Centers for Collaborative Research in Fragile X and FMR1-Associated Conditions Frequently Asked Questions (FAQs)

Overview

NIH created the Centers for Collaborative Research in Fragile X and FMR1-Associated Conditions Program 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 clinical trials to basic genetic, molecular, and cellular research involving animal models. However, substantial gaps in understanding remain about the processes that drive variability in clinical features (“phenotypic heterogeneity”) and variation in responses to interventions among individuals with FMR1-associated conditions. Furthermore, there is a need to identify novel targets for intervention and validated, translatable biomarkers for potential use in clinical trials.

Request for Applications (RFA)

Please note: NOT-HD-24-026: Notice to Extend the Application Receipt Date for RFA-HD-25-002, "Centers for Collaborative Research in Fragile X and FMR1-Associated Conditions (P50 Clinical Trial Optional)," extends the RFA deadline to August 20, 2024.

  • RFA-HD-25-002: Centers for Collaborative Research in Fragile X and FMR1-Associated Conditions (P50 Clinical Trial Optional)

Technical Assistance (TA) Webinar

NIH program staff hosted an hour-long virtual TA webinar and question-and-answer session on this RFA on June 21, 2024.

NIH RFA Contacts

Applicants should contact the following staff from the participating NIH institutes to discuss how their proposals will align with the goals and requirements of this RFA:

FAQs (Includes new FAQs as of 8/08/24)

If a research project uses more than one species (e.g., mice + humans, mice + rats, or Drosophila + humans), do experiments still need to be conducted in more than one background strain?

No. In projects that employ more than one species using parallel analyses, use of multiple background strains is not required. Please note that, in all projects, it is necessary for applicants to justify why the chosen range of backgrounds or genetic ancestry is sufficient to achieve project and center goals.

Is cost-sharing allowed?

Cost-sharing is not required, but it is allowed. Please review the following section of the RFA from Research Plan – Administrative Core: “Applicants must describe...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.”

How many Resource-Sharing Plans are required?

Applicants must submit one Resource-Sharing Plan for the Overall component in addition to a separate resource-sharing plan for each research project. Additionally, please note that if any resources are developed through the Administrative Core, then those should be included with the Resource-Sharing Plan for the Overall component.

Is the Statistical Analysis Plan a separate document, or is it contained within the Overall Research Strategy? How will it be reviewed?

The Statistical Analysis Plan is contained within the Overall Research Strategy and will be assessed during the review of the Overall component. The plan will also count against the 12-page limit for the Overall component. Please check the review criteria for the Overall component for more detail. Also, please note that there are additional statistics-related review criteria for research projects that involve clinical trials or Basic Experimental Studies in Humans, although the Research Project component does not require a formal Statistical Analysis Plan.

If comparisons are made across species between two projects within the center (but not within each individual project), does that satisfy the requirement that “[a]ny 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”?

No. If a project with animal models uses only one species, each experiment must be conducted in at least two different genetic background strains. For example, the requirement would be satisfied by conducting each proposed mouse experiment in both C57BL6 and FVB strains.

Can a single individual serve as key personnel on multiple submitted applications?

No. Please review Section III: Eligibility Information: “No individual may serve as key personnel on more than one application submitted to this funding opportunity.” However, the same individual could be listed as a key personnel on one application and a consultant or other significant contributor on another application. Please review the NIH Grants & Funding FAQ page on Senior/Key Personnel for more information.

The RFA states that center director(s) must commit a minimum combined total of 1.8 person-months (15%) effort to the center. Can that effort be spread between the Administrative Core and one or more research project(s)?

No. The center director(s) must collectively contribute 15% effort to the Administrative Core. The director(s) may elect to contribute additional effort to one or more research projects, but at minimum, the director(s) must collectively contribute a minimum of 1.8 person-months to the Administrative Core alone.

What is meant by the requirement that animal research must use “multiple background strains or species”?

This requirement is intended to increase the translatability of the animal research conducted across the centers by modeling the impact of varying genetic backgrounds and epigenetic variation on specific phenotypes or disease mechanisms. 

Simply using males and females from the same strain would not satisfy this requirement, nor would using homozygous and heterozygous animals from the same strain. Similarly, a hybrid strain alone would not satisfy the requirement unless paired with research conducted in another strain or species. Applicants must be sure to justify why the number and characteristics of the strains and/or species chosen are sufficient to address the project’s aims, how they model the impact of varying genetic backgrounds/epigenetic variation on specific phenotypes or disease mechanisms, and how the outcome measures being used correlate with clinical or behavioral outcomes.

What type of human subjects research is required in applications submitted to this RFA?

Although clinical trials are not required, all centers must include at least one project that uses human subjects or large-scale human phenotypic data (either prospective or retrospective). Projects that exclusively use human cells or other human-derived materials, while welcome in applications, do not satisfy this requirement. If you have questions about whether a specific project would satisfy this requirement, please reach out to the NIH RFA Contacts.

Is there any limitation on the participation of key personnel across projects?

No. Individuals may not serve as key personnel on multiple proposals, but there is no restriction on the participation of a single individual in multiple projects within the same center.

Can projects have multiple PIs, or only one main PI with other co-PIs?

Either option is acceptable. Centers are encouraged to assign key personnel in a manner that makes the most sense for their proposal and that best reflects the needs of the proposed projects and Administrative Core.

Do Letters of Intent (LOIs) need to have a finalized list of key personnel, or can additions or modifications still be made before the application deadline?

NIH strongly encourages the submission of LOIs, and for those letters to be as complete as possible. However, LOIs are both optional and non-binding, and modifications or additions can be made in the final application submitted.

Do all projects in a proposal need to respond to the goals of a single participating NIH institute?

Center applications can certainly align with the goals of more than one institute, as long as all projects within the center are still united under a common theme.

If the overarching theme of the center addresses the first research priority area, does the center need to address responses to specific interventions?

No. Proposals that address intervention response are welcome, but this is not a requirement for addressing the first priority area.

Are there any restrictions on collaborating with a company that has a new medication that has not yet been FDA approved but which will be approved within the first two years of the project?

The RFA does not include any special restrictions on industry collaborations; however, applicants should be careful that any clinical trials meet either the definition of a “mechanistic trial” or a “Basic Experimental Study in Humans.” Furthermore, project feasibility is a priority. If a medication will not be approved until two years into the funding cycle, that timeline will be taken into consideration when determining the feasibility of implementing the proposal.

Are there any restrictions on an international contributor serving as a PI on a project?

No, there are no special restrictions on an international contributor serving as a PI on a project. However, the international contributor may not serve as the PI of the center as a whole.

What are the main goals of this RFA?

  • Address complex, difficult-to-solve problems in FMR1 research not readily addressed by standard investigator-initiated mechanisms
  • Fund projects that are interdependent and interrelated, focused on a common unifying theme, and achievable within a 5-year grant period

Do the Fragile X Centers need to have an overarching research theme?

Yes. All centers must identify an overall theme, directed at broadening the understanding of at least one of the following research priority areas in one or more FMR1-associated conditions:

  • Identifying, characterizing, and/or modeling factors that predict subgroup- or individual-level differences in phenotypic heterogeneity and/or responses to specific interventions among affected individuals
  • Identifying novel mechanisms and targets for intervention that modulate symptom severity or therapeutic efficacy
  • Identifying and/or validating translatable biomarkers and/or outcome measures for potential use in clinical trials

What research areas are of interest to the NIH institutes participating in this RFA?

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 (FXS) and Fragile X-Associated Primary Ovarian Insufficiency in its populations of interest, including infants, children, pregnant people, and women.

NIMH is interested in supporting FXS research that examines co-occurring mental health conditions.

NINDS is committed to fostering research aimed at understanding motor and cortical functions in FXS and Fragile X-Associated Tremor and Ataxia Syndrome (FXTAS) as they relate to neurodevelopment and neurodegeneration. Studies focused on the cellular and molecular mechanisms that drive circuit dysfunction are of particular interest.

NIDCD is interested in supporting research that examines hearing, balance, taste, smell, voice, speech, or language in individuals with FXS and FMR1-associated conditions.

What are the major changes from RFA-HD-20-003?

  • All centers must include a least one project that involves human subjects or human phenotypic data. Projects that exclusively use human cells or human-derived materials, while welcome in center proposals, do not satisfy this requirement.
  • Each project must clearly describe the range of genetic/strain backgrounds that will be used and justify why the distribution is sufficient to address the project objective(s) and the overall theme of the center.
  • Projects involving animal models must use multiple background strains and/or species to model the impact of varying genetic backgrounds/epigenetic variation on specific phenotypes or disease mechanisms.
  • No individual may serve as key personnel on more than one application submitted to this funding opportunity.
  • Applicants must submit a Plan for Enhancing Diverse Perspectives (PEDP) as an attachment under Other Project Information in the Overall component. The PEDP cannot exceed two pages.
  • In the Research Strategy section of the Overall component, applicants must discuss how their 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.
  • All applications should describe how standardization of data collection and data collection instruments, including the use of existing NIH common data elements (CDEs), will be promoted and how these data collection techniques will facilitate data integration and collaboration.
  • 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.

Will an investigator lose their ESI status if they serve as the lead on a project or core?

No. If an ESI is made the lead of a project or core, that individual will maintain their ESI status. However, if an ESI is assigned as a program director/principal investigator for the overall center, then the individual will lose their ESI status upon award.

What must applicants include in a PEDP?

This RFA requires a PEDP, which will be assessed as part of the scientific and technical peer review evaluation. Applications that do not include a PEDP will be considered incomplete and will be administratively withdrawn before review.

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 supported throughout the application. The PEDP may be no more than two 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

The PEDP will be submitted as an attachment under Other Project Information in the Overall component. Applicants are strongly encouraged to read the RFA instructions carefully and view the available PEDP guidance materials.

Are centers required to address more than one FMR1-associated condition?

No. Such applications are allowed, but this is not a requirement.

Are multi-institution proposals allowed?

Yes. Such collaborations are not required but are allowed if they are likely to increase synergy between projects and/or provide the required expertise to meet the requirements of the RFA.

What is the “multiple levels of analysis” requirement?

The projects within one center must include at least two distinct levels of analysis within one or more strains or species. This requirement applies to the projects of a center taken as a whole; each project alone does not need to include multiple levels of analysis or multiple strains/species. Studies involving brain or behavioral outcomes should include at least two from the following levels of analysis:

  • Genomic/molecular measures
  • Circuit/network measures
  • Clinical/behavioral measures

Studies involving outcomes in other organ systems or clinical domains should include at least two from the following levels of analysis:

  • Genomic/molecular measures
  • Tissue-specific/organ-level measures
  • Clinical/whole organism measures
  • Endocrine measures (for studies involving reproductive outcomes)

What types of clinical trials are allowed?

NIH defines clinical trials as 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 RFA, clinical trials are allowed but not required. If proposals do include clinical trials, only the following types 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

Note: 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) inventions will not be supported under this funding opportunity.

If you have questions about whether a proposed project is allowable under these guidelines, please reach out to the previously identified NIH program staff before submitting an application.

Do applications need to comply with the NIH Policy for Data Management and Sharing (DMS)?

Yes. Applicants must follow the NIH Policy for DMS, which expects researchers to maximize the sharing of scientific data and to make data accessible as soon as possible but no later than the time of an associated publication or the end of the award period, whichever comes first. NIH program staff will review and approve the plan prior to award.

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.
  • For human data on other FMR1-associated conditions, NICHD encourages the use of the Data and Specimen Hub (DASH). If use of DASH is not feasible, NICHD expects awardees to share data through other equivalent broad-sharing data repositories.
  • 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 the National Center for Biotechnology Information’s database of Genotypes and Phenotypes and Sequence Read Archive, in line with the NIH Genomic Data Sharing Policy (NOT-OD-14-124).
  • For applications that strive 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.
  • 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.

Additional information on the DMS policy is available from the NICHD Office of Data Science and Sharing.

Visit the NIH Scientific Data Sharing’s Writing a Data Management & Sharing Plan page to find sample DMS plans.

What are the requirements surrounding resource 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 following:

Applicants should describe plans for biomaterial sharing in the Resource Sharing Plan.

Applications proposing to create or use tools, workflows, and/or pipelines with support from this RFA should include a Resource Sharing Plan addressing how they will be shared with the wider scientific community. Plans should align to open-source practices and other NIH Best Practices for Sharing Research Software as much as possible.

How many awards will be made?

NICHD and partnering institutes intend to commit an estimated total of $5.45 million for this funding opportunity to fund three awards.

How much funding can be requested?

Applications may request up to $1.2 million in direct costs per year, excluding subaward facilities and administrative costs. This request must reflect the actual needs of the proposed projects.

Can an individual serve as key personnel on more than one application submitted to this RFA?

No. Any individual can only be listed as key personnel on one application submitted this cycle.

Are renewal applications allowed?

No. Research teams that have previously received funding for a Fragile X Center are welcome to apply but cannot submit a renewal application. Progress reports are not allowed or expected.

Are resubmission applications allowed?

No. Research teams that have previously received funding for a Fragile X Center are welcome to apply but cannot submit a resubmission application.

How much research effort is required for center director(s)?

The center director(s) must commit a combined total of 1.8 person-months (15% effort) to lead and administer their center.

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