RDCRN Applicant Information

What is the purpose of this Notice of Funding Opportunity?

The objective of this Notice of Funding Opportunity (NOFO) is to invite new and renewal applications for the Rare Diseases Clinical Research Consortia (RDCRC) that comprise the Rare Diseases Clinical Research Network (RDCRN). The RDCRCs are intended to advance and improve diagnosis, management, and treatment of numerous, diverse rare diseases through highly collaborative, multi-site, patient-centric, translational and clinical research. Special emphasis will be placed on the early and timely identification of individuals with rare diseases and clinical trial readiness.

This is a reissue of RFA-TR-18-020. What are the major changes?

• In the required Rare Disease Status attachment (under Other Attachments), all applicants must justify that the diseases/conditions being studied are rare in the United States.
  • The Rare Disease Status attachment may be no more than 3 pages in length and must include all targeted diseases/conditions.
  • In an "Other Attachment" entitled "Rare Disease Status", all applicants must include a justification that the diseases/conditions being studied are rare in the U.S.
  • This section may include one or more references confirming that the prevalence of the diseases/conditions that are the primary focus of the research application is 200,000 or fewer patients in the U.S., as defined by The Rare Diseases Act of 2002 (Public Law 107-280). If the diseases/conditions have been granted orphan status by the U.S. Food and Drug Administration, provide this information in the justification.
  • If it is a rare variant or subset of a more common condition, provide a justification for including this variant in the RDCRC. Describe the scientific basis for separating biomarker/clinical outcome assessment validation for this rare variant or subset from that of the common condition.
  • Applications missing a Justification for Rare Disease Status may be deemed incomplete and not sent forward for review.
• Applications must include at least two and no more than four Clinical Research Projects.
• It is imperative that RDCRC applicants carefully review the Data Management and Coordinating Center (DMCC) NOFO (RFA-TR-24-021) to fully understand the resources and services that will be provided to the network participants by the DMCC. Applicants should ensure that planned activities involve coordination with the DMCC and do not replicate efforts.
• Advancing rare disease research by freely sharing high-value data is a critical goal of the program. All RDCRC award recipients are required to work collaboratively within the RDCRN DMCC cloud environment and to ultimately share their data within the RDCRN Data Repository. Informed Consent for every protocol should include language that allows broad sharing of the data while protecting the confidentiality of and minimizing the risk for re-identification of the participant.

What qualifies as a rare disease for the RDCRN?

In this NOFO, a rare disease is defined as a condition affecting fewer than 200,000 people in the U.S., as defined by the Rare Diseases Act of 2002 (Public Law 107-280).

What is “clinical trial readiness"?

For this NOFO, clinical trial readiness is the state of having validated clinical research tools and sufficient knowledge of disease natural history to design efficient clinical trials. Validated clinical research tools can include biomarkers or clinical outcome assessment measures that are fit-for-purpose within a defined context of use relevant to the clinical trials. Knowledge of disease natural history necessary for clinical trial design can include, but is not limited to, characteristics for stratification or determining inclusion and exclusion criteria, the stage of disease progression that may be responsive to treatment, and data needed for determining sample size through power calculations.

Who needs to have an eRA account?

Applicant organizations must be registered in eRA Commons and should start the registration process at least six weeks before the grant application submission deadline to allow plenty of time to address unforeseen issues. All Senior/Key Personnel, as defined in the NIH Grants Policy Statement (NIH GPS 1.2), and Other Significant Contributors (OSCs) must be listed on the R&R Senior/Key Person Profile Form and must also be registered in the NIH eRA system (see NOT-OD-24-042, Create and Manage an eRA Commons Account webpage, and the Application Guide). Note: All Errors must be corrected before an application can be successfully submitted to the agency.

Where can I find the RDCRN Data Sharing Document (Section V1.3 Data Management and Sharing)?

Data sharing is a key aspect of the RDCRN framework and a priority for many stakeholders involved with the network and the RDCRN Data Management and Coordinating Center provides non-binding guidance to consortia on general principles for data sharing and key factors to consider when developing data sharing policies. For more information, review the RDCRN Data Sharing Guidance.

How many awards will be made?

The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications that align with the specific research interests and priorities of the participating NIH ICO.

Can we receive matching funds from a patient advocacy group to support the Pilot/Feasibility Core research projects?

The NOFO does not require cost share and/or matching. The NOFO also does not prohibit an application from providing voluntary committed cost share. All funds utilized to support the goals of the application and included in the application budget must be allowable per the NOFO requirements, NIH Grants Policy and applicable cost principles. Any pilot project supported by voluntary committed cost share must also comply with all NOFO requirements.

Is the funding for each RDCRC coming from NIH or from each specific Institute?

The RDCRC funding comes from the ICs listed in the NOFO.

Does the PD/PI 2.0 person month effort need to be reflected in the budget?

Yes.

Is there a budget max or min per year for the pilot grant core?

No.

For the $100K cap on the Career Enhancement Core, should the budget cover the trainee’s role itself, as well as a stipend, or is that at the discretion of the RDCRC?

The determination of the use of the $100,000 is at the discretion of the applicant noting that all budget requests must be well justified and consistent with allowable costs as defined in the NIH Grants Policy Statement.

Is the $1million direct cost for each project or the whole RDCRC?

The $1 million in direct costs per year limitation is per application submitted. Specific information regarding allowable NIH direct and indirect costs can be found in the NIH Policy Grants Statement.

What are direct and indirect allowable costs?

The $1 million in direct costs per year limitation is per application submitted. Specific information regarding allowable NIH direct and indirect costs can be found in the NIH Grants Policy Statement. 

How should we structure subawards within our budget?

Applicants should work with their Office of Sponsored Projects as each organization may have their own requirements for the establishment of subaward agreements and how they are presented in the competing application budget.

Is the 3-page Rare Disease Status Justification a separate document or part of the Administrative Core application?

The Rare Disease Justification should be a separate 3-page attachment and should be included in the Other Attachment section of the application.

Should the Pilot and Feasibility Governance Core director be the overall PI or Co-I?

It is up to the RDCRC to determine if the overall PD/PI will also serve as PI for Cores.

Would a multi-PI plan be required if each project and core has its own PI?

The MPI Leadership plan is necessary for the entire application or project when there are multiple PIs involved. If the main application has only one PI and each of the individual cores and projects has different PIs, then there is no need for an MPI plan in that scenario.

The NOFO states that the Career Enhancement Core has a budget limit of 100K annually. Does this mean other cores don't have budget caps?

This is correct. Only the Career Enhancement component has a budget limit in the NOFO.

How should the responsibilities of each core be divided between the prime award site and sub-award sites in a single application?

It is up to the applicant to decide how to design their program as long as it meets the requirements of the NOFO. Section V of the NOFO outlines the criteria for evaluating the cores.

How do the data coordinating activities for a consortium relate to the data management and coordinating center for the RDCRN?

It is important that the RDCRC is prepared to identify a point of contact for communications with DMCC and share the following information with the DMCC. Each Administrative Core should also have identified statistical and bioinformatics team members to work collaboratively with the DMCC to coordinate and leverage DMCC core support and meet the needs of the RDCRC that extend beyond the scope of the DMCC.

Where can I find a list of the research tools through the DMCC?

Tools provided by NCATS are based on need and use and include, but are not limited to, Amazon Web Services, Atlassian, CODECOV, Facebook, Github, MAILCHIMP, Pantheon, Shippo, SHUTTERSTOCK, TWILIO, VIMEO PRO, Seven Bridges, Box.com.

All RDCRC applicants are encouraged to review the Data Management Coordinating Center (DMCC) for Rare Diseases Clinical Research Network Notice of Funding Opportunity (RFA-TR-24-021) to fully understand the resources and services that will be provided to the network participants by the DMCC.

If the consortium works with a registry, can data be captured within that registry, or must all data be stored with the data coordinating center?

Working collaboratively with the DMCC is a requirement of the RDCRN. The RDCRCs must not replicate services provided by the DMCC. To advance rare disease research as broadly and effectively as possible, investigators funded under this NOFO who are collecting data from humans are expected to share that data via the RDCRN Data Repository (RDCRN-DR).

How have registries worked with the DMCC in the past?

Applicants should review the DMCC NOFO (RFA-TR-24-021) to fully understand the resources and services that will be provided to the network participants by the DMCC. The DMCC will continue to manage the RDCRN Contact Registry and provide a management system for collection, storage, and quality control of clinical research data.

Should we get a letter of support from the DMCC specifically stating how we will work together?

No.

Will being a PI or co-investigator of a core or project affect Early Stage Investigator (ESI) Status?

See the NIH Grants & Funding Determining Early Stage Investigator (ESI) Status:
If an ESI is assigned a PD/PI role for the overall multi-project application, the individual will lose their ESI status when the award is made.
If the ESI is the lead of a project or core, but not the PD/PI for the overall application, the individual will retain ESI status when the award is made.

Please clarify this instruction: "Applicants without an existing EAC should describe their plans for constituting an EAC but should not specify names and should not contact potential EAC members in advance of review of the application."

Unless a person is deeply involved in the science of the application, they should not be listed as an EAC member as this might remove that person as a possible reviewer for other applications. Everyone involved in the science should be listed.

If we have advisors who can serve on the EAC, can we name them, or should we just discuss their expertise?

Unless a person is deeply involved in the science of the application, they should not be listed as an EAC member as this might remove that person as a possible reviewer for other applications. Everyone involved in the science should be listed.

Can Institutions outside the United States apply?

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.

Can researchers outside the US be suggested as scientific reviewers?

Due to the unique nature of rare diseases, research communities focused on them are typically smaller and involve a great deal of collaboration. We will be searching both within and outside the US to find the expertise needed for the review.

Can investigators outside of US be a Co-I of a clinical project or core?

Yes, the Notice of Funding Opportunity allows for foreign components defined in the NIH Grants Policy Statement as the performance of any significant scientific element or segment of a project outside of the United States, either by the recipient or by a researcher employed by a foreign organization, whether or not grant funds are expended. Please refer to the NIH Grants Policy Statement for additional details.

Can EU institutions or clinical sites be other participating sites? Can PIs from EU institutions serve as multi-/co-investigators?

Yes, the Notice of Funding Opportunity allows for foreign components defined in the NIH Grants Policy Statement as the performance of any significant scientific element or segment of a project outside of the United States, either by the recipient or by a researcher employed by a foreign organization, whether or not grant funds are expended. Please refer to the NIH Grants Policy Statement for additional details.

What special requirements or prior approvals are mandatory for a foreign SME participating in the RDCRC as a "foreign component"?

If an applicant determines that a portion of the project will be conducted outside of the U.S., the applicant then will need to determine if the activities are considered significant. If both criteria are met, then there is a foreign component. To aid with what may be considered significant, please refer to the NIH Grants Policy Statement. Applicants should include a justification for any foreign components in the grant application.

If an activity does not meet the definition of foreign component because all research is being conducted within the U.S., but there is a non-U.S. resource that supports the research of an investigator and/or researcher, it must be reported as other support.

For example, if an NIH-funded grant has a collaborator outside of the U.S. who performs experiments in support of the NIH-funded project, this would constitute a foreign component, regardless of whether the foreign collaborator receives funding from the NIH grant. Additional funding from a foreign source for the NIH-supported research at a U.S. institution would not constitute a foreign component but would necessitate reporting in the other support documentation.

Please clarify the eligibility for funding when a company has more than 50% non-US investors.

Foreign organizations are not eligible to apply. The NIH Grants Policy Statement defines a foreign organization as an entity that is:

• A public or private organization located in a country other than the United States and its territories that is subject to the laws of the country in which it is located, irrespective of the citizenship of project staff or place of performance;
• A private nongovernmental organization located in a country other than the United States that solicits and receives cash contributions from the general public;
• A charitable organization located in a country other than the United States that is nonprofit and tax exempt under the laws of its country of domicile and operation, and is not a university, college, accredited degree granting institution of education, private foundation, hospital, organization engaged exclusively in research or scientific activities, church, synagogue, mosque or other similar entities organized primarily for religious purposes; or
• An organization located in a country other than the United States not recognized as a Foreign Public Entity.

Can an RDCRC collaborate with an intramural NIH investigator and/or use the NIH clinical center for phenotyping?

The requests by NIH intramural scientists will be limited to the incremental costs required for participation. As such, these requests will not include any salary and related fringe benefits for career, career conditional or other Federal employees (civilian or uniformed service) with permanent appointments under existing position ceilings or any costs related to administrative or facilities support (equivalent to Facilities and Administrative or F&A costs). These costs may include salary for staff to be specifically hired under a temporary appointment for the project, consultant costs, equipment, supplies, travel, and other items typically listed under Other Expenses. Applicants should indicate the number of person-months devoted to the project, even if no funds are requested for salary and fringe benefits.

If selected, appropriate funding will be provided by the NIH Intramural Program. NIH intramural scientists will participate in this program as PDs/PIs in accord with the Terms and Conditions provided in this NOFO. Intellectual property will be managed in accord with established policy of NIH in compliance with Executive Order 10096, as amended, 45 CFR Part 7; patent rights for inventions developed in NIH facilities are NIH property unless NIH waives its rights.

Should an extramural application include the collaboration with an intramural scientist, no funds for the support of the intramural scientist may be requested in the application. The intramural scientist may submit a separate request for intramural funding as described above.

Should an intramural collaborator be listed in the grant application?

Yes, an intramural collaborator should be listed in the application.
 

Do we need the central IRB for the longitudinal trial, or could we use some existing registries with data use agreements?

The NOFO requires a single IRB for all multisite research projects. See the NIH Grants & Funding Single IRB for Multi-Site or Cooperative Research. SMART IRB provides resources for investigators describing the sIRB process, policies and practical guidance.

Does the single IRB need to be at the same place as the administrative core for all projects, or can there be different primary IRBs for different clinical research projects?

The Administrative Core will be responsible for coordinating the required single IRB. The NOFO requires a single IRB for all multisite research projects. See the NIH Grants & Funding Single IRB for Multi-Site or Cooperative Research. SMART IRB provides resources for investigators describing the sIRB process, policies and practical guidance.

Is there a section where all Letters of Support should be included? Should core-specific Letters of Support be included/repeated in relevant sections?

There is a specific section for Letters of Support.

Should we include a letter of support from our current External Advisory Committee members, as we are an existing consortium with an existing EAC?

Yes, a Letter of Support in this situation would be appropriate as this is an existing EAC, which has influenced the science.

Are the only biomarker studies allowed those that validate biomarkers that meet FDA requirements?

The NOFO does not require biomarkers studied to be validated to meet FDA requirements.

Is there a sample application for such a grant?

Unfortunately, the NIH does not provide sample applications for review. However, applicants can refer to the publicly available NIH RePORTER, which offers insights into the activities supported by current and previous RDCRC grants.

How many awards will be funded?

The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications that are within Institute Specific Research Interests and Priorities.

Will this Notice of Funding Opportunity be offered again in the next few years?

This funding announcement has historically been reissued every five years. Future announcements will be based on funding availability via NIH appropriations and program priorities.

What if a specific NIH institute is not listed on the NOFO? Will they still participate?

The participating institutes are listed on PAR-24-206. However, these institutes may be updated through a related Notice (NOT) added to the NOFO.

Does each clinical project need a 12-page component or are they bundled together?

Each of the individual clinical project components (2-4 required) is allowed a 12-page research plan. See the NIH Grants & Funding Page Limits. The U54 mechanism falls under the category of "all other activity codes" and requires following NOFO instructions.

Where do the references for the other attachments go? In the three pages or with all the other references?

See the NIH Grants & Funding Multi-project (M) instructions (page M-46):
Overall and Other Components: Unless specific instructions are provided in the FOA, applicants have the option of including the "Bibliography & References Cited" attachment in the Overall Component, Other Components, or both. User-defined bookmarks provided in the Bibliography & References Cited attachment will be included with the bookmarks of the assembled application image in eRA Commons. If you include the “Bibliography & References Cited” attachment only in the Overall Component, you may want to use bookmarks to organize references by component.

Is an Appendix allowed, and if so, what should be included?

Only limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the How to Apply- Application Guide.

Please clarify the page limitations for each component.

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

Is a specific aims page required for the Administrative Core component? 

Yes.

Does each component of the applicant require a Specific Aims page? 

Each component of a multi-component application requires a specific aims page. All page limitations described in the How to Apply- Application Guide and the Table of Page Limits must be followed.

Which components should include a Data Management and Sharing Plan? 

The Data Sharing and Management Plan should submitted under "Other Plans" as part of the Overall Component.

Is the head of a PAG a PI, Co-I, or a collaborator?

PAG members can, but are not required to, be a PI, Co-I, or collaborator.

Can a PAG serve as the primary applicant for an RDCRC if academic partners are involved as research sites?

Any applicant that meets the organization eligibility requirements as stated in the NOFO may apply as the primary applicant. All applications submitted must meet the NOFO requirements.

What qualifies as a Patient Advocacy Group?

There is no specific rule for what constitutes a patient advocacy group. The intent is for the lived perspective of patients, and their needs and priorities, to be meaningfully incorporated into decisions and activities of the proposed RDCRC.

Can an RDCRC Program Director (PD)/Principal Investigator (PI) serve as the PI of a project in a different RDCRC?

The RDCRC PD(s)/PI(s) cannot serve as the PD/PI of a project in another active RDCRC at the time of award; however, collaborations among RDCRCs are encouraged. For example, an RDCRC PD/PI could serve as a co-investigator or a consultant.

If an individual is PI of multiple components, do they need 2.0 person months devoted to each component or across components?

Individual PIs should have at least 2.0 person months effort per year across all the RDCRC projects and/or cores.

For example, an individual with 1.0 person month effort in one core and another 1.0 month effort in a project associated within the same RDCRC grant application would be in compliance with the minimum 2.0 month effort requirement.

Applicants may determine how best to allocate their time within the components of the application as long as the minimum 2.0 months effort is met, and the effort is commiserate to the activity being conducted. Reminder that if there are multiple PD/PIs, each individual must meet the minimum 2.0 person month requirement.

Is the overall PI typically also the PI of the Administrative Core?

It is the discretion of the applicant how they develop their application leadership structure.

If someone is the PI of one single project, is that considered a Co-I or Co-PI? Are they also obligated to the 2.0 person month requirement?

Each core and project need a PI. Only the application PD/PIs are required to have a minimum 2.0 person months. Generally, a single project PI is considered a Co-Investigator.

Is there a limit to the number of multiple PDs/PIs for the application?

NIH does not limit the number of multi-PD/PIs (MPIs). All MPI roles and responsibilities should be well justified and all MPIs should be included in the MPI Leadership Plan.

Are site PIs required to have 2.0 person months?

Only the application PD/PIs are required to have a minimum 2.0 person months.

Can clinical research projects be led by a co-PI?

Yes.

What is the difference between a Co-Principal Investigator (Co-PI) and a Co-Investigator (Co-I)?

NIH defines multiple individuals serving in a PI role as MPI. Other lead investigative leads may be considered co-investigator. It is important to include a Co-PI plan if there are multiple PIs on any component. However, please make sure to utilize the budget justification to clearly define the roles and responsibilities of each individual. Please refer to the Multiple Principal Investigators - General Information for additional details.

Can one investigator serve as a project PI on two separate RDCRC applications (as long as they are not a PD/PI of one?)

Yes.

Please explain the concepts of multi-/co-investigators and other participating sites.

Please refer to How to Apply- Application Guide and Multiple Principal Investigators for descriptions of roles and multiple PD/PI requirements.

Research studies must all be conducted at multiple sites. However, sites may also participate in other collaborative roles.

Who is required to have 2.0 person month effort - Consortium PI and/or all project and core PIs?

Only the application PD/PIs are required to have a minimum 2.0 person months.

Does each component that proposes multi-PIs require a multi-PI plan?

Each component that proposes multiple PIs requires a multi-PI plan. Please refer to the Multiple Principal Investigators - General Information for additional details.

Is there an optimal number of disorders that should be included in an RDCRC?

A minimum of three rare diseases must be included. There is no maximum number however, it is important to keep in mind budget restraints.

How many rare diseases must be represented in the application?

Each RDCRC application must indicate at least three different rare diseases that may share, but are not limited to, common pathways/mechanisms of action/organ system, and may be defined as:

• Conditions — a particular state of being that limits/restricts something else.
• Disorders — abnormal physical or mental conditions or ailments.
• Syndromes — a group of symptoms that occur together, or a condition characterized by a set of associated symptoms.
• Diseases — a disorder of structure or function that affects a specific location and is not simply a result of physical injury.

Would focusing on three different organ systems in one disease qualify as three rare diseases?

No - it would be considered a single rare disease.

Does the natural history study need to be its own individual project, or can it be an aim within each project?

One of the projects must be longitudinal in nature with the intent of understanding the clinical course of the disease and helping inform future clinical trials (e.g., natural history studies).

A lack of interest in basic science was mentioned. Is this limited to animal models, or does it encompass all basic science (such as genetics, cell models, etc.)?

The focus of the NOFO is clinical research. Applications proposing basic sciences studies will be considered non-responsive.

Is there a limit to the number of RDCRCs an institution can have as a primary site?

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

What is the difference between the "overall" project aims and the "clinical Project" aims?

The Overall specific aims should describe the overall goals of the RDCRC for the performance period of the grant. Applicants should describe the research objectives of the RDCRC for promoting understanding of rare diseases, facilitating early and timely diagnosis and establishing clinical trial readiness. The Clinical Research Project aims should state the goals of the proposed Clinical Research Projects concisely and summarize the expected outcome(s).

Is the PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record required for longitudinal studies?

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.

Should progress reports be described in the research strategy of respective cores and projects of a renewal application?

The Progress Report falls within the Research Strategy and is therefore included in the page limits for the Research Strategy. See NIH Grants & Funding Multi-project (M) instructions (page M-101).

How can we assess if the research scope of the prospective RDCRC does not overlap with already funded research?

Information on previous research can be found on NIH RePORTER. You may also contact a program officer with your specific aims, and they can confirm whether the research overlaps with prior projects.

Is there a specific number of sites that are desired?

There is no specific number of sites required, however you should consider the scientific needs and budget.

As part of clinical trial/therapy readiness, is there a role for translational laboratory bench work as part of an RDCRC, for example, using patient-induced pluripotent stem cells (iPSCs)?

The use of in vitro models must be relevant to clinical endpoints (i.e., testing drugs, validating biomarkers versus more basic research). Note that in vitro studies that utilize human tissues that cannot be linked to a living individual do not meet the NIH definition of Clinical Research.

What scale is used to score the Admin Core?

The Admin Core is scored on a scale from 1 to 9, while the other cores will be evaluated qualitatively as acceptable, acceptable with concerns, and unacceptable.

Do reviewers evaluate and score the entire grant as a whole, or do they assess and score each component separately?

Each component is scored separately, and then the scores are factored into the overall impact score.

Will previously funded RDCRNs be reviewed by the same group of reviewers as the first-time applicants?

The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications that align with the specific research interests and priorities of the participating NIH ICO.

All new and renewal applications are being solicited from the same NOFO and will be accepted and reviewed together.

How are the cores reviewed and what information should we include?

The Admin Core is scored on a scale from 1 to 9, while the other cores will be evaluated qualitatively as acceptable, acceptable with concerns, and unacceptable. The cores will only be reviewed based on language in the NOFO for the cores.