGE consortium meetings per year.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

PHS 398 Research Plan (Admin Core)

The most commonly referenced Research Plan attachments are listed below for your convenience. FOA specific instructions are required for the Specific Aims and the Research Strategy in each component. FOA-specific instructions are optional for Letters of Support. Delete Letters of Support if there are no FOA-specific instructions.

Specific Aims: Provide a concise description of the goals of the Administrative Core.

Research Strategy: The Administrative Core is expected to have appropriate and effective administrative and organizational capabilities to support multidisciplinary research, outreach, to foster synergy, and to support planning and evaluation activities.
Describe how each Project or Resource Core (as applicable) will draw upon the Administrative Core and how it in turn will respond to Project or Resource Core needs. The description of the Administrative Core should clearly indicate the services and professional skills that the Core will provide. Provide information about how the collective operation of the Core will be affected in a coherent manner. Describe how the Administrative Core will collaborate with the Translational Coordination and Dissemination Center (TCDC) to disseminate the Program's data, and to facilitate the development of a shared learning and training education hub.

A Team Director must be identified, and a governance plan be proposed.

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, with the following modification:

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

Generally, Resource Sharing Plans are expected, but they are not applicable for this FOA.

Appendix:

Only limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.

PHS Human Subjects and Clinical Trials Information (Admin Core)

When involving human subjects research, clinical research, and/or NIH-defined clinical trials 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 a 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.

Resource Cores

When preparing your application in ASSIST, use Component Type Core.

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

SF424 (R&R) Cover (Resource Cores)

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant’s Project
• Proposed Project Start/Ending Dates

PHS 398 Cover Page Supplement (Resource Cores)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Resource Cores)

Human Subjects: Answer only the Are Human Subjects Involved? and 'Is the Project Exempt from Federal regulations? questions.

Vertebrate Animals: Answer only the Are Vertebrate Animals Used? question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

Project /Performance Site Location(s) (Resource Cores)

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

Research & Related Senior/Key Person Profile (Resource Cores)

In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Project Lead and provide a valid eRA Commons ID in the Credential field.

In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.

Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.

If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.

Budget (Resource Cores)

Budget forms appropriate for the specific component will be included in the application package.

Applicant should also budget for two in-person SCGE consortium meetings per year.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

PHS 398 Research Plan (Resource Cores)

Specific Aims: Provide a concise description of the goals of the Resource Core.

Research Strategy: Explain how the Resource Core will contribute to individual Research Projects.

A Resource Core can be a laboratory, a facility, a service, or other shared resource that supports at least two Research Projects. Descriptions for each Resource Core should include a brief overview and a description of the services and resources to be provided to the Research Projects. This section should address how the Resource Core will contribute to the overall goals of the Program as well as which Research Projects will be supported by the Resource Core and the manner in which that support will be rendered. The description of each Resource Core should clearly indicate the facilities, resources, services, and professional skills that the facility will provide. Issues to be addressed can include quality control, special expertise, cost effectiveness, and increased efficiency.

Where appropriate, describe how Resource Cores will be a point of contact for dissemination of technology, expertise, materials, and potential collaborations with other research individuals, teams and communities.

Significance: Describe overall goals of the science proposed in relation to the state of the field. This section should also explain the contribution of the core to the overall goals of the program and how the component will interact with and benefit from other components.

Innovation: Describe the unique and innovative contributions that will be made by this component. Explain how these contributions will be made possible by team synergy.

Approach: Describe and offer evidence for the feasibility of the proposed experiments, the advantages of any new methodologies, the potential pitfalls and alternative approaches for the Core and how these might impact overall progress.

Appendix:

Limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.

PHS Human Subjects and Clinical Trials Information (Resource Cores)

When involving NIH-defined human subjects research, clinical research, and/or clinical trials 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, there must be at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record within the application. The study record(s) must be included in the component(s) where the work is being done unless the same study spans multiple components. To avoid the creation of duplicate study records, a single study record with sufficient information for all involved components must be included in the Overall component when the same study spans multiple components.

Study Record: PHS Human Subjects and Clinical Trials Information

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

Delayed Onset Study

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

Research Project

When preparing your application in ASSIST, use Component Type Project.

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

SF424 (R&R) Cover (Research Project)

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant’s Project
• Proposed Project Start/Ending Dates

PHS 398 Cover Page Supplement (Research Project)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Research Project)

Human Subjects: Answer only the Are Human Subjects Involved? and 'Is the Project Exempt from Federal regulations? questions.

Vertebrate Animals: Answer only the Are Vertebrate Animals Used? question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

Project /Performance Site Location(s) (Research Project)

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

Research & Related Senior/Key Person Profile (Research Project)

• In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Project Lead and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.

Budget (Research Project)

Budget forms appropriate for the specific component will be included in the application package.

The Project Lead must commit at least a total minimum effort of 1.8 person-months per year to the Project. Each Project applicant should also budget for two in-person SCGE consortium meetings per year.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

PHS 398 Research Plan (Research Project)

The most commonly referenced Research Plan attachments are listed below for your convenience. FOA specific instructions are required for the Specific Aims and the Research Strategy in each component. FOA-specific instructions are optional for Letters of Support. Delete Letters of Support if there are no FOA-specific instructions.

Specific Aims:

This section should provide a concise description of the aims for each of the research Projects.

All specific aims for every Project should include milestones that should be well-described, quantifiable, and scientifically justified to allow Program Staff to assess progress for each proposed Project.

Research Strategy:

The Research Strategy should include the entire scope of each proposed Project and provide a clear description of proposed activities including:

Significance:

Describe overall goals, alignment with the overall Program activities, the impact of the science proposed in relation to the state of the field. This section should also explain the contribution of the research Project to the overall goals of the U19 program and how the component will interact with and benefit from other components targeting the same tissue or cell type. Applicants should include a brief statement of the therapeutic hypothesis that includes: the projected patient reduction of symptoms, slowing disease progression, side effects, dose administration and regimen, and sustainability of effect. Provide a Target Product Profile (TPP) that summarizes the minimal/ideal profile of the final product and shows the ultimate goals of the proposed drug development effort, such as disease indication, patient population, delivery mode, treatment duration, treatment regimen, and standards for clinical efficacy. Discuss how the therapy would be an improvement over currently available therapy. Describe the target clinical population and how treatment would be most efficacious at different stages of disease (therapeutic window). Describe how the target patient population may be identified (e.g., based on the pathogenic variant and other common disease characteristics and clinical manifestations).

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

Provide the evidence and any POC data that altering (editing) target activity as proposed will give the desired clinical outcomes and is appropriate for the identified genetic disease.

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

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

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

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

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

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

Innovation:

Describe the unique and innovative contributions that will be made by each proposed Project. Explain how these contributions will be made possible by team synergy beyond the otherwise independent research Projects.

Approach:

Describe how proposed experiments will address considerations for preclinical studies to culminate in an IND submission and expound how the genome editing product and its individual components will be evaluated to assess its manufacturability, delivery, activity, efficacy, safety, and potential risks associated with in vivo administration of the product. Describe and offer evidence for the feasibility of the proposed experiments, the advantages of any new methodologies, the potential pitfalls, and alternative approaches for each Project and how these might impact overall progress. Describe how the research design will maximize the reliability and replicability of the findings.

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

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

Describe plans for data analysis and interpretation of outcomes, including what effect size would be considered minimally acceptable and clinically relevant (i.e., what constitutes a Go-No go decision for advancement future clinical trials).

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

Specific to Lead Project 1: For the lead trailblazer Project, discuss plans to incorporate any translatable, clinically relevant biomarkers into the preclinical and clinical development plan. Explain how the anticipated clinical testing of the therapeutic will be addressed including aspects such as the proposed study design, study duration, study population, primary outcomes and safety measures, and data analysis methods.

Specific to follower Project 2 and subsequent projects: Describe how each less mature follower Project will leverage advances made by the more advanced lead trailblazer Project 1 during the funding period.

Intellectual Property:

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

Letters of Support:

Statements of individual and institutional commitment, as appropriate to the Research Project, should be included in this section.

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, with the following modification:

Not Applicable for each component. Resource Sharing Plan should be submitted only in the Overall section only. See instructions in Overall section.

Appendix:
Limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

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) using ASSIST or other electronic submission systems. 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.

For information on how your application will be automatically assembled for review and funding consideration after submission go to: http://grants.nih.gov/grants/ElectronicReceipt/files/Electronic_Multi-project_Application_Image_Assembly.pdf.

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) and component Project Leads must include their eRA Commons ID in the Credential fieldof the Senior/Key Person Profile form. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH.

The applicant organization must ensure that the unique entity identifier (DUNS number or UEI as required) provided 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, NIH. Applications that are incomplete or non-compliant will not be reviewed.

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

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. NIH intramural scientists will participate in this program as PDs/PIs in accord with the Terms and Conditions provided in this FOA. Intellectual property will be managed in accord with established policy of the 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 and in the NIH Intramural Source Book.

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.

Section V. Application Review Information

Only the review criteria described below will be considered in the review process. Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.

Specific for this FOA, note the following:

The entire Research Program will receive one Impact Score based on critical considerations of the Overall Program and the collective assessment of the Research Projects, the Administrative Core, and Resource Core(s). To guide the final scoring, reviewers will make interim assessment scores of the Overall Program and each Research Project (scores 1-9), along with evaluation of the Administrative Core and each Resource Core (exceptional, adequate, or inadequate). The final Impact Score will reflect assessment of aggregate impact and synergies of the Overall Program that will balance the collective strengths and weaknesses of the overall goals and the individual components, and not necessarily the arithmetic average of the interim assessment scores.

The Common Fund SCGE Program seeks applications that meet the goals outlined under Research Objectives and have high levels of innovation. Reviewers should evaluate whether a sound rationale has been provided as to how and why the research is tractable and likely to generate an exceptionally high impact if successful. Although reviewers will consider feasibility, they will be instructed to not penalize unavoidable risks that are intrinsic to new and innovative approaches.

The collective U19 team effort will be evaluated as an integrated therapeutic development research effort. The relationship and contributions of the Research Projects, Administrative Core, and Resource Core(s) to the overall objectives will be discussed and evaluated.

Individual Components will be assessed for relevant strengths and weaknesses in the context of the integrated Program. Final Impact Score need not reflect a cumulative enumeration of minor weaknesses but should reflect a balance of both the quality of the individual components, and the collective synergies and expected impacts of all the components.

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).

Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

Significance

Does the project address an important problem or a critical barrier to progress in the field? Is the prior research that serves as the key support for the proposed project rigorous? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Specific for this FOA:

1. Does the Program offer potentially transformative and paradigm-shifting advances in the development of in vivo genome editing based therapeutics?

2. Are the Projects and core (if proposed) synergistic, such that they will interact and inform each other in ways not possible as separate research project grants, and at an economy of scale?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or those in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

Specific for this FOA:

Is the team diverse and interdisciplinary, such that it is comprised of appropriate content experts recognizable as leaders in their field? Are the team management plans clear and appropriate? Is there evidence that the research team has been/will be able to work together effectively to accomplish the research proposed in the Program?

Team Director: Has the proposed Team Director demonstrated leadership in science proposed with a strong record of scientific achievements? Has the proposed Team Director demonstrated his/her ability to organize, direct, and administer a complex research program?

Innovation

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?

Specific to this FOA:

Does the Program offer novelty and innovation appropriate for/commensurate with the goals of the Common Fund SCGE Initiative?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) 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), justified in terms of the scientific goals and research strategy proposed?

Environment

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

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.

Program Timeline and Milestones

Is the projected timeline feasible and well justified? Does the Program incorporate efficiencies and utilize existing resources?

Are the Program milestones considered to be achievable and appropriate to attain the proposed Program deliverables?

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 committee 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 committee 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 committee 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 committee 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

Not Applicable

Renewals

Not Applicable

Revisions

Not Applicable

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.

Scored Review Criteria - Research Projects

Reviewers will consider each of the review criteria in the determination of scientific merit and give a separate score for each. A Project does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a Project that by its nature is not innovative may be essential to advance a field.

Impact Score

Reviewers will provide an impact score to reflect their assessment of the likelihood for the research project to exert a sustained, powerful influence on the research field, in consideration of the following review criteria

Significance

Does the Project address an important problem or a critical barrier to progress in the field? Is the prior research that serves as the key support for the proposed Project rigorous? If the aims of the Project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Is there appropriate synergy of the Research Projects to the Overall Program objectives?
Is the description adequate for how to identify the eligible patient population?
How strong are the evidence supporting the choice of therapeutic intervention for the identified genetic disease?
Is understanding of the pathogenic variant and its consequences adequate to form the basis for the proposed therapeutic approach?
Do the POC data (in vitro and/or in vivo models) support the therapeutic hypothesis for the patient population and establish a potential clinical significance for the therapeutic intervention?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the Project? If Early Stage Investigators or those in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the Project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the Project?

Innovation

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the Project? Have the investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed Project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

Have the applicants addressed appropriate research designs to maximize the reliability and replicability of their findings?

Are rigorous testing methodologies, e.g., biomarker assays, available and proposed to assess the safety and efficacy outcomes of the therapeutic for IND-enabling and subsequent clinical trials?

Specific for the lead Project 1: Are the proposed studies appropriate, feasible and consistent with the proposed TPP and late-stage nonclinical activities, and expected to advance the Trailblazer Project, at a minimum, to filing of an IND package within the proposed timeframe?

Specific to follower Project 2 and subsequent projects: Is the approach of the U19 adequate to move the novel therapeutic lead(s) through rigorous preclinical testing to culminate at a minimum in the completion of in vitro and in vivo proof of concept studies as the basis to nominate a clinical candidate that is poised for IND-enabling studies within the proposed timeframe?

Does the applicant describe how each less mature follower Project will leverage advances made by the more advanced lead Trailblazer Project 1 prior to or during the funding period?

Environment

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements? Does the Project leverage the use of other resources and proposed partnership(s) to increase the likelihood to achieve the stated Overall Aims and meet the Project milestones?

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

Review Criteria - Administrative Core

Reviewers will provide only one adjectival rating (exceptional, adequate, or inadequate) for the Administrative Core (criterion scoring is not used for this component). Reviewers will consider the following criteria to determine an impact score:

• Does the Administrative Core have appropriate and effective administrative and organizational capabilities to support multidisciplinary research, to foster synergy, and to support planning and evaluation activities?
• Does the Administrative Core section clearly indicate that the collective operation of the whole Program will be managed in a coherent manner?
• Is there an organizational structure that will facilitate coordination and integration of progress?
• Is a process described that will resolve disagreements within the collective Program?
• Does the plan for collaborating with the SCGE TCDC demonstrate a clear willingness to ensure dissemination of the Program's data through the TCDC's platform?

Review Criteria - Resource Core(s)

Reviewers will provide only one adjectival rating for the Resource Core (criterion scoring is not used for this component). Reviewers will consider the following criteria to determine an impact score

• Does the Resource Core(s) offer supporting services to two or more Research Projects?
• Does each Resource Core address a critical need or technical barrier to progress in the Research Project components?
• Does the application describe how each Resource Core will respond to Research Project needs and other Program needs like dissemination of resources, products, and expertise to the greater research community?
• Does the proposed Core Lead offer appropriate expertise and sufficient independence from the Research Project components to distribute efforts and resources equitably?

Additional Review Criteria - Research Projects and Cores

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

Protections for Human Subjects

For research that involves human subjects but does not involve one of the categories of research that are exempt under 45 CFR Part 46, the committee 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 committee 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 committee 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 committee 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

Not Applicable

Renewals

Not Applicable

Revisions

Not Applicable

Additional Review Considerations - Research Projects and Cores

As applicable for the project or core 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 .

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

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

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

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

Appeals of initial peer review will not be accepted for applications submitted in response to this FOA

Applications will be assigned to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the appropriate national Advisory Council or Board. The following will be considered in making funding decisions:

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

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 theNIH 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.

Recipients must comply with any funding restrictions described in Section IV.6. 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: Grantee 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 recipient must provide NIH copies of documents related to all major changes in the status of ongoing protocols.

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: Generaland Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Recipients, and Activities, including of note, but not limited to:

• Federalwide Research Terms and Conditions
• Prohibition on Certain Telecommunications and Video Surveillance Services or Equipment
• Acknowledgment of Federal Funding

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

Should the applicant organization successfully compete for an award, 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 (including gender identity, sexual orientation, and pregnancy). This includes ensuring programs are accessible to persons with limited English proficiency and persons with disabilities. 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 https://www.hhs.gov/civil-rights/for-individuals/nondiscrimination/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.

Recipients of FFA must ensure that their programs are accessible to persons with limited English proficiency. For guidance on meeting the legal obligation to take reasonable steps to ensure meaningful access to programs or activities by limited English proficient individuals see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/fact-sheet-guidance/index.htmlandhttps://www.lep.gov.

• For information on an institution's specific legal obligations for serving qualified individuals with disabilities, including reasonable accommodations and making services accessible to them, see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html.

• HHS funded health and education programs must be administered in an environment free of sexual harassment, see https://www.hhs.gov/civil-rights/for-individuals/sex-discrimination/index.html; For information about NIH's commitment to supporting a safe and respectful work environment, who to contact with questions or concerns, and what NIH's expectations are for institutions and the individuals supported on NIH-funded awards, please see https://grants.nih.gov/grants/policy/harassment.htm.

• For guidance on administering programs in compliance with applicable federal conscience protection and associated anti-discrimination laws see https://www.hhs.gov/conscience/conscience-protections/index.html and https://www.hhs.gov/conscience/religious-freedom/index.html.

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 and 2 CFR Part 200.206 Federal awarding agency review of risk posed by applicants. This provision will apply to all NIH grants and cooperative agreements except fellowships.

The following special terms of the award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Part 75, 2 CFR Part 200 and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the recipients is anticipated during the performance of the activities. Under the cooperative agreement, the NIH's purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility reside with the recipients for the project, although specific tasks and activities may be shared among the recipients and the NIH as defined below.

The PD(s)/PI(s) will have the primary responsibility for:

• Determining research approaches, designing protocols, setting project milestones, and conducting research.
• Participating in group activities, including a Consortium-wide SCGE Program Steering Committee and subcommittees as needed.
• The SCGE Consortium will meet in person at least twice a year and the SCGE Program Steering Committee will recommend the frequency of other in-person and teleconference meetings.
• Providing reports and data in a timely fashion as agreed upon by the SCGE Program Steering Committee.
• Submitting all required data, SOPs, protocols, and resources as soon as they are scheduled for submission to the SCGE TCDC for quality control and compilation in the SCGE Phase II Platform.
• Preparing abstracts, presentations, and publications and collaborating Consortium-wide in making the public and professionals aware of the program.
• Assessing and disseminating data, protocols, and methods developed for or derived from the SCGE program within and outside the Consortium.
• Adhering to policies regarding data sharing and publication established by the NIH and the SCGE Program Steering Committee.
• Abiding by common definitions, protocols, and procedures, as chosen by a majority vote of the SCGE Program Steering Committee.
• Submitting periodic progress reports in a standard format, as agreed upon by the SCGE Program Steering Committee and NIH SCGE Working Group.
• Attending and participating in SCGE Program Steering Committee meetings; accepting and implementing decisions by the NIH SCGE Working Group, as appropriate.
• Overseeing all aspects of the organization and execution of the studies outlined in the application and approved by NIH Working Group Program Staff after peer review.
• Putting all study materials and procedure manuals into the public domain. Recipients are expected to publish and publicly disseminate results, data, and other products of the study, concordant with governance policies and protocols. Publications and oral presentations of work performed under this agreement will require appropriate acknowledgment of support by NIH.
• Obtaining prior written approval of the Grants Management Specialist in consultation with the NIH Program Officer for any change in any of the key personnel identified in the Notice of Grant Award.

NIH staff have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:

• The NIH SCGE Working Group consists of NIH programmatic staff from multiple Institutes and Centers of the NIH as well as the Office of the Director.
• The NIH Project Scientist(s) will have substantial scientific and programmatic involvement during the conduct of this activity through technical assistance, advice, and coordination. However, the role of NIH staff will be to facilitate and not to direct the activities. The Project Scientist(s) will participate as members of the SCGE Program Steering Committee. The Project Scientist(s) will have the following substantial involvement:
• Participating with the other SCGE Program Steering Committee members in addressing issues that arise with SCGE planning, operation, assessment, and data analysis. The Project Scientist(s) will assist and facilitate the group process and not direct it.
• Serving as a liaison, helping to coordinate activities, including acting as a liaison to other NIH Institutes/Centers, and as an information resource for the recipients. The Project Scientist(s) will also help coordinate the efforts of the SCGE Consortium with other groups conducting similar efforts.
• Attending all SCGE Program Steering Committee meetings, assisting in developing standard operating procedures, and consistent policies for dealing with situations that require coordinated action. The Project Scientist(s) will be responsible for working with the grantee as needed to manage the logistic aspects of the SCGE program.
• Reporting periodically on SCGE progress to the Common Fund SCGE Working Group and through it to the NIH Common Fund.
• Serving on subcommittees of the SCGE Program Steering Committee as appropriate.
• Assisting recipients in the development, if needed, of policies for dealing with situations that require coordinated action.
• Providing advice in the management and technical performance of the award.
• Assisting in promoting the availability of the data and related resources developed in the course of this program to the scientific community at large.
• Participating in data analyses, interpretations, and, where warranted, co-authorship of the publication of results of studies conducted through the Program.
• Comparing actual results to the benchmarks and criteria identified in the application and negotiated prior to award; recipients who do not accomplish the negotiated milestones shall submit a milestone report which will include a discussion of why the milestones were not met in the agreed-upon timeframe and propose a corrective recruitment action plan. The corrective recruitment action plan shall include amended milestones, plans to achieve the amended milestones and any additional items required by NIH Working Group staff. The plan shall be provided to NIH Working Group staff no later than 2 months following the missed milestone.
• Other NIH SCGE Working Group staff may assist the recipient as designated by the Program Official.
• Additionally, an agency Program Official or IC Program Director will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice. Prior to funding an application, the Program Official will contact the applicant to discuss the proposed milestones and any changes suggested by NIH staff. The Program Official and Project Scientist will negotiate with the applicant and agree on a final set of approved milestones which will be specified in the Notice of Award.

NIH reserves the right to withhold funding or curtail an award in the event of:

• Substantive changes in the project, or failure to make sufficient progress toward the work scope with which NIH concurred, or
• Ethical or conflict of interest issues.

Areas of Joint Responsibility include:

The SCGE Program Steering Committee will serve as the main scientific body of the Program. The SCGE Program Steering Committee will be responsible for coordinating the activities being conducted by the program and is the committee through which the NIH SCGE Working Group formally interacts with the SCGE investigators. The SCGE Program Steering Committee membership will include PD(s)/PI(s) of each SCGE award (limited to one person for an award with multiple PIs), other staff as needed (ex-officio) and the NIH Project Scientist(s). The SCGE Program Steering Committee may add additional members, and other government staff may attend the SCGE Program Steering Committee meetings as desired. Each award recipient Steering Committee member will have one vote and the NIH Program Scientist(s) together will have one vote.

The SCGE Program Steering Committee may establish subcommittees as needed to address particular issues, which will include representatives from the Program and the NIH and possibly other experts. The SCGE Program Steering Committee will have the overall responsibility of assessing and prioritizing the progress of the various subcommittees.

The SCGE recipient agrees to work collaboratively to:

• Provide secure, accurate, and timely data, SOP, protocol, and resource submission.
• Participate in presenting and publishing new processes and substantive findings.
• Assess and disseminate the SCGE Phase II Platform.
• Participate in the governance of the SCGE program as a member of the SCGE Program Steering Committee.
• Interact with other relevant NIH activities, as needed, to promote synergy and consistency among similar projects.

Program Consultants (PCs):

• PCs will be responsible for reviewing and evaluating the progress of the entire SCGE program. PCs will also, as appropriate and at the request of the NIH SCGE Working Group, provide input to the NIH about the progress of the individual SCGE projects in meeting their individual and Consortium goals and milestones. The PCs will include 4-6 senior, non-federal scientific experts who are not directly involved in the activities of the SCGE program. NIH will appoint PCs and may adjust the roster of PCs in response to program needs. The SCGE POs, PSs, NIH SCGE Working Group, and other NIH staff may attend the PC meetings.
• The PCs will meet at least once a year, in conjunction with a meeting of the SCGE Program Steering Committee in the DC Metro area, to allow the PCs to interact directly with the recipients, and by phone or email, at other times as needed.
• Annually, the PC members will provide their individual assessments to the NIH of the progress of the SCGE Consortium, and, as necessary, will present recommendations regarding any changes to the SCGE program. The assessments and recommendations will be provided, through the NIH SCGE Working Group, to the Director of the Office of Strategic Coordination, NIH.

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. It will have three members: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual recipient. This special dispute resolution procedure does not alter the recipient's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

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

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. NIH FOAs outline intended research goals and objectives. Post award, NIH will review and measure performance based on the details and outcomes that are shared within the RPPR, as described at 45 CFR Part 75.301 and 2 CFR Part 200.301.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for recipients of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All recipients 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 the threshold. See the NIH Grants Policy Statement for additional information on this reporting requirement.

In accordance with the regulatory requirements provided at 45 CFR 75.113and 2 CFR Part 200.113 and Appendix XII to 45 CFR Part 75 and 2 CFR Part 200, 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 75and 2 CFR Part 200 Award Term and Condition 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.

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: [email protected] (preferred method of contact)
Telephone: 301-480-7075

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

Chris H. Boshoff Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-0664
Email: [email protected]

Center for Scientific Review (CSR)
Email: [email protected]

Shellie Wilburn, M.B.A.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-9231
Email: [email protected]

Section VIII. Other Information

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

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75 and 2 CFR Part 200.