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 1. Overview Information
Part 2. Full Text of the Announcement

Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

Background

FMR1-associated conditions are a collection of disparate conditions that all stem from cytosine-guanine-guanine (CGG) nucleotide repeat expansions in the 5 untranslated region of the FMR1 gene, located on the human X chromosome. These conditions include:

• Fragile X Syndrome (FXS), the most common inherited cause of intellectual and developmental disability (IDD)
• Fragile X-associated Tremor/Ataxia Syndrome (FXTAS), which leads to disabling neurological symptoms in middle-age and elderly adults
• Fragile X-associated Primary Ovarian Insufficiency (FXPOI), which can lead to infertility and/or early menopause in women

FMR1 mutations are categorized by the number of CGG repeats.

• Full mutation: more than ~200 repeats. Individuals with FXS carry the full mutation.
• Premutation: ~55-200 repeats. Individuals with FXTAS and FXPOI carry the premutation.
• Gray zone: ~44-55 repeats
• Typical: ~23-45 repeats
• Low Zone: fewer than ~23 repeats

In addition to the three specific FMR1-associated conditions listed above, recent research advances suggest that FMR1 mutations of various sizes may also be linked to a range of additional symptoms and conditions.

NIH support for research on FMR1-associated conditions crosses the translational spectrum, ranging from basic genetic, molecular, and cellular research to research involving animal models of disease to human clinical research. NIH efforts also span multiple institutes and offices, reflecting the wide-ranging importance to NIH of generating knowledge to improve the health of individuals with FMR1-associated conditions.

The NIH Fragile X Centers program was originally created in response to the Children's Health Act of 2000. Since that time, NIH-funded Fragile X Centers have produced numerous major advances in the field of FMR1-related research.

Purpose

This Funding Opportunity Announcement (FOA) invites applications for Centers for Collaborative Research in Fragile X and FMR1-Associated Conditions (hereafter termed "Fragile X Centers").

In recognition of the rapidly evolving landscape of FMR1-associated research, NIH recently published a new Strategic Plan for Research on FMR1-Associated Conditions. This Strategic Plan, which was developed in collaboration with many members of the Fragile X community, articulates NIH’s current research priorities, which are directed toward an overarching vision of accelerating the development of effective interventions to prevent or treat FMR1-associated conditions. Successful Fragile X Centers will be composed of multidisciplinary teams of basic, translational and clinical investigators collaborating to address one or more of the research priorities from the Strategic Plan that are specifically named below. Applications should strive to address complex, difficult-to-solve problems within these priority areas that are not readily addressed by standard investigator-initiated grant mechanisms and that can be completed within the proposed grant period.

Structural Requirements

Each Fragile X Center will consist of an administrative core and between 2-3 interdependent and interrelated research projects. Meaningful and committed interactions among projects and disciplines must be evident. Projects may share materials, results, data, patient populations, or methodologies. Results of one project may well affect the understanding and interpretation of data from another project and thereby influence the nature of the research performed in one or more of the other projects. In addition, each project must have goals and objectives that focus on a common unifying theme that integrates the projects.

Specific Areas of Research Interest

Research projects should address one or more of the following three priority research areas drawn from the NIH FMR1 Strategic Plan:

(1) Identify novel mechanisms and targets for intervention across models of FMR1-associated conditions

• Characterize genetic and epigenetic mechanisms that underlie FMR1-associated conditions, including
• the stability/instability of CGG repeats and potential modifiers of repeat expansions
• the role of repeat-associated non-AUG (RAN) translation in the pathophysiology of premutation conditions
• Characterize brain circuit/network-level mechanisms that underlie key features of human phenotypes and may be amenable to therapeutic interventions

Such studies may require development and validation of cellular and animal models that more closely mimic the genetics, physiology, phenotypes and development of FMR1-associated conditions in humans.

(2) Develop and validate biomarkers that translate across human and animal models

• Conduct concomitant, iterative studies of biomarkers that are conserved across human and animal models of FMR1-associated conditions and thus have the potential to accelerate bidirectional translation of discoveries. Research addressing this priority area must include both animal studies and preliminary human validation research using carefully standardized human samples or human clinical studies.

(3) Characterize phenotypes of FMR1-associated conditions and risk factors for disease severity across developmental stages and diverse populations

• Conduct natural history studies to characterize the evolution of phenotypes over time, and identify genetic and environmental influences upon key phenotypes
• In the case of premutation conditions, such natural history studies may require validation of diagnostic criteria to facilitate accurate and timely identification of affected individuals
• Any such efforts must include individuals from diverse racial, ethnic and socioeconomic backgrounds

Applications that do not address one or more of the above priority research areas will not be considered responsive to this funding opportunity.

In addition, Centers must propose hypothesis-driven projects, as appropriate, that include at least two distinct levels of analysis within one or more species.

For studies involving brain/behavioral outcomes, investigators should choose at least two from among the following levels of analysis:

• genomic/molecular measures
• circuit/network measures
• clinical/behavioral measures

Projects involving brain/behavioral outcomes must include human subjects or human materials (e.g. human tissues, human-derived cell lines) as one of the species being studied.

Circuit/network measures are defined as taking data from at least two brain regions simultaneously, such as dorsolateral prefrontal cortex and posterior parietal cortex, or at least two simultaneous measurements from within one brain region, such as multielectrode arrays within a cortical area, laminar arrays within a cortical column, or CA3 and CA1 recordings from hippocampus. Parallel use of animals and humans is strongly encouraged. Applications can include genomic manipulations for gene reactivation in animals. In addition to cognitive and behavioral outcomes, assessments of clinical neurophysiology and the study of stereotypies, sensory issues, motor planning and hypotonia are also of interest.

For studies involving reproductive outcomes, investigators should choose at least two from among the following levels of analysis:

• genomic/molecular measures
• endocrine measures
• tissue specific and/or cell-type specific measures
• clinical/whole organism measures

Endocrine measures include studies of hypothalamic-pituitary-gonadal (HPG) hormone levels and feedback loops of the HPG axis or other reproductive hormonal signaling systems. Tissue-specific outcomes include studies of the gonads or their functional units (e.g., ovary, ovarian cortex, follicles), and cell-type specific measures would address functional or structural changes to granulosa, theca, ovarian stromal cell, or oocytes. Clinical/whole organism outcomes include reproductive outcomes (e.g., fertility, fecundity, response to ovulatory challenge, follicle count, age at menopause/reproductive decline) and comorbid conditions.

For studies involving outcomes in other organ systems or clinical domains, investigators should choose at least two from among the following levels of analysis:

• genomic/molecular measures
• tissue-specific/organ-level measures
• clinical/whole organism measures

Investigators are strongly encouraged to consult with relevant NIH program staff in ensuring that the proposed studies will be considered to meet this requirement for multiple levels of analysis.

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

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

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)

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

Other

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

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

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

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

Applicant Organizations

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

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• System for Award Management (SAM) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
• NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
• eRA Commons - Applicants must have an active DUNS number to register in eRA Commons. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration, but all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

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

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

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.

Center PD(s)/PI(s) cannot serve as the Lead of a core or research project on another active Fragile X Center.

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

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

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

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101).

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.

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.

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:

Tracy M. King, MD, MPH
Telephone: 301-402-1822
Email: tracy.king@nih.gov

Available Component Types	Research Strategy/Program Plan Page Limits
Overall	12 pages
Admin Core	6 pages
Project	12 pages per project

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

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; minimum 1, maximum 1
• Projects: required; minimum 2, maximum 3

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.

Complete entire form.

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

Follow standard instructions.

Facilities and Other Resources:

Each application must provide a statement that addresses how the institutional commitment will be established and sustained, and how the Center's research effort will be prioritized within the participating institution(s).

Describe institutional commitment to tenured faculty positions, dedicated space and other resources, and sufficient time release to allow the investigators to pursue the goals of the Center.

Describe institutional commitment that promotes the mission of team-based research.

Describe how the environment and infrastructure of the Center are beneficial in accomplishing the goals of the projects.

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.

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

Describe the roles of Senior/Key persons for the Center. The applicant is expected to integrate junior faculty-level investigators within the structure of the Center.

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.

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.

Specific Aims: Provide a summary of the Center's overall specific aims. They should clearly describe a common unifying theme for the Center that is also reflected in the individual research projects

Research Strategy: In the Research Strategy Section, provide an overview of the center including the following information:

Purpose of the Program - Discuss the overall P50 Center’s objectives and general plans for the proposed grant period.

Administrative Structure - Include information on the support and commitment of the parent institution for the program, the authority of the PD/PI. Describe the organizational framework and provide an organizational chart for the overall Center, including the Administrative Core and all Research Projects.

Research Program - Discuss the overall research program, highlighting its central theme. Explain the strategy for achieving the Center's goals, and how each research project relates to that strategy. The Center should be viewed as interrelated research projects, each of which is not only individually meritorious but is also complementary to the other projects and related to the overall theme developed for the Center. Describe how the proposed research will contribute to the development of effective prevention and treatment interventions for FMR1-associated conditions.

To be responsive to this funding opportunity, Centers must propose hypothesis-driven projects, as appropriate, that address one or more of the three priority areas from the NIH FMR1 strategic plan described in Section I. Proposed projects must include at least two distinct levels of analysis within one or more species, and, in studies involving brain/behavioral outcomes, must include human subjects or human materials (e.g. human tissues, human-derived cell lines). The priority areas, levels of analyses, and species being studied must be explicitly identified in the application.

Description of Assurances and Collaborative Agreements - Provide an overview and rationale for any collaborative and cooperative endeavors or subcontracts. Letters of Assurance/Agreement for these arrangements are included below.

Letters of Support: Provide Letters of Support/Assurance for the Center Overall. Letters of Support specific for individual projects should be placed in those sections of the application.

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:

Resource sharing is required. All applications, regardless of the amount of direct costs requested for any one year, must include a detailed Resource Sharing Plan. The degree to which a proposed Resource Sharing Plan is appropriate and consistent with the goals of the NIH Fragile X Centers program will be considered during peer review and by program staff as award decisions are being made.

NIH intends to maximize the availability of publications and the sharing of underlying data and biospecimens for FMR1-related projects. Applicants must describe plans, including a timeline, for making data and key biological resources publicly available. Data and resource sharing plans should also include the sharing of other resources (e.g., research tools and key reagents, analytic software code).

The NIMH Data Archive (NDA; formerly the National Database for Autism Research (NDAR)) houses research data of all types (genetic, imaging, clinical assessment, etc.) from human subjects involved in autism spectrum disorder (ASD) studies. All autism-related projects involving human subjects, including projects on Fragile X Syndrome, are required to contribute data to NDA, which will function as a data repository. NDA will be involved to facilitate sharing activities. Central clinical coordination and local data management for data cleaning and entry and bio-statistical consulting will be the responsibility of the research project. For more information on NDA, please visit https://ndar.nih.gov/.

Applications studying neurological outcomes and proposing to collect biospecimens are strongly encouraged to use the NINDS Biomarkers Repository BioSpecimen Exchange for Neurological Disorders (BioSEND). The NINDS BioSEND repository receives, processes, stores, and distributes biospecimen resources that can be shared by the neuroscience research community, and currently banks a variety of biospecimens including DNA, plasma, serum, RNA, CSF, and saliva. All specimens collected and banked with BioSEND must come from individuals who have consented to banking and sharing broadly with academia and industry. Applicants planning projects in which biospecimens will be collected are strongly advised to consult the NINDS Biomarkers Repository website for more information about samples banked at the repository (https://www.biosend.org). In addition, applicants are advised to consult with NINDS Biomarkers Repository staff to obtain a quote for biospecimen banking costs (email:biosend@iu.edu).

The following resource describing Common Data Elements may be helpful during the planning phases of a project when considering ways to optimize data collection in order to facilitate broad data sharing: https://www.nlm.nih.gov/cde/.

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

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

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.

Complete only the following fields:

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

Enter Human Embryonic Stem Cells in each relevant component.

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.

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.

• In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Core 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 forms appropriate for the specific component will be included in the application package.

Describe the specific functions of key scientific and technical personnel, consultants, collaborators and support staff. For all years, explain and justify any unusual items such as equipment purchase or alterations and renovations. For additional years of support requested, justify any significant increases in any category over the first 12-month budget period. No recurring annual escalations in costs are allowed.

Allowable costs for the Administrative Core may include:

• Salaries for the Center Director(s) (PD(s)/PI(s)) specifying a minimum total combined commitment of 1.8 person-months (15%) effort to the Center;
• Salaries and support for a limited number of administrative and clerical personnel, such as a Center Administrator, secretaries, and clerical support staff;
• Administrative support services, including supplies, duplication, telephone, and maintenance contracts for equipment when not covered by institutional F & A charges;
• Costs related to dissemination and communication of research results to investigators, the scientific community and lay public;
• Costs related to seminars or meetings designed to promote interdisciplinary interaction, education, or Center cohesiveness;
• Costs related to External Advisory Committee meetings;
• Travel to one Fragile X Centers meeting annually to confer with other Centers and program staff to promote scientific interaction. This meeting will be held in the Washington, DC area.

Costs that are NOT allowable include:

• Salary and support for central institutional administrative personnel usually paid from institutional F & A charges, such as budget officers, grant assistants, and building maintenance personnel;
• Salary and support for administrative activities such as public relations, health or educational services unrelated to the proposed research.

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.

Specific Aims: Describe the goals of the Administrative Core and how these goals will contribute to substantial and sustained support of the Fragile X Center. The specific aims should address plans for communication and coordination across projects and participating sites.

Research Strategy: The Research Strategy section must provide a description of the following items:

• Purpose of the Core
• Organizational structure and staffing of the Core (professional and support staff)
• Services provided to Center Research Projects
• Management plan for the overall center, including management of contractual agreements, resource sharing activities, and publication plans.
• Plans for communicating and collaborating with other NIH-funded Fragile X Centers wherever possible.
• Dissemination and Outreach efforts. Such efforts should occur at all stages of research, ranging from identification of key study outcomes to recruitment of study participants to dissemination of research findings.
• Advisory Committee - The Administrative Core must establish an External Advisory Committee including external scientific and lay members. Describe the types of individuals who will be appointed to the committee, but specific individuals should not be named or contacted.
• Evaluation Plan. A plan should be articulated for evaluating center activities on at least an annual basis. This should include specific steps for reporting and responding to evaluation findings.

Letters of Support: Only letters of support specific to the Administrative Core should be attached to 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:

Resource sharing is required. All applications, regardless of the amount of direct costs requested for any one year, must include a detailed Resource Sharing Plan. The degree to which a proposed Resource Sharing Plan is appropriate and consistent with the goals of the NIH Fragile X Centers program will be considered during peer review and by program staff as award decisions are being made.

NIH intends to maximize the availability of publications and the sharing of underlying data and biospecimens for FMR1-related projects. Applicants must describe plans, including a timeline, for making data and key biological resources publicly available. Data and resource sharing plans should also include the sharing of other resources (e.g., research tools and key reagents, analytic software code).

The NIMH Data Archive (NDA; formerly the National Database for Autism Research (NDAR)) houses research data of all types (genetic, imaging, clinical assessment, etc.) from human subjects involved in autism spectrum disorder (ASD) studies. All autism-related projects involving human subjects, including projects on Fragile X Syndrome, are required to contribute data to NDA, which will function as a data repository. NDA will be involved to facilitate sharing activities. Central clinical coordination and local data management for data cleaning and entry and bio-statistical consulting will be the responsibility of the research project. For more information on NDA, please visit https://ndar.nih.gov/.

Applications studying neurological outcomes and proposing to collect biospecimens are strongly encouraged to use the NINDS Biomarkers Repository BioSpecimen Exchange for Neurological Disorders (BioSEND). The NINDS BioSEND repository receives, processes, stores, and distributes biospecimen resources that can be shared by the neuroscience research community, and currently banks a variety of biospecimens including DNA, plasma, serum, RNA, CSF, and saliva. All specimens collected and banked with BioSEND must come from individuals who have consented to banking and sharing broadly with academia and industry. Applicants planning projects in which biospecimens will be collected are strongly advised to consult the NINDS Biomarkers Repository website for more information about samples banked at the repository (https://www.biosend.org). In addition, applicants are advised to consult with NINDS Biomarkers Repository staff to obtain a quote for biospecimen banking costs (email:biosend@iu.edu).

The following resource describing Common Data Elements may be helpful during the planning phases of a project when considering ways to optimize data collection in order to facilitate broad data sharing: https://www.nlm.nih.gov/cde/.

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.

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

When preparing your application, 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 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.

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)

As noted previously, Research Projects proposed for inclusion in a Fragile X Center should be interdependent and interrelated projects that strive to address complex, difficult-to-solve problems within the identified priority areas that are not readily addressed by standard investigator-initiated grant mechanisms and that can be completed within the proposed grant period.

Specific Aims: Provide a description of specific aims for the research project. Identify the goal areas from the FMR1 strategic plan and the priority topic(s) for this RFA that will specifically be addressed by the proposed research.

Research Strategy: Follow the instructions in the SF424 Application Guide. In addition, the Research Strategy section should address the following items.

Describe the relationship of the Project to the overall theme of the Center and the interactions with other Research Projects. A compelling case should be presented describing how collaborations between projects and participating investigators are expected to yield results beyond those achievable if each project were pursued separately and without formal interaction among the participating investigators.

For any project that involves preclinical research, describe what measures will be taken to assure adequate rigor with regard to experimental design, minimizing bias, interpretation of results, and transparency of reporting.

Any clinical trials proposed as part of a Fragile X Center must be mechanistic or early stage proof-of-concept trials. Such clinical trials should be designed to provide insight into the biological or behavioral processes underlying FMR1-associated conditions, or provide specific data necessary to design a subsequent definitive efficacy trial.

Examples of relevant clinical trials or studies include, but are not limited to, the following:

• Studies aimed at elucidating potential mechanisms by which interventions act to modify outcomes of interest.
• Studies designed to evaluate whether an intervention produces sufficient evidence of short-term activity (e.g., biomarker activity) in humans to justify an efficacy trial.
• Studies to identify inclusion and exclusion criteria to be applied in a subsequent efficacy trial.

When proof-of-concept trials are proposed, there should be strong evidence provided in support of the potential value and feasibility of the study, including a clear preclinical rationale if applicable, unimpaired regulatory status, evidence of drug/biologic availability for use in a trial, and agreement of all participating clinical/corporate partners.

This funding opportunity will not support clinical trials that seek to answer specific questions about safety, tolerability, clinical efficacy, effectiveness, clinical management, and/or implementation of pharmacologic, behavioral, biologic, surgical, or device (invasive or non-invasive) interventions, preventive, therapeutic, and services interventions. Applicants are strongly advised to consult with relevant NIH Scientific/Research staff prior to submitting an application.

Letters of Support: Only letters of support specific to this Research Project should be attached to 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:

Resource sharing is required. All applications, regardless of the amount of direct costs requested for any one year, must include a detailed Resource Sharing Plan. The degree to which a proposed Resource Sharing Plan is appropriate and consistent with the goals of the NIH Fragile X Centers program will be considered during peer review and by program staff as award decisions are being made.

NIH intends to maximize the availability of publications and the sharing of underlying data and biospecimens for FMR1-related projects. Applicants must describe plans, including a timeline, for making data and key biological resources publicly available. Data and resource sharing plans should also include the sharing of other resources (e.g., research tools and key reagents, analytic software code).

The NIMH Data Archive (NDA; formerly the National Database for Autism Research (NDAR)) houses research data of all types (genetic, imaging, clinical assessment, etc.) from human subjects involved in autism spectrum disorder (ASD) studies. All autism-related projects involving human subjects, including projects on Fragile X Syndrome, are required to contribute data to NDA, which will function as a data repository. NDA will be involved to facilitate sharing activities. Central clinical coordination and local data management for data cleaning and entry and bio-statistical consulting will be the responsibility of the research project. For more information on NDA, please visit https://ndar.nih.gov/.

Applications studying neurological outcomes and proposing to collect biospecimens are strongly encouraged to use the NINDS Biomarkers Repository BioSpecimen Exchange for Neurological Disorders (BioSEND). The NINDS BioSEND repository receives, processes, stores, and distributes biospecimen resources that can be shared by the neuroscience research community, and currently banks a variety of biospecimens including DNA, plasma, serum, RNA, CSF, and saliva. All specimens collected and banked with BioSEND must come from individuals who have consented to banking and sharing broadly with academia and industry. Applicants planning projects in which biospecimens will be collected are strongly advised to consult the NINDS Biomarkers Repository website for more information about samples banked at the repository (https://www.biosend.org). In addition, applicants are advised to consult with NINDS Biomarkers Repository staff to obtain a quote for biospecimen banking costs (email:biosend@iu.edu).

The following resource describing Common Data Elements may be helpful during the planning phases of a project when considering ways to optimize data collection in order to facilitate broad data sharing: https://www.nlm.nih.gov/cde/.

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 (Research Project)

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

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.

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.

This initiative is not subject to intergovernmental review.

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.

Mechanistic or early proof-of-concept clinical trials involving the testing of new investigational therapeutics, new indications for FDA-approved drugs, or other medical interventions under a research protocol must be performed under an IND/IDE, unless otherwise agreed upon by the FDA.

If not exempt, applicants must provide evidence of IND/IDE approval, or at a minimum, IND/IDE filing, at the time of submission. This should include the name and organization of the IND/IDE holder, the date the IND/IDE was filed with the FDA, the FDA IND/IDE number, and any comments from the FDA. Studies will not be funded unless necessary regulatory approval has first been obtained; regulatory approval at the time of submission is strongly preferred.

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 field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH.

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

See more tips for avoiding common errors.

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

Prior Consultation with Scientific/Program Staff

Consultation with the appropriate Institute or Center (IC) staff prior to the application due date is strongly encouraged for all applicants. If requested, IC staff will consider whether the proposed research addresses one or more high priority research areas and meets the goals and mission of the Institute/Center. IC staff will not evaluate the technical and scientific merit of the proposed project; technical and scientific merit will be determined during peer review using the review criteria indicated in this FOA. During the consultation phase, if the proposed application is not seen as responsive to this FOA's priorities, applicants will be strongly encouraged to consider other funding opportunities.

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.

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

For this particular announcement, the overall score for applications will emphasize the interrelatedness and synergy among the proposed research projects, as reflected by meaningful and committed interactions among projects and disciplines; sharing of materials, results, data, patient populations, or methodologies between projects as appropriate; and integration around a common unifying theme.

The review will evaluate the potential for the Center as a whole to have a significant impact on the field during the terms of the award, weighing the balance of more conventional approaches with highly innovative components or projects in which success is not guaranteed. The overall score for the center application may be higher or lower than the average of the individual components based on the assessment of whether the whole is greater than the sum of its parts.

In addition, for applications involving clinical trials

A proposed Clinical Trial application may include study design, methods, and intervention that are not by themselves innovative but address important questions or unmet needs. Additionally, the results of the clinical trial may indicate that further clinical development of the intervention is unwarranted or lead to new avenues of scientific investigation.

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the Center 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 projects 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.

Does the Center 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 Center 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?

Will the proposed Center make an important contribution to one or more of the identified priority areas from the NIH FMR1 strategic plan? Will the proposed work move the field toward the overarching vision of accelerating the development of effective interventions to prevent or treat FMR1-associated conditions?

In addition, for applications involving clinical trials

Are the scientific rationale and need for a clinical trial to test the proposed hypothesis or intervention well supported by preliminary data, clinical and/or preclinical studies, or information in the literature or knowledge of biological mechanisms? For trials focusing on clinical or public health endpoints, is this clinical trial necessary for testing the safety, efficacy or effectiveness of an intervention that could lead to a change in clinical practice, community behaviors or health care policy? For trials focusing on mechanistic, behavioral, physiological, biochemical, or other biomedical endpoints, is this trial needed to advance scientific understanding?

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the Center? 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?

Do the proposed PD(s)/PI(s) have appropriate experience and expertise to lead a multi-project center? Will junior faculty-level investigators be integrated within the structure of the Center?

In addition, for applications involving clinical trials

With regard to the proposed leadership for the project, do the PD/PI(s) and key personnel have the expertise, experience, and ability to organize, manage and implement the proposed clinical trial and meet milestones and timelines? Do they have appropriate expertise in study coordination, data management and statistics? For a multicenter trial, is the organizational structure appropriate and does the application identify a core of potential center investigators and staffing for a coordinating center?

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?

Does the proposed research have the potential for transformative (rather than incremental) progress in the field of FMR1 research?

In addition, for applications involving clinical trials

Does the design/research plan include innovative elements, as appropriate, that enhance its sensitivity, potential for information or potential to advance scientific knowledge or clinical practice?

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the Center? Have 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? Is the Resource Sharing Plan adequate and appropriate for the proposed research?

If the Center 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?

In addition, for applications involving clinical trials

Does the application adequately address the following, if applicable?

Study Design

Is the study design justified and appropriate to address primary and secondary outcome variable(s)/endpoints that will be clear, informative and relevant to the hypothesis being tested? Is the scientific rationale/premise of the study based on previously well-designed preclinical and/or clinical research? Given the methods used to assign participants and deliver interventions, is the study design adequately powered to answer the research question(s), test the proposed hypothesis/hypotheses, and provide interpretable results? Is the trial appropriately designed to conduct the research efficiently? Are the study populations (size, gender, age, demographic group), proposed intervention arms/dose, and duration of the trial, appropriate and well justified?

Are potential ethical issues adequately addressed? Is the process for obtaining informed consent or assent appropriate? Is the eligible population available? Are the plans for recruitment outreach, enrollment, retention, handling dropouts, missed visits, and losses to follow-up appropriate to ensure robust data collection? Are the planned recruitment timelines feasible and is the plan to monitor accrual adequate? Has the need for randomization (or not), masking (if appropriate), controls, and inclusion/exclusion criteria been addressed? Are differences addressed, if applicable, in the intervention effect due to sex/gender and race/ethnicity?

Are the plans to standardize, assure quality of, and monitor adherence to, the trial protocol and data collection or distribution guidelines appropriate? Is there a plan to obtain required study agent(s)? Does the application propose to use existing available resources, as applicable?

Data Management and Statistical Analysis

Are planned analyses and statistical approach appropriate for the proposed study design and methods used to assign participants and deliver interventions? Are the procedures for data management and quality control of data adequate at clinical site(s) or at center laboratories, as applicable? Have the methods for standardization of procedures for data management to assess the effect of the intervention and quality control been addressed? Is there a plan to complete data analysis within the proposed period of the award?

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?

Is the Center able to provide adequate infrastructure to support the proposed research across all performance sites? Is the academic and physical environment as it bears on research subjects, space, and equipment, and on the potential for interaction with scientists from other departments and institutions conducting relevant research, sufficient and conducive for the Center as a whole?

In addition, for applications involving clinical trials

If proposed, are the administrative, data coordinating, enrollment and laboratory/testing centers, appropriate for the trial proposed?

Does the application adequately address the capability and ability to conduct the trial at the proposed site(s) or centers? Are the plans to add or drop enrollment centers, as needed, appropriate?

If international site(s) is/are proposed, does the application adequately address the complexity of executing the clinical trial?

If multi-sites/centers, is there evidence of the ability of the individual site or center to: (1) enroll the proposed numbers; (2) adhere to the protocol; (3) collect and transmit data in an accurate and timely fashion; and, (4) operate within the proposed organizational structure?

As applicable for the Center 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.

Integration of the Overall Center

A major emphasis is the integration or centeredness of the overall program. The Center will be evaluated as an integrated collection of activities oriented around a central theme. The reviewers will evaluate the following:

• Does the program function as a true Center rather than a collection of individual research projects, with the sum of the parts being greater than the individual components?
• To what extent will proposed communication, coordination and collaboration efforts between various Center components, with other NIH-funded Fragile X Centers, and among key stakeholders accelerate the Center's progress?
• Is value added by having the proposed Research Projects comprise a Center that allows the Center to leverage additional resources that would not have been possible without an integrated Center structure?
• Is the Center multidisciplinary in scope and does it have the ability to catalyze significant research advances in FMR1-associated research?
• Is a dissemination plan integrated with the scientific goals of the Center and likely to fulfill the purpose of facilitating communication among stakeholders, including families affected by FMR1-associated conditions?

Study Timeline

Specific to applications involving clinical trials

Is the study timeline described in detail, taking into account start-up activities, the anticipated rate of enrollment, and planned follow-up assessment? Is the projected timeline feasible and well justified? Does the project incorporate efficiencies and utilize existing resources (e.g., CTSAs, practice-based research networks, electronic medical records, administrative database, or patient registries) to increase the efficiency of participant enrollment and data collection, as appropriate?

Are potential challenges and corresponding solutions discussed (e.g., strategies that can be implemented in the event of enrollment shortfalls)?

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.

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.

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.

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.

Not Applicable

Not Applicable

Not Applicable

As applicable for the Center 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.

Not Applicable

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).

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 .

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.

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

• Reviewers will assign an impact score to the Administrative Core based on the following review criteria:
• How well does the Administrative Core fit into the central theme of the Center?
• Does the proposed Core Director have adequate experience in the administration of large research centers?
• Does the application clearly describe and justify the proposed Administrative Core operational plan and organizational structure?
• Does the application describe adequate plans for management of day-to-day program activities?
• Does the application adequately describe plans for implementation of the Resource Sharing Plan?
• Does the application include adequate provisions for dissemination and outreach efforts to support all stages of the proposed research and to share study progress with relevant stakeholders? Where appropriate, do these plans include strategies for communicating information to diverse populations, including non-English-speaking people and racial and ethnic minorities?
• Does the application include an appropriate plan for program evaluation, including convening an External Advisory Committee (EAC) with appropriate scientific and lay expertise, and specific procedures for acting upon evaluation findings and EAC recommendations?

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for each Research Project to exert a sustained, powerful influence on the field of FMR1-associated research, in consideration of the following review criteria and additional review criteria (as applicable for the projects 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 scientific project that by its nature is not especially innovative or one that is highly innovative with little pilot data -- could both be essential to advance a field.

Significance

Does the Research 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 Research 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?

Will the Center structure facilitate the Research Project's ability to make substantive advances in the field? If high-risk or exploratory, does the Research Project have the potential to achieve transformative, paradigm-shifting advances in the field?

In addition, for applications proposing clinical trials:

Are the scientific rationale and need for a clinical trial to test the proposed hypothesis or intervention well supported by preliminary data, clinical and/or preclinical studies, or information in the literature or knowledge of biological mechanisms? For trials focusing on mechanistic, behavioral, physiological, biochemical, or other biomedical endpoints, is this trial needed to advance scientific understanding?

Investigator(s)

Are the Project Lead(s), collaborators, and other researchers well suited to the Research 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 Research Project?

Are trainees and junior faculty-level investigators appropriately integrated into the proposed research?

In addition, for applications proposing clinical trials:

With regard to the proposed leadership for the project, do the PD/PI(s) and key personnel have the expertise, experience, and ability to organize, manage and implement the proposed clinical trial and meet milestones and timelines? Do they have appropriate expertise in study coordination, data management and statistics? For a multicenter trial, is the organizational structure appropriate and does the application identify a core of potential center investigators and staffing for a coordinating center?

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?

Does the proposed research have the potential for transformative (rather than incremental) progress in the field of FMR1 research?

In addition, for applications proposing clinical trials:

Does the design/research plan include innovative elements, as appropriate, that enhance its sensitivity, potential for information or potential to advance scientific knowledge or clinical practice?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the Research Project? Have 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 Research 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? Is the Resource Sharing Plan adequate and appropriate for the proposed research?

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?

Is adequate rigor incorporated into study design, analysis, interpretation, and reporting? If the Research Project is high-risk or exploratory, will interpretable results be obtained?

How do the methods for the proposed project fit into the Center's overall proposal to utilize multiple levels of analysis to address the central research theme of the Center? Is the Research Project well integrated into the Center as a whole?

In addition, for applications proposing clinical trials:

Does the application adequately address the following, if applicable?

Study Design

Is the study design justified and appropriate to address primary and secondary outcome variable(s)/endpoints that will be clear, informative and relevant to the hypothesis being tested? Is the scientific rationale/premise of the study based on previously well-designed preclinical and/or clinical research? Given the methods used to assign participants and deliver interventions, is the study design adequately powered to answer the research question(s), test the proposed hypothesis/hypotheses, and provide interpretable results? Is the trial appropriately designed to conduct the research efficiently? Are the study populations (size, gender, age, demographic group), proposed intervention arms/dose, and duration of the trial, appropriate and well justified?

Are potential ethical issues adequately addressed? Is the process for obtaining informed consent or assent appropriate? Is the eligible population available? Are the plans for recruitment outreach, enrollment, retention, handling dropouts, missed visits, and losses to follow-up appropriate to ensure robust data collection? Are the planned recruitment timelines feasible and is the plan to monitor accrual adequate? Has the need for randomization (or not), masking (if appropriate), controls, and inclusion/exclusion criteria been addressed? Are differences addressed, if applicable, in the intervention effect due to sex/gender and race/ethnicity?

Are the plans to standardize, assure quality of, and monitor adherence to, the trial protocol and data collection or distribution guidelines appropriate? Is there a plan to obtain required study agent(s)? Does the application propose to use existing available resources, as applicable?

Data Management and Statistical Analysis

Are planned analyses and statistical approach appropriate for the proposed study design and methods used to assign participants and deliver interventions? Are the procedures for data management and quality control of data adequate at clinical site(s) or at center laboratories, as applicable? Have the methods for standardization of procedures for data management to assess the effect of the intervention and quality control been addressed? Is there a plan to complete data analysis within the proposed period of the award?

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 Research Project proposed? Will the Research Project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

In addition, for applications proposing clinical trials:

If proposed, are the administrative, data coordinating, enrollment and laboratory/testing centers, appropriate for the trial proposed?

Does the application adequately address the capability and ability to conduct the trial at the proposed site(s) or centers? Are the plans to add or drop enrollment centers, as needed, appropriate?

If international site(s) is/are proposed, does the application adequately address the complexity of executing the clinical trial?

If multi-sites/centers, is there evidence of the ability of the individual site or center to: (1) enroll the proposed numbers; (2) adhere to the protocol; (3) collect and transmit data in an accurate and timely fashion; and, (4) operate within the proposed organizational structure?

As applicable for the Research 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.

Study Timeline

Specific to applications proposing clinical trials

Is the study timeline described in detail, taking into account start-up activities, the anticipated rate of enrollment, and planned follow-up assessment? Is the projected timeline feasible and well justified? Does the project incorporate efficiencies and utilize existing resources (e.g., CTSAs, practice-based research networks, electronic medical records, administrative database, or patient registries) to increase the efficiency of participant enrollment and data collection, as appropriate?

Are potential challenges and corresponding solutions discussed (e.g., strategies that can be implemented in the event of enrollment shortfalls)?

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 Center as a whole or specific Research 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 five points: 1) proposed use of the animals, and species, strains, ages, sex, and numbers to be used; 2) justifications for the use of animals and for the appropriateness of the species and numbers proposed; 3) adequacy of veterinary care; 4) procedures for limiting discomfort, distress, pain and injury to that which is unavoidable in the conduct of scientifically sound research including the use of analgesic, anesthetic, and tranquilizing drugs and/or comfortable restraining devices; and 5) methods of euthanasia and reason for selection if not consistent with the AVMA Guidelines on Euthanasia. 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 Research Project, 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.

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.

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s), convened by NICHD 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:

• 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.
• Will receive a written critique.

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 National Advisory Child Health and Human Development (NACHHD) Council. 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.

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.

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

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

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

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

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

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

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

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

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

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

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person’s race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency. 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. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/index.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-individuals/section-1557/index.html; and https://www.hhs.gov/civil-rights/for-providers/laws-regulations-guidance/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see https://www.hhs.gov/civil-rights/for-individuals/disability/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. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

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

Cooperative Agreement Terms and Conditions of Award

Not Applicable

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

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

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

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

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: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-945-7573

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

Tracy King, M.D., M.P.H.
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-402-1822
Email: tracy.king@nih.gov

Bettina Buhring, Ph.D.
National Institute of Mental Health (NIMH)
Phone: 301-443-1576
Email: bettina.buhring@nih.gov

Lisa Gilotty, Ph.D.
National Institute of Mental Health (NIMH)
Phone: 301-443-3825
Email: gilottyl@mail.nih.gov

Laura Mamounas, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-5745
Email: mamounal@ninds.nih.gov

Tiina K. Urv, Ph.D.
National Center for Advancing Translational Sciences (NCATS)
Telephone: 301-827-2746
Email: urvtiin@mail.nih.gov

Sherry Dupere, Ph.D.
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-451-3415
Email: duperes@mail.nih.gov

Bonnie Jackson
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-496-5482
Email: jacksonbo@mail.nih.gov

Tamara Kees
National Institute of Mental Health (NIMH)
Telephone: 301-443-8811
Email: tamara.kees@nih.gov

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

Brian Quillin II
National Center for Advancing Translational Sciences (NCATS)
Telephone: 301-443-4295
Email: brian.quillin@nih.gov

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.