Part 1. Overview Information

Key Dates

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

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

No late applications will be accepted for this Notice of Funding Opportunity (NOFO).

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

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

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



Table of Contents
Part 1. Overview Information
Key Dates
Part 2. Full Text of Announcement
Section I. Notice of Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

Part 2. Full Text of Announcement

Section I. Notice of Funding Opportunity Description

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
• Fragile X-associated Neuropsychiatric Disorder (FXAND), a constellation of neuropsychiatric symptoms seen in children and adults

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, FXPOI and FXAND carry the premutation.
• Gray zone: ~45-55 repeats
• Typical: ~23-44 repeats
• Low Zone: fewer than ~23 repeats

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. 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 clinical observational studies and clinical trials.

Despite many remarkable advances in fundamental knowledge about FMR1-associated conditions and identification of promising targets for intervention in cellular and animal models, many therapeutics tested in individuals with FXS and other FMR1-associated conditions have failed to demonstrate efficacy in rigorous clinical trials.  Substantial gaps in understanding remain about the processes that drive the variability in clinical features (“phenotypic heterogeneity”) and variation in responses to interventions seen among individuals with FMR1-associated conditions across ages, developmental stages, genetic backgrounds, and socioenvironmental contexts. Furthermore, there is a need to identify novel targets for intervention and validated, translatable biomarkers for potential use in clinical trials. 

Purpose

This Notice of Funding Opportunity (NOFO) invites new applications for Centers for Collaborative Research in Fragile X and FMR1-Associated Conditions ("Fragile X Centers").

In this round of competition, each center will be required to identify an overarching theme directed at one or more of these three research areas in one or more FMR1-associated condition(s): (1) identifying, characterizing, and/or modeling factors that predict subgroup- or individual-level differences in clinical features (“phenotypic heterogeneity”) and/or responses to specific interventions; (2) identifying novel mechanisms and targets for intervention that modulate symptom severity or therapeutic efficacy; or (3) identifying and/or validating translatable biomarkers and/or outcome measures for potential use in clinical trials. This focus is driven by a convergence of the following considerations:

• The wide variability in phenotypes seen in all FMR1-associated conditions that is not explained by repeat size, patterns of X chromosome inactivation, or other existing knowledge regarding the FMR1 gene and its transcription/translation products.
• The use of a limited number of cellular and animal models in FMR1 research, which limits the ability of researchers to understand the pathophysiology of FMR1-associated conditions in order to identify targets for intervention. 
• The limited number of cellular and animal models also impairs the ability of researchers to fully replicate the phenotypic heterogeneity seen among affected individuals, and to model the potential impact of genetic background and epigenetic variation on clinical manifestations of FMR1-associated conditions.
• The lack of sensitive, specific, and well-validated biomarkers and outcome measures that could be used to assess treatment efficacy in future clinical trials. 
• The lack of efficacy seen across multiple clinical trials for FXS for numerous pharmacological agents with promising preclinical data.
• The overrepresentation of individuals with European ancestry, high household income, and/or high family education levels seen in many previous studies of FMR1-associated conditions, with resulting limitations in the ability to confidently generalize or extrapolate findings to populations from other ancestral groups or other socioenvironmental contexts.

Specific Areas of Research Interest

Within the scope of each center’s identified central theme, applicants are required to propose projects that address at least one of the following priority areas, drawn from the NIH Strategic Plan for Research on FMR1-Associated Conditions:

(1) Characterize phenotypes of FMR1-associated conditions and risk factors for disease severity across developmental stages and diverse populations (considering different strains and/or species for animal models or inclusion of minority health and health disparity populations for human studies)

Examples of projects responsive to this requirement include, but are not limited to, the following:

• Observational natural history studies to characterize the range of phenotypes, the evolution of phenotypes over time and developmental stages, and/or the association of genetic and socioenvironmental influences with specific phenotypes or disease mechanisms.
• Studies of preclinical models that use multiple background strains within a single species to model the impact of varying genetic backgrounds/epigenetic variation on specific phenotypes or disease mechanisms.
• Studies of human-derived materials drawn from donors of varying ancestry to model the impact of genetic background / epigenetic variation on specific phenotypes or disease mechanisms.
• Data science studies that utilize electronic health record databases or other extant data sources to characterize variability in phenotypes, or to identify associations between risk factors such as sociodemographic characteristics or clinical comorbidities with phenotypic heterogeneity across specific populations or subpopulations.  

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

Examples of projects responsive to this priority area include, but are not limited to, the following:

• Studies that explore genetic and epigenetic mechanisms that underlie FMR1-associated conditions – particularly mechanisms underlying heterogeneity.
• Studies that characterize brain circuit/network-level mechanisms that underlie key features of human phenotypes and may be amenable to therapeutic interventions.
   

(3) Develop and validate translatable biomarkers and/or outcome measures for potential use in clinical trials

Examples of projects responsive to this priority area include, but are not limited to, the following:

• 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 could include both animal studies and preliminary human validation research using carefully standardized human samples or human clinical studies.

Phenotypes and outcomes of interest for all projects may include developmental, cognitive, language, behavioral, social, neurodevelopmental, neurodegenerative, mental health, auditory, motor, reproductive, and other domains aligned with the missions of the NIH institutes and centers participating in this funding opportunity.  In justifying their selections of target outcomes, investigators should provide evidence that their selected outcomes, or the clinical correlates of their selected outcomes, are considered meaningful among people with lived experiences (PWLE) with the FMR1-associated condition(s) being studied.

Research areas of particular interest to the participating institutes and centers include the following: 

National Institute on Deafness and Other Communication Disorders (NIDCD): NIDCD is interested in supporting research that examines hearing, balance, taste, smell, voice, speech, or language in individuals with Fragile X and FMR1-Associated conditions. Applicants are strongly encouraged to contact NIDCD staff to discuss potential applications and areas of interest. 

National Institute of Mental Health (NIMH): NIMH is interested in supporting FXS research that examines co-occurring mental health conditions. Applicants are strongly encouraged to contact NIMH staff to discuss potential applications and areas of interest.

National Institute of Neurological Disorders and Stroke (NINDS): NINDS is committed to fostering research aimed at understanding motor and cortical functions in FXS and FXTAS as they relate to neurodevelopment and neurodegeneration.  Studies focused on the cellular and molecular mechanisms that drive circuit dysfunction are of particular interest. Applicants are strongly encouraged to contact NINDS staff to discuss potential applications and areas of interest.

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): NICHD is particularly interested in supporting clinical and translational research to elucidate biological mechanisms, novel therapeutic targets and outcome measures, and/or drivers of phenotypic heterogeneity in Fragile X Syndrome and Fragile X-Associated Primary Ovarian Insufficiency in its populations of interest, including infants, children, pregnant people, and women. Applicants are strongly encouraged to contact NICHD staff to discuss potential applications and areas of interest. 

Description of Required Components

Each Fragile X Center must consist of an administrative core and 2 or 3 interdependent and interrelated research projects. Each research project must have goals and objectives that address the center’s overarching theme. 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.

Additional structural requirements include the following:

1. Due to the focus on translatability in the current cycle, all centers must include at least one project that involves human subjects or human phenotypic data. Projects that exclusively use human cells or human-derived materials, while welcome for inclusion in center proposals, do not satisfy this requirement.
    
2. Each project must clearly describe the range of genetic/strain backgrounds that will be utilized and must justify why the distribution is sufficient to address the project objective and the overall theme of the center.
    
3. The projects within one center must include at least two distinct levels of analysis within one or more strains or species. The multiple levels of analysis can occur across two or more projects and strains or species. See Section IV for a detailed description of this requirement. 
    
4. For this funding opportunity, the only trials permitted will be mechanistic trials and Basic Experimental Studies with Humans (BESH). See section IV for more details.

5. Due to the focus in the current cycle on phenotypic heterogeneity and diversifying the pool of participants (see NIH Inclusion Policies) and source materials for all projects, all Centers will be required to develop plans for an External Advisory Board to promote guidance and interaction with members of the scientific community and broader community not directly involved in the conduct of the proposed research activities and operations. For this NOFO, diversifying participants generally refers to inclusion of minority health and health disparity populations within the age- and sex-specific manifestations of the FMR1-related disorder(s) proposed for study.

Plan for Enhancing Diverse Perspectives (PEDP)

The NIH recognizes that teams comprised of investigators with diverse perspectives working together and capitalizing on innovative ideas and distinct viewpoints outperform homogeneous teams. There are many benefits that flow from a scientific workforce rich with diverse perspectives, including: fostering scientific innovation, enhancing global competitiveness, contributing to robust learning environments, improving the quality of the research, advancing the likelihood that underserved populations participate in, and benefit from research, and enhancing public trust.

To support the best science, the NIH encourages inclusivity in research guided by the consideration of diverse perspectives. Broadly, diverse perspectives can include but are not limited to the educational background and scientific expertise of the people who perform the research; the populations who participate as human subjects in research studies; and the places where research is done.

This NOFO requires a Plan for Enhancing Diverse Perspectives (PEDP), which will be assessed as part of the scientific and technical peer review evaluation.  Assessment of applications containing a PEDP are based on the scientific and technical merit of the proposed project. Consistent with federal law, the race, ethnicity, or sex of a researcher, award participant, or trainee will not be considered during the application review process or when making funding decisions. Applications that fail to include a PEDP will be considered incomplete and will be administratively withdrawn before review.

The PEDP will be submitted as Other Project Information as an attachment (see Section IV).  Applicants are strongly encouraged to read the NOFO instructions carefully and view the available PEDP guidance materials.

Any application not meeting all of these structural requirements will be considered nonresponsive to this NOFO and will be administratively withdrawn from consideration prior to review.

Funding Duration

It is anticipated that the underlying science of FMR1-associated conditions will evolve over time, and will benefit from broadening the pool of supported investigators and research institutions.  Therefore, all projects should propose research that can be accomplished within five years.

Expectations and Requirements for Data and Resource Sharing for NIH-Funded Research

NIH expects that data, biospecimens, tools/software, and results of NIH-funded research will be shared with the larger research community and/or public in alignment with NIH policies. See section IV for more details.

NIH’s Interest in Diversity

To help accomplish the goal of increasing the diversity of the NIH-supported research community, NIH encourages applications from diverse investigators, including those that are underrepresented in the biomedical, behavioral or clinical research workforce (see data at http://www.nsf.gov/statistics/showpub.cfm?TopID=2&SubID=27 and the most recent report on Women, Minorities, and Persons with Disabilities in Science and Engineering). Such individuals include women, those from underrepresented racial and ethnic groups, those with disabilities, and those from disadvantaged backgrounds. See, Notice of NIH's Interest in Diversity, NOT-OD-20-031.

Rigor and Transparency

NIH strives for rigor and transparency in all research it funds. For this reason, NIH explicitly emphasizes and provides supplemental guidance to NIH application instructions related to rigor and transparency (https://grants.nih.gov/policy/reproducibility/guidance.htm). For example, the biological rationale for the proposed experiments must be based on rigorous and robust supporting data, e.g., by minimizing bias and transparently reporting methods and results as described at https://www.ninds.nih.gov/Funding/grant_policy. As stated in the NIH application guidelines, if previously published or preliminary studies do not meet these rigor standards to an acceptable degree, applicants should address how the current study design addresses the deficiencies. Proposed experiments should likewise be designed in a manner that minimizes bias and ensures validity and transparency of experimental results. 

 If proposed, clinical trials must be based on robust and rigorous supporting data, e.g., from non-clinical in vivo and/or in vitro studies or preliminary clinical studies that demonstrate that there is an adequate scientific foundation to justify the proposed trial. The proposed study design must likewise demonstrate a rigorous and transparent approach. 

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 NOFO. During the consultation phase, if the proposed application is not seen as responsive to this NOFO's priorities, applicants will be strongly encouraged to consider other funding opportunities.

Pre-submission Informational Webinar and FAQs

A Pre-submission informational webinar will be held prior to the application due date. Please check the website for the Centers for Collaborative Research in Fragile X and FMR1-Associated Conditions for specific information and FAQs.
 

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

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

Section II. Award Information

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

Section III. Eligibility Information

1. Eligible Applicants

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Local Governments

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

Federal Governments

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

Other

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

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

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

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

Applicant organizations

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

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

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

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

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 diverse backgrounds, including individuals from underrepresented racial and ethnic groups and individuals with disabilities, are always encouraged to apply for NIH support. See, Reminder: Notice of NIH's Encouragement of Applications Supporting Individuals from Underrepresented Ethnic and Racial Groups as well as Individuals with Disabilities, NOT-OD-22-019. 

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

2. Cost Sharing

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

3. Additional Information on Eligibility

Number of Applications

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

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

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

No individual may serve as key personnel on more than one application submitted to this funding opportunity.

Section IV. Application and Submission Information

1. Requesting an Application Package

The application forms package specific to this opportunity must be accessed through ASSIST or an institutional system-to-system solution. A button to apply using ASSIST is available in Part 1 of this NOFO. See the administrative office for instructions if planning to use an institutional system-to-system solution.

2. Content and Form of Application Submission

It is critical that applicants follow the Multi-Project (M) Instructions in the How to Apply - Application Guide, except where instructed in this notice of funding opportunity to do otherwise and where instructions in the How to Apply - Application Guide are directly related to the Grants.gov downloadable forms currently used with most NIH opportunities. Conformance to the requirements in the How to Apply - Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

Letter of Intent

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

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

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

The letter of intent should be sent to:

Alice Kau, PhD
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-496-1385
Email:  kaua@mail.nih.gov

Melissa Parisi, MD, PhD
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-435-6880
Email: parisima@mail.nih.gov  

Page Limitations

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

Instructions for the Submission of Multi-Component Applications

The following section supplements the instructions found in How to Apply- Application Guide and should be used for preparing a multi-component application.

Overall Component

When preparing the application, use Component Type ‘Overall’.

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

SF424(R&R) Cover (Overall)

Complete entire form.

PHS 398 Cover Page Supplement (Overall)

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

Research & Related Other Project Information (Overall)

Follow standard instructions.

Other Attachments: The following “Other Attachment” must be included with the Overall Component in order to aid in the review of applications.

Plan for Enhancing Diverse Perspectives (PEDP)

• In an "Other Attachment" entitled "Plan for Enhancing Diverse Perspectives," all applicants must include a summary of actionable strategies to advance the scientific and technical merit of the proposed project through expanded inclusivity.
• Applicants should align their proposed strategies for PEDP with the research strategy section, providing a holistic and integrated view of how enhancing diverse perspectives and inclusivity are buoyed throughout the application.
• The PEDP will vary depending on the scientific aims, expertise required, the environment and performance site(s), as well as how the project aims are structured.
• The PEDP may be no more than 2 pages in length and should include:
  • Actionable strategies using defined approaches for the inclusion of diverse perspectives in the project;
  • Description of how the PEDP will advance the scientific and technical merit of the proposed project;
  • Anticipated timeline of proposed PEDP activities;
  • Evaluation methods for assessing the progress and success of PEDP activities.

Examples of items that advance inclusivity in research and may be appropriate for a PEDP can include, but are not limited to:

• Partnerships with different types of institutions and organizations (e.g., research-intensive; undergraduate-focused; HBCUs; emerging research institutions; community-based organizations).
• Project frameworks that enable communities and researchers to work collaboratively as equal partners in all phases of the research process.
• Outreach and planned engagement activities to enhance recruitment of individuals from diverse groups as human subjects in clinical trials, including those from underrepresented backgrounds.
• Description of planned partnerships that may enhance geographic and regional diversity.
• Outreach and recruiting activities intended to diversify the pool of applicants for research training programs, such as outreach to prospective applicants from groups underrepresented in the biomedical sciences, for example, individuals from underrepresented racial and ethnic groups, those with disabilities, those from disadvantaged backgrounds, and women.
• Plans to utilize the project infrastructure (i.e., research and structure) to enhance the research environment and support career-advancing opportunities for junior, early- and mid-career researchers.
• Transdisciplinary research projects and collaborations among researchers from fields beyond the biological sciences, such as physics, engineering, mathematics, computational biology, computer and data sciences, as well as bioethics.

Examples of items that are not appropriate in a PEDP include, but are not limited to:

• Selection or hiring of personnel for a research team based on their race, ethnicity, or sex.
• A training or mentorship program limited to certain researchers based on their race, ethnicity, or sex.

For further information on the Plan for Enhancing Diverse Perspectives (PEDP), please see PEDP guidance materials.

Project/Performance Site Locations (Overall)

Enter primary site only.

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

Research and Related Senior/Key Person Profile (Overall)

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

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

Budget (Overall)

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

PEDP implementation costs

• Applicants may include allowable costs associated with PEDP implementation (as outlined in the Grants Policy Statement section 7: https://grants.nih.gov/grants/policy/nihgps/html5/section_7/7.1_general.htm).

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

PHS 398 Research Plan (Overall)

Specific Aims:

Provide a summary of the Center's Overall Specific Aims.  Each center is required to identify an overarching theme targeting at least one of the following research areas in one or more FMR1-associated conditions: (1) identifying, characterizing, and/or modeling factors that predict subgroup- or individual-level differences in clinical features (“phenotypic heterogeneity”) and/or responses to specific interventions, (2) identifying novel mechanisms and targets for intervention that modulate symptom severity or therapeutic efficacy, or (3) identifying and/or validating translatable biomarkers and/or outcome measures for potential use in clinical trials. For the purposes of this funding announcement, FMR1-associated conditions include Fragile X syndrome in addition to conditions associated with the premutation, including FXTAS, FXPOI, and FXAND. The Overall Specific Aims should clearly articulate the Center’s overarching theme and outline how the administrative core and projects synergize to advance that theme. 

Research Strategy:

The Research Strategy should be organized into the following sections: Significance/Innovation, Approach, and Investigators/Environment.

Significance/Innovation:

Describe the current gaps in knowledge being addressed by the Center and its overarching theme. Explain how the proposed activities constitute innovations in FMR1 research, particularly with regard to the range of cells, animal models, human subjects, and/or human data being studied. Describe why the research questions being asked are meaningful for People with Lived Experiences (PWLE) of FMR1 conditions. Discuss how the Center will engage respectfully with stakeholders (including patients, families, their representatives, and health professionals) to promote equitable and bidirectional knowledge transfer between investigators and community members, including those from populations that experience health disparities. Explain how the Center’s activities will advance at least one research priority from the NIH FMR1 Strategic Plan named in this funding opportunity.  

Investigators are urged to follow the NIH guidance for rigor and transparency in grant applications (https://grants.nih.gov/policy/reproducibility/guidance.htm); NIH additionally recommends the research practices described at https://www.ninds.nih.gov/Funding/grant_policy to ensure that robust experiments are designed, experimenter biases are minimized, results and analyses are transparently reported, and results are interpreted carefully. These recommended research practices include rationale for the chosen model(s) and primary/secondary endpoints, blinding, randomization, ensuring adequate sample size, pre-specified inclusion/exclusion criteria, handling of missing data and outliers, appropriate controls, preplanned analyses, appropriate quantitative techniques, clear indication of exploratory vs. confirmatory components of the study, consideration of limitations, and plans for transparent reporting of all methods, analyses, and results so that other investigators can evaluate the quality of the work and potentially perform replications. 

Investigators must indicate whether data presented in the application as key support for the proposed work were collected, analyzed, and reported in a rigorous and transparent manner as indicated above. A plan to address any ambiguity, weaknesses, or limitations in the prior research should be included in the application. Proposed experiments should similarly adhere to these high standards of rigor and transparency. 

For Basic Experimental Studies involving Humans (BESH), the proposed study design should describe expected effect size and describe potential biases and/or challenges in the study design and how they will be addressed. For mechanistic clinical trials, the proposed study design should be designed to understand a biological or behavioral process, the pathophysiology of a disease, or the mechanism of action of an intervention. 

Approach:

Provide an overview of the Center’s proposed research program. Describe the relationships between the Administrative Core and the Projects, and how the methods and strategies proposed align to advance the Center’s central theme and the priorities of the NIH FMR1 Strategic Plan.

The following requirements apply to the Center as a whole; therefore, they should be introduced and described in the “Overall” research strategy section.

1.  Describe the range of backgrounds that will be utilized for any subjects, animal models, or source materials/data, and justify why the distribution of backgrounds within and across projects is sufficient to address the Center’s overarching theme and specific aims.
2. Describe the relationship of each 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. 
3. Describe the level(s) of analysis that will be applied in each project. Centers must propose hypothesis-driven projects that include at least two distinct levels of analysis within one or more strains or species. The multiple levels of analysis can occur across two or more projects and strains or 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 are recommended to include human subjects or human materials (e.g. human tissues, human-derived cell lines) as one of the species being studied. 

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 
• endocrine measures (for studies involving reproductive outcomes) 

Investigators are strongly encouraged to consult with relevant NIH program staff to ensure that the proposed studies will be considered to meet this requirement for multiple levels of analysis. All Centers must include at least one project that involves human subjects or human phenotypic data. Further description and examples of projects responsive to this requirement are described under the Research Strategy section for Research Projects, below. In the Overall section, applicants must describe how the project(s) involving human subjects or large-scale human phenotypic data fit into the overall structure of the Center, and the measures that will be taken to ensure that the diversity of the source of the sample(s) with regard to representing populations described in the NIH Inclusion Policies as well as minority health and health disparity populations is sufficient to address the Center’s overarching theme and specific aims.

Applicants should provide a Statistical Analysis Plan (SAP) for analyses specified in the study protocol, including a description of how the statistical analysis of the primary, secondary, and other endpoints will be performed; how the sample size was determined; how missing data will be handled; plans for interim analyses for safety, efficacy, and futility; plans for recalculation of the sample size midway through the trial (if applicable); etc. Sufficient details should be provided in the SAP about any computer simulations used to investigate the operating characteristics of complex clinical trial designs (such as adaptive designs); to choose between alternative outcome measures; or to determine sample size, accounting for the impact of noncompliance, missing data, subject eligibility criteria, etc. It is particularly important to discuss the range of conditions that were considered in the simulation and why this range was considered appropriate, how robust the findings were across the range of conditions considered, and how the study will adjust for any design deficiencies (e.g., bias, loss of power) the simulations revealed. 

Milestones: When applicable, milestone reports should adhere to rigorous principles, including statistically adequate sample sizes with biologically relevant effect sizes, randomization, blinding, control of bias, independent replication, and adequate reporting of experimental details and results as described at https://www.ninds.nih.gov/Funding/grant_policy.

Investigators/Environment:

Describe the range of disciplines and expertise being brought together by the Center, and why they are uniquely suited to address the center’s overarching theme.

Fragile X Centers offer the opportunity to provide outstanding environments for the next generation of FMR1 researchers, who will then be well positioned to bring  diverse perspectives to the field.  Therefore, the NIH strongly encourages Centers to design at least one Research Project that includes as key personnel an investigator who meets the NIH definition of an Early Stage Investigator (ESI) at the time of application submission.  If applicable, describe in the overall section how one or more ESIs fit into the overall structure of the Center, how their contributions will be elicited and meaningfully incorporated into the Center’s activities, and how their involvement brings innovation to specific projects and the Center as a whole. Finally, the NIH encourages investigators to carefully review the criteria for maintaining ESI status when participating in this center application. Specifically, ESI status can be maintained if a key personnel participant acts as a co-Investigator, but not if they are one of the Principal Investigators on the overall application. ESIs can also maintain their ESI status if they are the lead on a project. 

The additional following information should be included if applicable:

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 should be included in the Letters of Support section.

Letters of Support:  Please include only letters that reflect support for overall activities of the entire Center. Letters of Support for specific 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 How to Apply - Application Guide.

Data sharing

Data management and sharing plans should NOT be included in this section. Data sharing information must be described in the Data Management & Sharing Plan that is submitted in the Other Plans section of the application.

Biospecimen Sharing

NIH resource sharing policy requires broad sharing of biomaterials collected under scientific studies. Several NIH institutes maintain biorepositories for the purpose of dissemination of biomaterials. Examples include the NIMH Repository and Genomics Resource, the NINDS Human Cell and Data Repository (NHCDR), and the NINDS BioSEND Repository. These resources offer centralized sources of curated materials that are widely accessible to investigators in the international scientific community.  Applicants are strongly encouraged to contact these resources prior to submission to determine the suitability, requirements, and costs of any specific resource for the proposed research.

Tool/Software Sharing

All applications proposing to create or use tools, workflows, and/or pipelines with support from this NOFO should include a Resource Sharing Plan addressing how they will be shared with the wider scientific community in a timely manner that would enable other researchers to replicate and build on for future research efforts. Plans should align to open-source practices and other NIH Best Practices for Software Sharing (https://datascience.nih.gov/tools-and-analytics/best-practices-for-sharing-research-software-faq) as much as possible.

The Resource Sharing Plan will be considered during peer review and by program staff as award decisions are being made as appropriate and consistent with achieving the goals of the program. 

Other Plan(s): 

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

All applicants planning research (funded or conducted in whole or in part by NIH) that results in the generation of scientific data are required to comply with the instructions for the Data Management and Sharing Plan. All applications, regardless of the amount of direct costs requested for any one year, must address a Data Management and Sharing Plan. 

The NIH Policy for Data Management and Sharing (Policy) expects researchers to maximize the sharing of scientific data and data be accessible as soon as possible and no later than the time of an associated publication or the end of the award period, whichever comes first. NIH requires all applications submitted in response to this NOFO to include a Data Management and Sharing Plan (Plan). The Plan is expected to address the Elements as described in Supplemental Information to the NIH Policy for Data Management and Sharing: Elements of an NIH Data Management and Sharing Plan (NOT-OD-21-014). The Plan will be reviewed and approved by NIH Program staff prior to award. Awardees will be required to comply with their approved Plan and any approved updates. During peer review, reviewers will not be able to view the Data Management and Sharing (DMS) Plan nor will they factor the DMS Plan into the Overall Impact score. Applicants should develop the DMS Plan taking the following into consideration:

• For human data generated from individuals with FXS or FXTAS, investigators will be required to share their data via the NIMH Data Archive (NDA; http://nda.nih.gov). Fulfilling this expectation by the awardee will be among the terms and conditions of the award. Established by the NIMH, and supported by other NIH Institutes, the NDA is a secure informatics platform for scientific collaboration and data-sharing that enables the effective communication of detailed research data, results, tools, and supporting documentation. Data resulting from existing samples, cells, or sequences previously collected are also expected to be submitted to the NDA. Products such as tools, pipelines, and algorithms that will not result in a commercial product are expected to be shared via the NDA.
• For applications that aim to co-analyze already shared data with data that have not yet been shared with the broader research community, applicants should be aware that such primary data should be shared with the broader research community. Additional information on the Data Management and Sharing Policy is available on the NICHD Office of Data Science and Sharing website.
• For human data on other FMR1-associated conditions, NICHD encourages the use of the Data and Specimen Hub (DASH), a centralized resource for researchers to store and access de-identified data from studies funded by NICHD. Information about DASH may be obtained at https://dash.nichd.nih.gov. For projects generating large-scale human genetic data, applicants should provide a Provisional or Institutional Certification specifying whether the individual-level data can be shared through an NIH approved repository, such as dbGaP and the Sequence Read Archive, in line with the NIH Genomic Data Sharing Policy. If use of DASH is not feasible, NICHD expects awardees to share data through other equivalent broad-sharing data repositories.
• Use of Common Data Elements (CDEs) and Validated Measures in the Research of FMR1-Associated Conditions. For applications using CDEs, applications should describe how standardization of data collection and data collection instruments – including the use of existing NIH CDEs – will be promoted, and how these data collection techniques will facilitate data integration and collaboration. Examples of CDE resources include the NIH Common Data Elements Repository and NINDS Common Data Elements. Applicants are encouraged to use the PhenX Toolkit, which includes a web-based catalog of social determinants of health (SDOH) measurement protocols recommended by experts. 

Appendix:

Only limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in How to Apply- Application Guide; any instructions provided here are in addition to the How to Apply - 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 How to Apply - Application Guide, with the following additional instructions:

If you answered “Yes” to the question “Are Human Subjects Involved?” on the R&R Other Project Information form, 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 How to Apply - Application Guide must be followed.

Delayed Onset Study

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

PHS Assignment Request Form (Overall)

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

Administrative Core

When preparing your application, use Component Type ‘Admin Core.’

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

Note: Effective for due dates on or after January 25, 2023, the Data Management and Sharing Plan will be attached in the Other Plan(s) attachment in FORMS-H application forms packages. If required, the Data Management and Sharing (DMS) Plan must be provided in the Overall component.

SF424 (R&R) Cover (Administrative Core)

Complete only the following fields:

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

PHS 398 Cover Page Supplement (Administrative Core)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Administrative Core)

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

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

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

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

List all performance sites that apply to the specific component.

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

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

• 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 (Administrative Core)

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 Board meetings;
• Costs related to data/resource management and sharing
• 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.
• Applicants may include allowable costs associated with PEDP implementation (as outlined in the Grants Policy Statement section 7: https://grants.nih.gov/grants/policy/nihgps/html5/section_7/7.1_general.htm.

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.

PHS 398 Research Plan (Administrative Core)

Specific Aims:

Include Specific Aims for the Administrative Core.

Research Strategy:

The Administrative Core must have appropriate and effective administrative and organizational capabilities to provide overall scientific leadership, provide administrative oversight, and create mechanisms and procedures for ensuring interaction across the Center.

Applicants must describe the following: 

• Overall management and administration plans for the Center. Applications must clearly describe how administrative core activities extend beyond mere administrative/budgetary support to accelerate the progress and impact of center activities.
• Experience, accomplishments, and expertise of the Administrative Core Lead and other key core personnel that illustrate how their complementary and synergistic expertise will be leveraged to amplify the impact of the center beyond that attributable to individual projects. Information in the biographical sketches may be referenced and should not be repeated.
• Concrete steps to be taken to ensure that the core is cost-efficient. If there are cost-sharing arrangements (note that cost-sharing is not a requirement of this NOFO), describe them.
• SMART (specific, actionable, measurable, realistic, and timely) benchmarks that will be used to evaluate the success of the Administrative Core, including concrete plans for implementation and accountability.

External Advisory Board: Due to the focus in the current cycle on phenotypic heterogeneity and diversifying the pool of participants and source materials for all projects by inclusion of minority health and health disparity populations, all Centers will be required to seek guidance and interaction with members of the scientific community and broader community not directly involved in the conduct of the proposed research activities and operations. Applicants must develop plans for an External Advisory Board to provide objective outside counsel and periodic review of the Center’s activities and progress (i.e., prospective and retrospective input). Applicants should emphasize creative prospective utilization of advisory board members to provide opportunity for ongoing project enhancement and timely input. This includes objective input to the PD/PI on the review. Applicants must not contact or select Advisory Board members at the time of application. If an applicant has an advisory board or external panel and has been funded in the current cycle (FY2020-2025), those advisory board members should be listed. All applicants should describe the operation of the Board, including size, structure, function, and frequency of meetings, as well as the type and level of experience of Board members to be recruited. 

Note: Advisory Boards must include at least one non-scientific member who brings the perspective of a Person with Lived Experience (PWLE) of an FMR1-associated condition, or a family member or other close associate of a PWLE who can provide input on the meaningfulness of the Center’s research questions and interpretation of results. Only after an award is made should members of the Advisory Board be selected and confirmed, and notification sent to program staff at NICHD, within three months after the award date. Provisions for costs of the Advisory Board are to be included in the Administrative Core budget request and justification.

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:

Do not include a Resource sharing plan for this component. Any resources to be developed under this component should be included with the Resource Sharing Plan for the Overall Component.

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 (Administrative Core)

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

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

Study Record: PHS Human Subjects and Clinical Trials Information

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

Delayed Onset Study

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

Research Project

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. 

Note: Effective for due dates on or after January 25, 2023, the Data Management and Sharing Plan will be attached in the Other Plan(s) attachment in FORMS-H application forms packages. If required, the Data Management and Sharing (DMS) Plan must be provided in the Overall component.

SF424 (R&R) Cover (Research Project)

Complete only the following fields:

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

PHS 398 Cover Page Supplement (Research Project)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Research Project)

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

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

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

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

List all performance sites that apply to the specific component.

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

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

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

Budget (Research Project)

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

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)

Specific Aims:

Provide a description of specific aims for the research project. Describe how the proposed project will address the Center’s overarching theme and specific goal areas from the FMR1 strategic plan. 

Research Strategy:

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

1. All Centers must include at least one project that involves human subjects or large-scale human phenotypic data. Observational clinical studies, including natural history studies, as well as studies of large datasets comprised of human phenotypic data, such as EHR data or population-based datasets, will be responsive to this requirement. Data science studies that allow for estimation of ascertainment bias or facilitate disaggregation of the impact of timing of ascertainment from other exposures/risk factors in their associations with phenotypic heterogeneity are of particular interest.

Any project involving human subjects or large-scale human phenotypic data must clearly describe the range and distribution of genetic ancestry among participants and justify why the distribution is sufficient to address the specific aims of the project.  When genetic ancestry information is not available, applicants must describe other dimensions of diversity of the study sample, which may include minority health and health disparity status, self-identified race/ethnicity, household income, educational attainment, or other socioenvironmental characteristics, and justify why they are sufficient to address the project’s aims. 
 
2. Any project involving human cells or human-derived materials must clearly describe the range and distribution of genetic ancestry among donors of source materials, and justify why the distribution is sufficient to address the project’s aims.  Note: projects that exclusively use human cells or human-derived materials are welcome but do not satisfy the requirement that at least one project involve human subjects or large-scale human phenotypic data. Projects involving human subjects or human data where genetic ancestry information is not available should describe other dimensions of diversity of the study sample, which may include minority health and health disparity status, self-described race/ethnicity, household income, educational attainment, or other socioenvironmental characteristics, and justify why it is sufficient to address project and center aims.
3. Any project involving animal models must use multiple background strains or species to model the impact of varying genetic backgrounds/epigenetic variation on specific phenotypes or disease mechanisms. Applicants must justify why the number and characteristics of strains or species chosen are sufficient to address the project's aims. Applicants must also clearly justify how the outcome measures being used correlate with clinical or behavioral outcomes.

Clinical trials

Clinical trials are research studies in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes. For this funding announcement, only the following types of clinical trials will be supported:

• Mechanistic trials, defined as studies designed to understand a biological or behavioral process, the pathophysiology of a disease, or the mechanism of action of an intervention (i.e., HOW an intervention works, but not IF it works or is safe).
• Basic Experimental Studies with Humans (BESH), defined as basic research studies involving humans that seek to understand the fundamental aspects of phenomena.

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 will not be supported under this funding opportunity. 

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.

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.

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

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

4. Submission Dates and Times

Part I. 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 Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications.

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

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

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

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

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

7. Other Submission Requirements and Information

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

For information on how applications will be automatically assembled for review and funding consideration after submission, refer 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 form. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH.

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

See more tips for avoiding common errors.

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

 Applications must include a PEDP submitted as Other Project Information as an attachment. Applications that fail to include a PEDP will be considered incomplete and will be withdrawn before review.

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 NOFO. During the consultation phase, if the proposed application is not seen as responsive to this NOFO’s priorities, applicants will be strongly encouraged to consider other funding opportunities. 

Post Submission Materials

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

Section V. Application Review Information

1. Criteria

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

For this specific funding opportunity, please note the following:

The overall P50 Center will be evaluated as an integrated and synergistic research effort focused on an overarching theme that addresses one or more of three research priority areas in one or more FMR1-associated conditions: (1) identifying, characterizing, and/or modeling factors that predict subgroup- or individual-level differences in clinical features (“phenotypic heterogeneity”) and/or responses to specific interventions, (2) identifying novel mechanisms and targets for intervention that modulate symptom severity or therapeutic efficacy, or (3) identifying and/or validating translatable biomarkers and/or outcome measures for potential use in clinical trials. The relationship and contributions of each Research Project to the central theme will be discussed and evaluated. Reviewers do not need to weigh all components of the application equally and may weigh certain research projects and the overall review more heavily in their final review of impact of the application.
 

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 project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).  As part of the overall impact score, reviewers should consider and indicate how the Plan to Enhance Diverse Perspectives affects the scientific merit of the project.

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

Significance

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

Specific to this NOFO:

To what extent will the Center’s activities advance the priority areas from the NIH FMR1 strategic plan targeted in this funding opportunity?  How effectively will the Center engage with stakeholders, including those from populations that experience Health Disparities (HDPs) and People with Lived Experience (PWLE)? 

Does the application describe whether prior research that serves as the key support for the proposed project employed rigorous practices such as minimization of experimenter biases, robust experimental designs, transparent reporting of results and analyses, and careful interpretation? How does the application address ambiguity, weaknesses, or limitations in rigor of the prior research, if applicable?

In addition, for applications involving BESH or 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?

Investigator(s)

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

Specific to this NOFO:

Are the roles of early stage investigators substantive and meaningful? Does their involvement bring innovative perspectives and approaches to the work of the center?

In addition, for applications involving BESH or 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?

Specific to this NOFO:

To what extent do the proposed activities constitute innovations in FMR1 research, particularly with regard to the range of cells, animal models, human subjects, and/or human data being studied?

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?

Approach

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

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address:

1) the protection of human subjects from research risks, and
2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of individuals of all ages (including children and older adults), justified in terms of the scientific goals and research strategy proposed?

Specific to this NOFO:

Are the approaches proposed appropriately matched to the Center’s overarching theme, specific aims and subjects/data sources? How likely are the approaches and subjects/data sources to meaningfully advance understanding of the research areas highlighted in this RFA?

Does the proposed research incorporate adequate methodological rigor including, but not limited to, rationale for the chosen model(s) and primary/secondary endpoints, blinding, randomization, adequate sample size, pre-specified inclusion/exclusion criteria, appropriate handling of missing data and outliers, appropriate controls, preplanned analyses, appropriate quantitative techniques, clear indication of exploratory vs. confirmatory components of the study, consideration of limitations, and plans for transparent reporting of all methods, analyses, and results so that other investigators can evaluate the quality of the work and potentially perform replications? Does the approach include the use of CDEs and/or validated measures that can facilitate data integration and collaboration? 

Do the proposed milestones, where applicable, adhere to rigorous principles, including statistically adequate sample sizes with biologically relevant effect sizes, randomization, blinding, control of bias, independent replication, and adequate reporting of experimental details and results? 

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?

Environment

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

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?

Additional Review Criteria - Overall

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

Center as an Integrated Effort

In addition to the individual review criteria described above, reviewers will assess the level of merit of the Center as an integrated effort, based on the following criteria:

• Will there be coordination, interrelationships, cohesiveness, and synergy among the research projects as they relate to the common theme of the Center? Are the mechanisms proposed for communication and coordination sufficient to achieve the stated goals?
• Are there clear advantages of conducting the proposed research as a program rather than through separate research efforts?
• Will the research efforts taken together have more impact on the field than each separate project conducted in isolation?
• Will the research proposed in individual projects be enhanced by the Center?

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)?

Protections for Human Subjects

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

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

Inclusion of Women, Minorities, and Individuals Across the Lifespan

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

Vertebrate Animals

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following three points: (1) a complete description of all proposed procedures including the species, strains, ages, sex, and total numbers of animals to be used; (2) justifications that the species is appropriate for the proposed research and why the research goals cannot be accomplished using an alternative non-animal model; and (3) interventions including analgesia, anesthesia, sedation, palliative care, and humane endpoints that will be used to limit any unavoidable discomfort, distress, pain and injury in the conduct of scientifically valuable research. Methods of euthanasia and justification for selected methods, if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals, is also required but is found in a separate section of the application. For additional information on review of the Vertebrate Animals Section, please refer to the Worksheet for Review of the Vertebrate Animals Section.

Biohazards

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

Resubmissions

Not Applicable

Renewals

Not Applicable

Revisions

Not Applicable

Additional Review Considerations - Overall

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

Applications from Foreign Organizations

Not Applicable

Select Agent Research

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

Resource Sharing Plans

Reviewers will comment on whether the Resource Sharing Plan(s) (e.g., Sharing Model Organisms) or the rationale for not sharing the resources, is reasonable.

Authentication of Key Biological and/or Chemical Resources:

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

Budget and Period of Support

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

Review Criteria – Administrative Core

Reviewers will assign an impact score based on the following review criteria. Separate criterion scores will not be assigned for the Administrative Core.

• Are the plans for overall management and administration of the Center well-defined? Do they include measures for maximizing the cost efficiency of center operations? To what extent do the core’s activities extend beyond administrative and budgetary support to accelerate the Center’s scientific progress?
• Are the experience, accomplishments, and expertise of the Core Lead and other key core personnel sufficiently synergistic to amplify the scientific impact of the center beyond that attributable to individual projects?   
• Are SMART (specific, actionable, measurable, realistic, and timely) benchmarks for evaluating success of the Administrative Core included and clearly defined? To what extent are they accompanied by concrete plans for implementation and accountability?
• Does the proposed External Advisory Board include the perspectives of PWLE (People with Lived Experience) and/or their families/caregivers? 

Review Criteria – Research Projects

Reviewers will assign an impact score for each project based on the extent to which its design, execution and subjects/participants/source materials are seen as sufficient to achieve the project’s aims and advance the overarching theme of the center.

Scored Review Criteria – Research Projects

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

Significance

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

In addition, for applications involving BESH or 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?

Investigator(s)

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

In addition, for applications involving BESH or 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?

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

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address:

1) the protection of human subjects from research risks, and
2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of individuals of all ages (including children and older adults), justified in terms of the scientific goals and research strategy proposed?

Specific to this NOFO:

For studies involving human subjects: Are the diversity of the sample -- and the characteristics along which diversity is being sought -- appropriate for the project’s scientific aims?  Is the plan for recruiting and retaining diverse participants feasible and sufficient to achieve the project aims within the funding period? Are plans for monitoring the diversity of the sample adequate for the aims and timeline of the project? Are contingency plans for recruitment and retention proposed, including triggers/thresholds for invoking such contingency plans?

For studies involving large-scale human phenotypic data: Is data of sufficient completeness and granularity available among the characteristics across which diversity is being sought to address the project’s scientific aims? Are contingency plans proposed in case diversity in the planned data source is found to be insufficient to address the project’s aims, including triggers/thresholds for invoking such contingency plans? Are there sufficient validated and reliable measures available for assessing phenotypic heterogeneity in humans with FMR1-associated conditions?

For studies involving human cells or human-derived materials: Are the range and distribution of genetic ancestry among donors of source materials sufficient to address the project’s scientific aims? Are contingency plans proposed in case the diversity in genetic ancestry among cell lines/materials obtained is found to be insufficient to address the project’s aims, including triggers/thresholds for invoking such contingency plans?

For projects involving animal models of FMR1-associated conditions: Are the number and diversity of background strains or species proposed for use sufficient to address the project’s scientific aims? Are contingency plans proposed in case the proposed range of strains or species cannot be obtained or derived, including triggers/threshold for invoking such contingency plans?

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? Does the proposed study design describe expected effect size and describe potential biases and/or challenges in the study design and how they will be addressed?

In addition, for applications involving BESH or 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 project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

In addition, for applications involving BESH or 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?

Study Timeline

Specific to applications involving BESH or 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 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 three points: (1) a complete description of all proposed procedures including the species, strains, ages, sex, and total numbers of animals to be used; (2) justifications that the species is appropriate for the proposed research and why the research goals cannot be accomplished using an alternative non-animal model; and (3) interventions including analgesia, anesthesia, sedation, palliative care, and humane endpoints that will be used to limit any unavoidable discomfort, distress, pain and injury in the conduct of scientifically valuable research. Methods of euthanasia and justification for selected methods, if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals, is also required but is found in a separate section of the application. For additional information on review of the Vertebrate Animals Section, please refer to the Worksheet for Review of the Vertebrate Animals 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.

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 Resource Sharing Plan(s) (e.g., Sharing Model Organisms) or the rationale for not sharing the resources, is reasonable.

Authentication of Key Biological and/or Chemical Resources

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

Budget and Period of Support

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

2. Review and Selection Process

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

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

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

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

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this NOFO. Following initial peer review, recommended applications will receive a second level of review by the 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, including the PEDP, as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities, including the PEDP, of the NIH institutes and centers participating in this funding opportunity.

3. Anticipated Announcement and Award Dates

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

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

Section VI. Award Administration Information

1. Award Notices

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. This request is not a Notice of Award nor should it be construed to be an indicator of possible funding.

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

Recipients must comply with any funding restrictions described in Section IV.6. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

Any application awarded in response to this NOFO 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 recipient must provide NIH copies of documents related to all major changes in the status of ongoing protocols.

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

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

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Recipients, and Activities, including of note, but not limited to:

• Federal-wide Standard Terms and Conditions for Research Grants
• Prohibition on Certain Telecommunications and Video Surveillance Services or Equipment
• Acknowledgment of Federal Funding

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

If a recipient receives and award, the recipient must follow all applicable nondiscrimination laws. The recipient agrees to this when registering in SAM.gov. The recipient must also submit an Assurance of Compliance (HHS-690). To learn more, see the Laws and Regulations Enforced by the HHS Office for Civil Rights website.

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

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 System for Award Management (SAM.gov) requirements. SAM.gov requires Federal agencies to review and consider information about an applicant in the designated integrity and performance system (currently SAM.gov) prior to making an award. An applicant can review and comment on any information in the responsibility/qualification records available in SAM.gov. NIH will consider any comments by the applicant, in addition to the information available in the responsibility/qualification records in SAM.gov, 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 2 CFR Part 200.206 “Federal awarding agency review of risk posed by applicants.” This provision will apply to all NIH grants and cooperative agreements except fellowships.

Not Applicable

3. Data Management and Sharing

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

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

Awardees will provide updates at least annually on implementation of the PEDP.

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

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

In accordance with the regulatory requirements provided at 2 CFR Part 200.113 and Appendix XII to  2 CFR Part 200, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period. The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (Responsibility/Qualification in SAM.gov, formerly 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 2 CFR Part 200 – Award Term and Condition for Recipient Integrity and Performance Matters.

Section VII. Agency Contacts

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

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

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

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-637-3015

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

Alice Kau, PhD
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-496-1385
Email: kaua@mail.nih.gov

Melissa Parisi, MD, PhD
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-435-6880
Email: parisima@mail.nih.gov 

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

David Panchision, Ph.D.
National Institute of Mental Health (NIMH)
Telephone: 301-402-3969
Email: panchisiond@mail.nih.gov

Holly Lynn Storkel
NIDCD - NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS
Phone: 301.451.6842
E-mail: holly.storkel@nih.gov

Robert D Riddle
NINDS - NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
Phone: 301-402-3315
E-mail: riddler@nih.gov

Joanna Kubler-Kielb, PhD
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-435-6916
Email: kielbj@mail.nih.gov

Jill Rogers
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-435-7008
Email: rogersj@mail.nih.gov 
 

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

Christopher Myers
NIDCD - NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS
Phone: (301) 435-0713
E-mail: myersc@nih.gov

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

Section VIII. Other Information

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

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