PAR-25-438_ Rare Diseases Clinical Research Consortia (RDCRC) for the Rare Diseases Clinical Research Network (RDCRN) (U54 Clinical Trial Optional).html

Department of Health and Human Services

Part 1. Overview Information

Participating Organization(s)

National Institutes of Health (NIH)

Components of Participating Organizations

National Center for Advancing Translational Sciences (NCATS)

National Heart, Lung, and Blood Institute (NHLBI)

National Human Genome Research Institute (NHGRI)

National Institute on Aging (NIA)

National Institute of Allergy and Infectious Diseases (NIAID)

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

National Institute of Dental and Craniofacial Research (NIDCR)

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

National Institute of Neurological Disorders and Stroke (NINDS)

Funding Opportunity Title

Rare Diseases Clinical Research Consortia (RDCRC) for the Rare Diseases Clinical Research Network (RDCRN) (U54 Clinical Trial Optional)

Activity Code

U54 Specialized Center- Cooperative Agreements

Announcement Type

Reissue of

PAR-24-206

Related Notices

Funding Opportunity Number (FON)

PAR-25-438

Companion Notice of Funding Opportunity

None

Number of Applications

See Section III. 3. Additional Information on Eligibility.

Assistance Listing Number(s)

93.350, 93.855, 93.866, 93.853, 93.172, 93.846, 93.837, 93.233, 93.838, 93.839, 93.840, 93.121, 93.865, 93.847

Notice of Funding Opportunity Purpose

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, 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.

Funding Opportunity Goal(s)

NCATS' mission is to turn research observations into health solutions through translational science. We work to develop or enhance the development, testing, and implementation of diagnostics and therapeutics for a wide range of diseases and conditions. Key approaches include understanding what’s similar across diseases to spur multiple treatments at a time, developing models that better predict a person’s reaction to treatment, enhancing clinical trials so results more accurately reflect the patient population, and leveraging real-world data and data science approaches to address public health needs. Facilitating these approaches are our robust partnerships with other government agencies, including other NIH institutes, centers, and offices; industry; academia; nonprofit organizations; and patients, patient advocates, and other communities. NCATS' vision is to bring more treatments for all people more quickly.

Key Dates

Posted Date

June 05, 2025

Open Date (Earliest Submission Date)

June 05, 2025

Letter of Intent Due Date(s)

Not Applicable

July 07, 2025

July 07, 2025

September 2025

October 16, 2025

October 16, 2025

July 2026

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.

Expiration Date

October 17, 2025

Due Dates for E.O. 12372

Not Applicable

Required Application Instructions

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.

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

The Division of Rare Diseases Research Innovation (DRDRI), within the National Center for Advancing Translational Sciences (NCATS), along with the Institutes, Centers, and Offices (ICOs) listed in Part I at the National Institutes of Health (NIH), invites applications in response to this Notice of Funding Opportunity (NOFO) for the Rare Diseases Clinical Research Consortia (RDCRC) component of the Rare Diseases Research Network (RDCRN). The RDCRCs were established with the intent of advancing the diagnosis, management, and treatment of rare diseases. Each RDCRC will promote highly collaborative, multi-site, and patient-centric translational and clinical research. The lived perspective of patients, and their needs and priorities, must be meaningfully incorporated into decisions and activities of the proposed RDCRC, with related patient advocacy groups having an active partnership role within the RDCRC. Each RDCRC must address specific unmet clinical research needs that will move the field of research forward from its current state of knowledge. This includes activities such as earlier diagnosis of individuals with targeted rare diseases and facilitating more rapid development of new treatments through a program in clinical trial readiness.

The previous iteration of the RDCRC (RFA-TR-18-020) indicated that it is the intent of the NIH to support individual RDCRCs for no more than three award cycles; that is, RDCRCs that have successfully competed for RDCRC funding with the same focus three times. New applications should not replicate the research project or aims of the previously funded RDCRC. The NIH will continue to support RDCRCs funded under previous, current, or future funding opportunities for no more than three award cycles. All new projects must address the specific interests of one or more NIH ICO. Prospective applicants are strongly encouraged to consult with the Scientific/Research Contacts of the NIH early in the preparation of the application (see Section VII. Agency Contacts).

Background The Rare Diseases Act of 2002 (Public Law 107-280 (https://www.gpo.gov/fdsys/pkg/PLAW-107publ280/content-detail.html)) defines a rare disease as a condition affecting fewer than 200,000 individuals in the United States. Collectively there are estimated to be over 10,000 diseases or conditions that fall into this category; cumulatively, there are approximately 25 – 30 million people in the United States who are affected by rare diseases or conditions. Many of these disorders lead to significant morbidity and mortality. These facts highlight that rare diseases are a significant public health concern.

Despite advances in our understanding of the causes and mechanisms of many diseases, effective treatments are available for fewer than 5% of rare diseases. Although advances in technologies such as gene-based therapies have recently led to promising and potentially transformative treatments, these are currently limited to a few rare diseases.

Bringing effective treatments to more people living with rare diseases is a risk-filled venture for numerous reasons. First, making a diagnosis can be challenging with many patients experiencing a "diagnostic odyssey" of years because of limited knowledge of the range of disease manifestations and of genotype-phenotype correlations. Second, many rare diseases have a spectrum of phenotypes, and there are often no high-quality natural history datasets documenting how the disease affects patients' functioning and how it progresses over time. Third, the relatively small number of patients and clinicians caring for them leads to challenges in the design and implementation of clinical trials. Fourth, there are often no sensitive and specific outcome measures or biomarkers that are appropriate for use in clinical trials or that are clinically relevant to patient needs. Fifth, the data quality and the rigor of scientific studies are often lacking and usage of data standards and adherence to FAIR principles for data management vary across rare disease research making collaborations difficult. Finally, the resources available for therapeutics development are limited, making it critical to find frameworks for leveraging partnerships among patient groups, industry, academic investigators, and federal funding agencies. The global burden associated with rare diseases necessitates international coordination and collaboration.

To facilitate progress in addressing these challenges, the Rare Diseases Act of 2002 directed the DRDRI to support regional "RDCRCs of Excellence" for clinical research, career enhancement, and demonstration of diagnostic, prevention, control, and treatment methods for rare diseases. Since the inception of this legislation, numerous NIH ICOs (NCATS, NCRR, OD, NICHD, NINDS, NIAMS, NHLBI, NIDDK, NIDCR, NIMH, NCI, NIAID and NEI), led by the DRDRI at NCATS, have partnered to support the RDCRN. The RDCRN was established to be a collaborative and coordinated network of investigators and patient groups committed to the investigation of rare diseases working in partnership with leaders in technology to enhance communication and sharing of resources through a multidisciplinary approach.

To date, this program has successfully supported 33 individual RDCRCs that have conducted research on nearly 250 individual disorders. The research conducted within the RDCRN has contributed to the Food and Drug Administration (FDA) approval for eleven treatments for rare diseases.

Organization of the RDCRN The RDCRN is a cooperative network composed of multiple Consortia (RDCRCs) and a Data Management and Coordinating Center (DMCC) established to coordinate RDCRN activities and to support and facilitate clinical research in rare diseases conducted by the RDCRCs. The RDCRN functions as a collaborative network with each RDCRC establishing and maintaining an environment that fosters collaborative, patient-oriented, multi-site, multi-disciplinary research collaborations and career enhancement.

The activities of the RDCRN are coordinated, facilitated, and supported by the DMCC. Patient advocacy group partners specific to the RDCRC participate in individual RDCRC activities as well as participating in Coalition of Patient Advocacy Group (CPAG) activities. The RDCRN governance consists of three committees: the Network Steering Committee (SC), the CPAG SC and the Joint Leadership Team (JLT). These committees are described in detail in the "Governance" section. The committees consist of the PIs of each funded RDCRC, their affiliated patient advocacy groups, the DMCC, and NIH program representatives including the NCATS RDCRN Program Director, Program Officials (PO) and Project Scientists (PS).

All recipients of an RDCRC and their teams are members of the RDCRN, and as such are part of a national rare diseases research resource. Each RDCRC will be expected to actively participate in network activities, including meetings of the Steering committee, biennial RDCRC meetings, and various relevant workgroups (e.g., bioinformatics, engagement, dissemination of information).

Each RDCRC must be willing to work towards being a member of a network that supports common data standards, FAIR data practices across sites; encourage the use of common data elements (CDEs); commit to community engagement; and agree to share data and other resources to the network, the broader scientific research community, and the general public.

RDCRC Elements:

Each RDCRC must focus on rare diseases. In this document, a rare disease is defined as one that affects fewer than 200,000 people in the United States (per the Rare Diseases Act 2002).

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:

Each RDCRC is required to have one natural history or longitudinal study. Research studies must all be conducted at multiple sites; however, pilot studies may be conducted at a single site.

Applicants are encouraged to emphasize new ideas, novel approaches, and state-of-the-art technologies to address the needs for early diagnosis and effective treatments along with other strategies to improve the lives of individuals with rare diseases.

Applicants with research agendas at varying stages of scientific development within the research program are encouraged to apply. This includes groups that would be considered early-stage RDCRC with many knowledge gaps that need to be addressed (e.g., groups that do not yet have established registries, groups with poorly defined natural history data that would benefit from an RDCRC effort).

Each RDCRC must form partnerships with patient advocacy groups. These groups must participate as active members of the RDCRC with meaningful roles within the RDCRC and as members of the RDCRN CPAG.

DMCC Structure The platform for the DMCC resides within the NCATS Information Technology Resources Branch (ITRB) provided cloud resource. All software licenses belong to NCATS. This is an NCATS-furnished infrastructure that the award recipient will use as a platform on which to build the data management and coordination center. This protects the integrity of the data and allows the RDCRN DMCC system to stay in the same location regardless of future DMCC award recipients.

Overall, the goal of the DMCC is to provide support to each individual RDCRC, and to coordinate and support the activities of the RDCRN as a whole. The structural requirements of the DMCC are:

It is the responsibility of the investigative teams of the DMCC cores (Administrative Core, Data Management Core, Clinical Research Core, and Engagement and Dissemination Core) to work collaboratively with each RDCRC to coordinate and support both RDCRC activities and RDCRN-wide efforts (e.g., develop and monitor best practices for clinical and research data handling and use as well as data sharing).

The RDCRCs will collaborate with the DMCC to establish and promulgate coordinated RDCRN data management and data sharing standards and policies within the RDCRC.

It is imperative that RDCRC applicants carefully review the DMCC NOFO to fully understand the resources and services that will be provided to the network participants by the DMCC. Applicants should ensure planned activities involve coordination with the DMCC and do not replicate efforts.

Coalition of Patient Advocacy Groups (CPAG) The RDCRN CPAG was established to promote collaboration between rare disease patient and stakeholder organizations and the RDCRN to facilitate better access to, and earlier benefit from, research conducted on rare diseases. Each RDCRC must be actively engaged with the CPAG.

Any RDCRC patient advocacy group members may participate in RDCRN activities. One patient advocacy group member from each RDCRC will be identified by the RDCRC to represent the consortia on the CPAG steering committee. As the patient advocacy arm of the RDCRN, CPAG members will use their position to advance the cause of rare disease research and improved patient outcomes through the network.

RDCRC Structure The structural requirements of an RDCRC under this NOFO are:

Cores Administrative Core Personnel An individual with demonstrated experience in the management of multisite clinical research programs, along with rare disease research should be identified as PI for the Administrative Core.

Administrative Coordinator - with appropriate skills and experience to assist the RDCRC Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) and Administrative Core PI with the day-to-day administrative details and program coordination.

Each Administrative Core should 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:

The Administrative Core of each RDCRC will be responsible for the following activities:

Administrative Support for RDCRC The Administrative Core is responsible for the overall management of day-to-day program activities for the RDCRC.

Clear policies and procedures should be established for the RDCRC that dovetail with those of the RDCRN. The core is responsible for funds allocation and establishing contracts with all participating RDCRC sites. The Administrative Core will facilitate the process of monitoring the progress of both the RDCRC and RDCRN program milestones that will be negotiated at the time of award.

All RDCRC-related meetings and calls will be managed by the Administrative Core along with coordination of the activities of the external advisory group. The Administrative Core is responsible for coordinating patient advocacy group involvement across RDCRC activities. The Administrative Core will also serve as the primary touchpoint for coordinating collaborations with the DMCC.

Management of RDCRC Agreements and Regulatory and Clinical Documentation The Administrative Core will coordinate and manage RDCRC agreements that regulate RDCRC activities. The Administrative Core will coordinate and manage all regulatory and clinical documents in collaboration with the NIH and the DMCC (e.g., Investigational New Drug Application (IND), Institutional Review Board (IRB), clinical protocols, consent forms). The Administrative Core will be responsible for coordinating the required single IRB.

The Administrative Core, in consultation with the DMCC, will establish RDCRN-specific data sharing and data use agreements within the RDCRC, for all clinical sites, and between the primary recipient institution and the DMCC..

Coordination of Activities with DMCC The RDCRC must not replicate services provided by the DMCC. The Administrative Core will work collaboratively with the DMCC Cores (Administrative Core, Data Management Core, Clinical Research Core, and Engagement and Dissemination Core) to coordinate and support both RDCRC activities and RDCRN-wide efforts (e.g., develop and monitor best practices for clinical and research data handling and use as well as data sharing). This includes the development and utilization of clinical trial readiness metrics for both regulatory requirements (e.g., protocols, IRBs) and clinical research components (e.g., natural history studies outcome measures, biomarkers) to evaluate their progress in clinical trial readiness.

They will also collaborate with the DMCC to establish and promulgate coordinated RDCRN data management and NIH data sharing standards and policies within the RDCRC. A plan should be developed to ensure effective use of the DMCC’s shared resources.

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:

Management and Sharing of Data and Biospecimens The Administrative Core will coordinate data sharing and biospecimen sharing, storage and tracking information across all clinical sites within the RDCRC and externally with agreements. The DMCC will provide resources for tracking specimens and, via a “virtual repository,” indexing biospecimens.

Engagement and Dissemination of Information The dissemination of information is an important component of the RDCRN. Outreach beyond academic activities is expected; this may include, but is not limited to, dissemination through social media, information and education for the patient community, and collaboration with the patient advocacy group(s) and the DMCC. The RDCRC will collaborate with the DMCC to create and manage a RDCRC-specific website. The RDCRC will provide information including:

Coordination of Patient Advocacy Group Participation The Administrative Core will establish communication and maintain engagement with all partnering patient advocacy groups.

Pilot/Feasibility Governance Core A Pilot/Feasibility Governance Core should be established to enable future innovative single- or multi-site pilot studies aimed at advancing the diagnosis, clinical trial readiness, management, and/or treatment of rare diseases. Pilot projects that extend RDCRC research collaborations beyond the RDCRN are allowed. Pilot projects may be awarded to institutions that are not already RDCRC members; however, execution of new subawards may be required.

The core should define the process by which pilot studies will be encouraged, assessed, and managed.

Specific pilot/feasibility projects must not be described in the current application and if described will not be considered in the review of the application. However, a plan for how pilots will be selected and how results will be disseminated must be included. Pilot projects may be clinical trials only with prior NIH institute approval, and policies may vary by institute.

The selection and initiation of future pilot/feasibility projects are contingent upon approval by the administering NIH institute and are subject to NIH clinical research regulations; see Prior NIH Approval of Human Subjects Research in Active Awards Initially Submitted without Definitive Plans for Human Subjects Involvement (Delayed Onset Awards): See https://grants.nih.gov/policy/nihgps/index.htm.

All pilot/feasibility projects must be documented within the DMCC’s network-tracking system once an award is made.

Career Enhancement Core The RDCRCs are expected to play a leadership role in career enhancement; attract new researchers for the rare diseases field; and contribute to the development of future research leaders. Each RDCRC should provide a Career Enhancement Program to provide support for career enhancement-related activities, as well as support for development of the institution's environment for the education of Career Enhancement candidates in rare diseases research. Examples of Career Enhancement candidates include, but are not limited to, the following:

Leveraging existing career enhancement programs and exploring fellowship opportunities from other public and private funding organizations is encouraged. This program may propose activities that expand the career enhancement environment through, for example, specialized coursework, a seminar program, retreats for presentation of Career Enhancement candidates’ research, mentoring programs, journal clubs, professional development programs, or other activities that contribute to the preparation of scholars and junior investigators for careers in rare diseases research. Exposure to research at other RDCRCs is also encouraged through exchange programs or visits to learn new research approaches. The leads of the Career Enhancement program should collaborate with the DMCC to develop disease agnostic, rare disease specific activities that would benefit participants of the Career Enhancement program. Results of projects supported by the core should be shared with the RDCRN.

The RDCRC must coordinate with the DMCC to track Career Enhancement recipients and activities within the RDCRN.

Clinical Research Projects The RDCRCs are intended to advance the diagnosis, management, and treatment of rare diseases with a focus on clinical trial readiness and early and timely diagnosis. A minimum of two but no more than four multi-site clinical research projects are required. 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). Clinical research supported under this NOFO includes mechanistic studies designed to understand a biological or behavioral process, the pathophysiology of a disease, or the mechanism of action of an intervention. Epidemiological, behavioral, and health outcomes research studies in rare diseases are also encouraged. Projects should address any relevant ethical, legal or social implications as needed.

Each of the proposed clinical research projects should address problems that require a substantial collaborative research effort as well as a multi-site RDCRC environment to solve and can benefit from NIH programmatic input. The research projects should be more substantial than what can be accomplished in a single site project. Success of each project should move the field closer to the design and/or implementation of pivotal clinical trials or earlier diagnosis.

Collectively, the projects should involve collaborative teams with experience in rare diseases, the RDCRC’s specific disease(s)/disorder(s)/syndrome(s)/condition(s), clinical research, biostatistics, and other requisite complementary expertise. Collaborations should ensure that input from all patients and partners (parents, caregivers, support, and advocacy groups) is sought at all stages in the clinical research process.

Any clinical trials proposed as part of a RDCRC must meet ICO-specific rules for clinical trials. Consultation with relevant ICO contact prior to proposing a clinical trial is highly encouraged. Such clinical trials should be designed to provide specific data that will be necessary to design a subsequent definitive efficacy trial. The proposed clinical trial must address questions that, when answered, will optimize the design of a subsequent definitive clinical trial rather than simply address the clinical question with lower power.

Small targeted clinical trials may be proposed if the project meets the criteria listed in the "Clinical Research - definitions and requirements" section. Knowledge from such clinical studies should be essential to direct subsequent clinical trials and can be invaluable for the targeted rare diseases. See Section IV.2 for additional guidance on projects that propose a clinical trial. Although clinical trials can be supported through an RDCRC, clinical trials are NOT a required component of an RDCRC application.

Examples of research areas that propose to advance rare disease research include but are not limited to:

Clinical Research - Definitions and requirements 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 study 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.

Clinical Research Clinical research, as it is defined by the NIH (https://grants.nih.gov/grants/glossary.htm#ClinicalResearch) is research with human subjects that is either:

In vitro studies with human biospecimens must be within the context of NIH-defined Clinical Research and relevant to clinical endpoints.

Studies based entirely on publicly available or deidentified data or specimens (thus falling under 45 CFR 46.101(b) (https://www.hhs.gov/ohrp/regulations-and-policy/regulations/45-cfr-46/index.html), Exemption 4) are not considered clinical research by this definition. However, these types of studies can be included in pilot studies or as a part of larger clinical research projects.

Clinical Trials A clinical trial, as defined by the NIH, is a research study 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. NIH provides a decision tool to determine whether a study meets the NIH definition of a clinical trial (https://grants.nih.gov/ct-decision/index.htm).

If a clinical trial is included in the application, it must demonstrate potential value of the trial and the feasibility of successfully completing the trial within the duration of the award, including the preclinical rationale, if applicable. The preclinical rationale should provide evidence that the rigor of preclinical efficacy studies and the level of effect of the agent are both sufficient to warrant clinical testing of the agent (for guidance, see https://grants.nih.gov/policy/reproducibility/index.htm).

Clinical trials involving the testing of new investigational therapeutics, new indications for FDA-approved drugs, or other medical interventions under a research protocol should be performed under an IND or Investigational Device Exemption (IDE), unless otherwise agreed upon by the FDA. Unless the investigational product or device is exempted from the FDA IND/IDE requirements, the applicant must provide the NIH with the name and organization of the IND/IDE holder, the date the IND/IDE was filed with the FDA, the FDA IND/IDE number, and any comments from the FDA regarding this protocol. Studies will not be funded unless necessary regulatory approval has first been obtained; regulatory approval at the time of application is preferred.

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

Although some clinical trials can be supported through the RDCRC, clinical trials are NOT a required component of a RDCRC application. RDCRC award recipients are encouraged to leverage the RDCRC infrastructure to support clinical trials funded through other sources. Award recipients that desire to seek support for projects that are single-site, basic, translational, or clinical trials outside of the scope of this NOFO should contact the Scientific/Research Contact listed in Section VII. Agency Contacts below for guidance on appropriate funding opportunities. Any clinical trial using the RDCRC resources must receive prior approval from the NIH awarding institute/center and be managed through an appropriate agreement between the RDCRC and funding source which requires all parties to adhere to NIH clinical trial policies and regulations.

Enhancing Reproducibility through Rigor and Transparency The NIH is committed to promoting rigorous and transparent research in all areas of science it funds (https://grants.nih.gov/policy/reproducibility/index.htm). The basic principles of rigor and transparency are: 1) rigor of the prior research; 2) rigorous experimental design for robust and unbiased research results; 3) consideration of relevant biological variables, and 4) authentication of key biological and/or chemical resources (https://grants.nih.gov/policy/reproducibility/guidance.htm). Investigators should consider how all four areas apply to their proposed research.

Additional Support Applicants are strongly encouraged to leverage other existing NIH-supported research resources, such as the SMART IRB (https://smartirb.org/), Clinical and Translational Science Award (CTSA) hubs (https://ncats.nih.gov/ctsa) and the Trial Innovation Network (https://trialinnovationnetwork.org/). Projects that leverage the resources of ongoing clinical trials or longitudinal studies supported through other Federal or private funds are also encouraged.

Funds from other sources are acceptable, such as support from advocacy groups, private research foundations, academic institutions, industry, and other government agencies. Memorandum of Understanding agreements between parties need to ensure transparency, prevent misuse of federal funds, and ensure that NIH policies with respect to sharing of data and resources, academic freedom, and publication rights are not violated. Any activity conducted via the Memorandum of Understanding must comply with NIH policies and regulations for conducting human subject's research.

Data Management and Coordinating Center (DMCC) Support Advancing rare disease research by freely sharing high-value data is a critical goal of the program.Deidentified data collected within this network will become a resource for the greater rare disease research community and will be made available to the scientific community, stakeholders and other relevant partners in a timely manner that meets all NIH human subject's protection, data safety and data sharing requirement.

RDCRC participants are required to work collaboratively within the RDCRN DMCC cloud environment and to ultimately share their data within RDCRN Data Repository (RDCRN-DR).

The DMCC will support the consortia by maintaining a robust secure data infrastructure for the RDCRN. The DMCC will work closely with NCATS to provide Cloud Computing Services and Engineering Support provisioned by the ITRB at NCATS. The DMCC will provide:

RDCRN Cloud-Based Working Environment The DMCC will provide:

Data Management Services The investigative team of the Data Management Core will also manage and facilitate use of Cloud Computing Services and Engineering Support provisioned by the ITRB, NCATS.

NCATS ITRB will provide access to various public cloud services and high-performance computing services for the needs of the RDCRN. The NCATS ITRB works directly with the DMCC. The DMCC is responsible for working with each individual RDCRC however, there may be special instances where the ITRB will work collaboratively with the DMCC and RDCRC (e.g., establishing use of a new tool in the cloud environment). This enables the DMCC to provide the RDCRCs systems, projects, and research in a secure environment with simplified implementation, deployment and operational reliability. Through these services, NCATS ITRB will prepare the recipients to gain a self-service capability.

The DMCC will provide RDCRCs access to the cloud instance through the NCATS' Federated Authorization Services and will have complete rights to all services provided by the Cloud Service Provider.

The DMCC will coordinate and support efforts, in collaboration with representatives of the RDCRC, to develop and monitor Good Data Practices (GDP) of clinical and research data and will assist in facilitating the use of the FAIR principles for data management. The DMCC will also facilitate and coordinate data standards across the network.

Investigators who participated in the RDCRN and shared data in the current RDCRN data environment will be provided by NCATS access to account management, tools, and data storage (provisioned by the DMCC) for their RDCRC data for up to five years post-award. Any custom development, setup, or data management will not be included; if needed, it can be provided by the former RDRCR, or a third party paid for by the former RDCRC. Access to this resource will be provided based upon application and NCATS approval.

Data Sharing Environment - The RDCRN-Data Repository (RDCRN-DR) The RDCRN-DR will serve as the central repository for RDCRN-generated clinical research data. It will host consented research data from RDCRC-initiated natural history studies, interventional studies and trials, patient reported outcomes and other modalities that were obtained under RDCRN protocols. The RDCRN-DR will also function as a central indexing site for RDCRN data that may be required to reside in other NIH-based data repositories, such as the database of Genotypes and Phenotypes (dbGaP https://www.ncbi.nlm.nih.gov/gap/), National Database for Autism Research (NDAR https://nda.nih.gov/).

Once the data has been transferred to the RDCRN-DR NCATS becomes responsible for regulating access to the RDCRN-DR through a Data Access Committee (DAC) made up of Federal representatives. The DAC will meet regularly to adjudicate access requests and ensure that data is only made accessible if the requests are compatible with data use limitations for the data in question. NCATS hosts this cloud-based platform and ensures its long-term sustainability.

Deidentified data collected within this network and housed within cloud services, provisioned by NCATS, will become a resource for the greater rare disease research community and will be made available, via controlled access, to the scientific community, stakeholders and other relevant partners in a manner that meets all NIH human subject's protection, data safety and data sharing requirements.

Milestones Both RDCRN and RDCRC milestones should inform annual evaluations of progress of the network. When applicable, any milestone report should describe how measurable outcomes will be collected using rigorous and transparent experimental approaches. These approaches include, but are not limited to, randomization, blinding, use of statistically adequate sample sizes with biologically relevant effect sizes, minimization of potential of scientific bias, independent replication, and adequate reporting of experimental details and results as described at https://www.ninds.nih.gov/Funding/grant_policy.

Prior to funding an application, the NIH PO will contact the applicant to discuss the proposed milestones and any concerns raised by the review panel or program staff. A final set of NIH-approved RDCRC and RDCRN milestones will be agreed upon prior to award.

RDCRN milestones will include, but are not limited to:

Finalization of milestones will be negotiated at the time of the award, as appropriate. Future year support is contingent on satisfactory achievement of performance milestones. If milestones are not achieved fully, NIH POs may request development of a remedial plan and more frequent monitoring of progress or take other remedial action.

Governance RDCRN Governance (Network-specific) The awards funded under this NOFO will be cooperative agreements (see Section VI.2. Cooperative Agreement Terms and Conditions of Award).

The RDCRN will consist of all the awarded RDCRCs, their affiliated patient advocacy group(s), the DMCC, and NIH program representatives. The RDCRN governance consists of the NCATS RDCRN Program Director, JLT, Network SC, and the CPAG SC.

NCATS RDCRN Program Director

RDCRN Joint Leadership Team The RDCRN JLT will serve as the Executive Committee of the RDCRN. The JLT will meet on a monthly basis to hold strategic discussions regarding the RDCRN functioning and will make executive decisions related to RDCRN activities. The JLT will screen any potential cross-network research projects from external or internal collaborators and make recommendations to the Network SC. In addition, the JLT will discuss any issues in need of consensus or resolution and will identify solutions to be discussed with the RDCRN SC and/or the CPAG SC. Each JLT member will have one vote, with the NCATS RDCRN Program Director casting the consensus vote on behalf of all NIH POs.

The JLT is composed of:

RDCRN Network Steering Committee The Network SC will identify scientific and policy issues that need to be addressed at the network level and review and approve all RDCRN-wide policies. The Network SC will identify broad issues in the field of rare diseases research that can be addressed by the network. It will also ensure dissemination of program data, career enhancement schedules and other materials to the wider scientific community. The Network SC may establish subcommittees and working groups to facilitate development, implementation, and monitoring of specific network functions as needed.