Part 1. Overview Information

Key Dates

Dates in bold and italics reflect changes per NOT-TR-24-027

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.

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.

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: 

• 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. 

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: 

• Administrative Core to facilitate network operation, governance, and communication. 
• Data Management Core to build and maintain a robust, secure data infrastructure. 
• Clinical Research Core to provide guidance in developing best practices in clinical research, protocol development and good data practices using the FAIR principles. 
• Engagement and Dissemination Core to promote patient engagement and broad research dissemination. 

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:

• Administrative Core
• Pilot/Feasibility Governance Core
• Career Enhancement Core
• 2-4 Clinical Research Projects

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: 

• Biostatistician - Individuals with demonstrated strong statistical experience working with rare diseases research as well as clinical trial design and implementation. 
• Bioinformatics - Individuals with demonstrated skills in managing RDCRN established data standards, FAIR data principles, and biological data, especially when the data sets are small and complex.  

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

• Administrative Support for RDCRC
• Management of RDCRC Agreements and Regulatory and Clinical Documentation 
• Coordination of Activities with DMCC
• Management and Sharing of Data and Biospecimens
• Collaborating with the DMCC in the Engagement and Dissemination of Information
• Coordination of Patient Advocacy Groups Participation 

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 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 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: 

• Key contacts for individual research studies
• Patient advocacy group contacts 
• Protocols and schedule of events
• List of diseases/disorders studied
• Consent
• Documents and data use limitations
• List of data elements and data modalities
• List of sites and personnel 

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 appropriate 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:

• Diseases studied, disease definitions, publications, clinical sites, studies, resources, funding opportunities, etc.
• Design (determine logo, colors, photos, site layout, etc.)
• Review (attend regular meetings and reviews with team to build and finalize site)
• Collaborate with DMCC to promote new RDCRC via RDCRN blog, podcast, newsletter, social media.
• Highlight new publications
• Highlight ongoing studies

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; foster diversity, equitability, inclusivity, and accessibility in the rare diseases research community; 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 diverse Career Enhancement candidates in rare diseases research. Career Enhancement plans aimed at fostering diverse scholars and investigators from populations traditionally underrepresented in research careers, such as race, ethnicity, geography (e.g., rural, urban), gender, and socioeconomic status, are especially welcome (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-22-019.html), as are Career Enhancement Programs at minority serving institutions. Examples of Career Enhancement candidates include, but are not limited to, the following: 

• Doctoral/Medical students
• Postdoctoral fellow/researchers
• Clinical fellows
• Early-stage investigators
• Investigators new to the rare disease field 

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: 

• Characterization of the rare disease cohort being studied, including demographic, genetic, phenotypic, imaging and laboratory data to identify disease subtypes, i.e., differentiate patients with similar morphological phenotypes but different genetic mutations and severity of outcomes.
• Clinical studies aimed at clinical trial preparation, including natural history studies.
• Development of algorithms connecting clinical and patient-reported outcomes with laboratory, imaging, environmental and -omics data to aid decision-making for clinical management of the rare diseases being studied.
• Early-stage clinical trials.
• Elucidation of genotype-phenotype interactions and multisystem phenotyping to develop reliable and valid predictive tools to determine who will respond to which treatments and when to intervene.
• Encouragement of dissemination and implementation research for rare diseases including:
  • Partnering with clinicians and patient communities to understand barriers to and facilitators of implementation of known treatments and interventions for rare diseases.
  • Study of implementation strategies to increase adoption, feasibility, and sustainability of known effective evidence-based interventions for rare diseases.
  • Strategies to understand how to disseminate evidence-based assessments or diagnostics and clinical guidelines to relevant rare disease populations. 
• Encouragement of innovative methods such as use of telemedicine and community-engagement approaches to improve inclusion of participants with rare diseases located in remote locations or facing other barriers to participating in research.
• Evaluation of the contribution of lifestyle factors to racial/ethnic and other demographic differences in rare-disease risk, severity, and treatment response.
• Generation of data (laboratory, clinical and imaging data) to improve diagnosis and to distinguish subtypes of the rare disease being studied.
• Identification of molecular pathways that can lead to therapeutic targets.
• Natural history of progression of rare disease being studied and clinical outcomes.
• New treatment modalities.
• Prevention studies.
• Repurposing of drugs.
• Studies that will address evidence gaps that are required for a successful Recommended Uniform Screening Panel nomination for newborn screening.
• Utilization of data science and other novel analytic techniques to study rare-disease risk, severity, and treatment response among specific populations (e.g., pregnant women, obese or low-weight patients, elderly patients).
• Validation of biomarkers that meet FDA requirements as a drug development tool for use in future Phase III Randomized Clinical Trials. 

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 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: 

• Patient-oriented research. Research conducted with human subjects (or on material of human origin such as tissues, specimens, and cognitive phenomena) for which an investigator (or colleague) directly interacts with human subjects. Excluded from this definition are in vitro studies that utilize human tissues that cannot be linked to a living individual. This definition includes (a) mechanisms of human disease, (b) therapeutic interventions, (c) clinical trials, or (d) development of new technologies.
• Epidemiological and behavioral studies.
• Outcomes research and health services research. 

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: 

• Studies to optimize the intervention strategy: for example, studies designed to investigate dose-concentration, dose-response, or concentration-response relationships that may inform optimal dosage selection for definitive trials.
• Studies to assess the appropriate delivery system or parameter settings of an electronic device or surgical technique.
• Studies to assess the safety and tolerability of various doses or concentrations of a specific intervention.
• Studies designed to evaluate whether an intervention produces sufficient evidence of short-term activity (e.g., biomarker activity) in humans to justify an efficacy trial.
• Studies designed to select the best of two or more potential interventions or dosing regimens to evaluate in a subsequent definitive trial, based on tolerability or evidence of biological activity. 

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 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: 

• A management system for collection, storage, and quality control of clinical research data, including a web-based platform that allows for real-time tracking of data quality and completeness and that facilitates remote monitoring.
• A management system that provides a "virtual repository" that indexes existing biosamples and other resources within the network.
• A portal and tools establishing a "tool garden" of shared research tools for research scientists and clinicians to access and manage their own data. 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. 

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 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: 

• All recipients will share the following information with the DMCC: 
  • Key contacts for individual research studies 
  • Key Patient Advocacy Group contacts
  • List of diseases/disorders studied
  • Consent documents and data use limitations
  • Protocols and schedule of events for all studies
  • List of participating sites and personnel
  • Anticipated date of enrollment of the first participant
  • Completion of data collection
  • Information regarding pilot studies
  • Information regarding Career Enhancement Core beneficiaries 
• In collaboration with the DMCC: 
  • Establish a plan for data management and data coordination-including the use of data standards and data sharing best practices. 
  • Establish a plan for effectively using RDCRN shared resources.
  • Establish a plan track project biospecimens in a virtual repository that indexes samples.
  • Establish a RDCRC-specific website.
  • Establish all required data use and data sharing agreements with the DMCC.
  • Establish data use and data sharing agreements across all sites within the RDCRC that correspond to network wide agreements. 

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  

• Provide coordination for network activities.
• In consultation with NIH staff, other federal agency staff, and non-NIH experts in the field, provide feedback and guidance on program activities.
• Coordinate with the DMCC to interact with PD(s)/PI(s) on a regular basis to facilitate access to NIH resources.
• Help organize the annual Network SC Meeting.
• Help coordinate collaborative efforts within the RDCRN.
• Help facilitate collaborative efforts with external partners (e.g., National Organization for Rare Disorders (NORD), European Rare Disease Research Coordination and Support Action consortium (ERICA), Chan Zuckerberg Initiative (CZI)).
• Be the vote casting NIH member of the Network SC (the NIH will have only one vote – that will be a consensus decision across PO).
• Advise the SC on drafting and applying operating policies that require coordinated action across the RDCRN.
• Work collaboratively with all PO and PS.
• Have responsibility for negotiating and approving RDCRN Milestones that are quantifiable for measuring success in meeting the goals of RDCRN membership. Each RDCRN milestone should have quantitative criteria associated with them.

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.  

The JLT is composed of:

• Network SC Chairs
• CPAG SC Chairs
• One DMCC PD/PI representative
• NCATS RDCRN Program Director

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.

The Network SC is composed of:

• The RDCRC PD(s)/PI(s)
• CPAG SC Chairs
• The PD(s)/PI(s) of the DMCC
• NCATS RDCRN Program Director
• NIH PO(s)/PS(s) from participating ICOs

RDCRN Coalition of Patient Advocacy Group Steering Committee

The CPAG SC will identify scientific and policy issues that need to be addressed at the network level, as well as broad issues in the field of rare diseases research that are specifically relevant to patients.  

The CPAG SC is composed of:

• One patient advocacy group representative from each RDCRC
• Two PD(s)/PI(s) representatives
• The PD(s)/PI(s) of the DMCC
• NCATS RDCRN Program Director
• NIH PO(s)/PS(s) from participating ICO

RDCRC Governance (Consortium-specific)

Each RDCRC will establish an External Advisory Committee (EAC) consisting of scientific, clinical, and patient group representation that will be composed of at least five members. The EAC serves in an advisory capacity to the RDCRC by providing an annual review and critique of the scientific progress of the RDCRC. The EAC should meet in-person or electronically at least once a year, beginning in the first or second year of the award.
 

Regulatory Requirements 

Single IRB (sIRB) for Multisite Projects 
Single IRBs are required for all multisite projects. Investigators are strongly encouraged to use SMARTIRB and its reliance agreements. https://smartirb.org/. 

Genomic Sequencing 
Due to regulatory requirements for using research results in clinical care, some sequencing data will be expected to be in compliance with the Clinical Laboratory Improvement Amendments (CLIA) when the results of genomic sequencing will be returned to participants or used for clinical decision-making purposes. In addition, an FDA IDE may be needed for new sequencing methods used in clinical care, separate from the requirement for the test to have been conducted within a CLIA-certified environment. Investigators must be prepared to discuss the possible need for an IDE with their IRBs and document the outcome of those discussions, and to subsequently engage in pre-submission discussions with the FDA. These typically involve submission of actual study protocols, including the entire sequencing pipeline from sample preparation to return of results. Applicants may wish to consult the following "Points to Consider in Assessing When an Investigational Device Exemption (IDE) Might be Needed" (http://www.genome.gov/27561291). 

Institute Specific Research Interests and Priorities

NOTE: Prospective applicants are urged to consult with the Scientific/Research Contacts of the NIH early in the preparation of the application (see Section VII. Agency Contacts).

National Heart, Lung, and Blood Institute (NHLBI)

The NHLBI seeks applications that will establish longitudinal cohorts in rare Heart, Lung, Blood, or Sleep (HLBS) diseases to investigate unaddressed research questions using epidemiologic study designs and methods that are appropriate for HLBS conditions affecting fewer than 200,000 persons in the US. These observational cohort studies should be designed to provide an evidence base for future interventional studies, including clinical trials; for developing better diagnostics than those that are currently available; for answering early translational questions; or for broader implementation of guidelines for managing these diseases. NHLBI encourages consortia study rare or related rare diseases, disorders, conditions, or syndromes together based on pathogenesis, affected biochemical, cellular, or physiological features or organ system involvement. Studying related rare diseases within the same cohort could help understand the nuances, and knowledge gained from one disease could accelerate the advances in related diseases.

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

• Natural history of progression of HLBS rare disease being studied and clinical outcomes;
• Generation of data (laboratory, clinical and imaging data) to improve diagnosis and to distinguish subtypes of the rare disease being studied;
• Development of algorithms clinical and patient-reported outcomes with laboratory, imaging, environmental and -omics data to aid decision-making for clinical management of the rare diseases being studied;
• Elucidate genotype-phenotype interactions and multisystem phenotyping to develop reliable and valid predictive tools to determine who will respond to which treatments and when to intervene;
• Encourage innovative methods such as telemedicine and community-engagement approaches to include participants with rare diseases located in remote locations;
• Characterization of the rare disease cohort being studied, including genetic, phenotypic, imaging and laboratory data to identify disease subtypes i.e., differentiate patients with same morphological phenotypes but different genetic mutations and severity of outcomes;
• Validation of biomarkers that meet FDA requirements as a drug development tool for use in future Phase III Randomized Clinical Trials
• Identification of molecular pathways that can lead to therapeutic targets;
• Comparative studies of newborn-screened cohorts diagnosed with an HLBS disease that receive prescribed standards of care versus those who do not and the factors (e.g., socioeconomic, geographic) that contribute to their health outcomes
• Encourage dissemination and implementation research for rare diseases including:
  • partnering with clinicians and patient communities to understand barriers to and facilitators of implementation of known treatments and interventions for rare diseases;
  • study of implementation strategies to increase adoption, feasibility, and sustainability of known effective evidence-based interventions for rare diseases;
  • strategies to understand how to disseminate evidence-based assessments or diagnostics and clinical guidelines to relevant rare disease populations
• Evaluate the contribution of lifestyle factors to racial/ethnic differences in rare-disease risk, severity, and treatment response
• Utilize data science and other novel analytic techniques to study rare-disease risk, severity, and treatment response among specific populations (e.g., pregnant women, obese or low-weight patients, elderly patients).
• Proposals are encouraged to include projects with significant unmet clinical and research needs which utilize teams from different clinical sub-specialties in HLBS mission areas, e.g. dedicated projects which study pulmonary and cardiovascular complications of sickle cell disease.

Research supported by this NOFO should fall within the NHLBI mission of (HLBS)-related disorders. Some examples of eligible rare HLBS diseases underrepresented in the current NHLBI portfolio include:

Rare Blood Diseases

Acquired aplastic anemia, antiphospholipid syndrome, hemophagocytic lymphohistiocytosis, hemophilias, hereditary hemorrhagic telangiectasia, heparin-induced thrombocytopenia, paroxysmal nocturnal hemoglobinuria, rare bleeding disorders, rare nutritional anemias, rare thrombotic disorders, rare hemolytic anemias, sickle cell disease, thrombocytopenias of different etiologies, thrombotic thrombocytopenic purpura, inherited bone marrow failure syndromes (IBMFS) that encompass a group of rare genetic blood disorders in which there is usually some form of aplastic anemia (failure of the bone marrow to produce blood), associated with a family history of the same disorder such as Fanconi Anemia, Diamond Blackfan Anemia (DBA), Dyskeratosis Congenita (DC) and Severe congenital Neutropenias (SCN), thalassemias (e.g. Cooley’s Anemia).

Rare Lung Diseases

Alpha-1-antitrypsin deficiency, Birt-Hogg-Dubé Syndrome, Hermansky-Pudlak Syndrome, pediatric interstitial lung diseases, primary ciliary dyskinesia, pulmonary alveolar microlithiasis, pulmonary alveolar proteinosis, pulmonary arterial hypertension, pulmonary Langerhans cell histiocytosis, sarcoidosis, lymphangioleiomyomatosis, studies of systemic autoimmune diseases that focus on pulmonary manifestations i.e. Systemic Sclerosis, primary Sjogren syndrome, Systemic lupus erythematosus (SLE), Dermatomyositis (DM) and polymyositis (PM), systemic (ANCA-associated) vasculitis and mixed connective tissue disease.

Rare Cardiovascular Diseases

Alagille Syndrome, Ehlers Danlos Syndrome, DiGeorge Syndrome, dysbetaliproproteinemia, familial hypercholesterolemia, Hutchinson-Gilford progeria syndrome, inherited channelopathies (Long-QT Syndrome, Brugada Syndrome), Kawasaki Disease, Klippel-Trenaunay-Weber Syndrome, Loeys Dietz Syndrome, Marfan Syndrome, Peripartum Cardiomyopathy, Pompe Disease, rare inherited cardiomyopathies (such as arrhythmogenic right ventricular dysplasia, Danon Disease, LEOPARD Syndrome, Noonan Syndrome), Tangier Disease, Turner Syndrome, Vascular malformations including capillary, venous, lymphatic, and rare arteriovenous malformations including but not limited to, pulmonary arteriovenous malformation, Sturge-Weber syndrome, Gorham-Stout syndrome, hereditary hemorrhagic telangiectasia, kaposiform lymphangiomatosis.

Rare Sleep Disorders

Advanced sleep phase circadian disorder, narcolepsy, Klein-Levine syndrome, sleep-related eating disorder, fatal familial insomnia, exploding head syndrome (episodic cranial sensory shock), central hypoventilation syndrome.

Prior to submission of an application in response to this NOFO, applicants are strongly encouraged to consult with the Scientific Research Contacts. Early contact is encouraged, as this provides an opportunity for NHLBI staff to provide information and guidance to a potential applicant.

National Institute of Allergy and Infectious Diseases (NIAID)

NIAID research activities on rare diseases are classified into four areas: infectious diseases, primary immunodeficiency diseases, autoimmune diseases, and allergic diseases.

• Infectious diseases include diseases caused by bacteria, parasites, viruses, fungi, and other pathogens.  Research on rare infectious diseases is aimed at delineating mechanisms of disease pathogenesis and developing more effective diagnostic, treatment, and prevention strategies.
• Primary immunodeficiency diseases are hereditary disorders caused by intrinsic defects in the cells of the immune system and are characterized by unusual susceptibility to infection. NIAID research is focused on the identification of gene defects and immunologic abnormalities that lead to defective function, and the development of new approaches for the diagnosis and treatment of primary immunodeficiency disease, including gene transfer as an effective and curative therapy.
• Autoimmune diseases are diseases in which the immune system mistakenly attacks and damages the body's own cells and tissues. NIAID research is focused on the identification of mechanisms of pathogenesis and the development of new approaches to prevention and treatment.
• Allergies are inappropriate or exaggerated reactions of the immune system to substances that cause no symptoms in the majority of people.

NIAID welcomes applications focused on rare diseases that fall within the four areas above and NIAID staff encourages prospective investigators to contact them regarding the fit of their research for this funding opportunity.  For applications that propose clinical trials, NIAID strongly encourages applicants to contact NIAID staff early in the planning stage to assist applicants in meeting NIAID clinical trial requirements.

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

Many arthritic, rheumatic, musculoskeletal and skin diseases affecting adults and children that are of importance to NIAMS are considered rare. NIAMS is interested in supporting research into the causes, treatment and prevention of these rare diseases.

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

Applicants are strongly encouraged to contact NICHD staff to discuss potential applications and disease areas of interest.

The NICHD conducts and supports research on topics related to health of children, adolescents, adults, families, and populations. NICHD also supports research on populations that are often excluded from research, such as pregnant and lactating people or people with intellectual, developmental, and/or physical disabilities. Many disorders that affect children and their families are rare and/or neglected diseases. Many of these diseases have a genetic basis, and many affect neurodevelopment. NICHD is especially interested in research proposals that include both underrepresented and underserved patient populations and whose team members represent diverse backgrounds. NICHD encourages applications in rare disorders, including (but not limited to):

• Conditions that are screenable in the newborn period:
  • This includes, but is not limited to, conditions currently on or with the potential to be added to the Recommended Uniform Screening Panel (RUSP; https://www.hrsa.gov/advisory-committees/heritable-disorders/rusp)
  • NICHD is especially interested in supporting natural history studies and longitudinal follow-up studies of newborn screenable conditions
• Metabolic disorders (e.g., organic acidemias, amino acidopathies, fatty acid oxidation disorders, neurotransmitter disorders)
• Storage diseases (e.g., gangliosidoses, mucopolysaccharidoses, mucolipidoses, peroxisomal disorders, glycogen storage disorders, other lysosomal storage diseases)
• Congenital anomalies and other structural malformations
• Genetic, genomic, and epigenetic disorders and syndromes:
  • Angelman, Fragile X, Prader-Willi, Williams, Smith-Magenis, Cornelia de Lange, and other syndromes
  • Copy number variation disorders, such as 22q11.2 deletion syndrome, 18q, 1p36, and other microdeletion or microduplication disorders
  • Sotos, Weaver, and Kabuki syndromes, and other Mendelian disorders of the epigenetic or chromatin remodeling machinery
• Sex chromosome disorders (e.g., Turner syndrome, Klinefelter syndrome, XXYY, XXXY, XXX, XYY)
• Disorders of sex development and other rare disorders of the renal and genitourinary systems
• Other rare, pediatric-onset disorders

National Institute on Deafness and Other Communication Disorders (NIDCD)

NIDCD is interested in supporting research that examines hearing, balance, taste, smell, voice, speech, or language in individuals with rare diseases.

National Institute of Dental and Craniofacial Research (NIDCR)

The NIDCR seeks to support clinical research on rare dental, oral, and craniofacial diseases and conditions. NIDCR is also interested in oral manifestations of rare diseases or conditions that severely impact oral health.

Interests include, but are not limited to, the conditions listed below. Applicants are strongly encouraged to contact NIDCR to discuss potential applications and areas of interest.

Examples include:

• Diseases associated with craniofacial or alveolar bone loss, early tooth loss, severe dental caries, and enamel and dentin defects;
• Diseases of the gingiva, periodontium, and other oral soft and hard tissues that may or may not be associated with metabolic, structural, or immune defects;
• Dental and craniofacial anomalies, syndromes, and disorders resulting from immunodeficiencies, inborn errors of metabolism, environmental factors, and other genetic defects;
• Dentofacial malformations and birth defects including hypodontia;
• Infantile to adult-onset forms of rare diseases or disorders that manifest in the oral cavity or craniofacial skeleton such as hypomineralization and hypophosphatasia;
• Rare tumors of the head and neck, including salivary gland cancers; and
• Oral diseases or conditions that are the result of head and neck radiotherapy or medication treatment for cancers such as medication-induced osteonecrosis of the jaw and osteoradionecrosis of the jaw.

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

The NIDDK supports research on selected rare diseases and conditions resulting in endocrine, metabolic, digestive, hematologic, urologic, and kidney disorders. Below are some examples of rare diseases that may be appropriate. Examples of rare liver diseases include biliary atresia or monogenic forms of severe liver diseases in children; diseases of the pancreas include hereditary recurrent acute and chronic pancreatitis; diseases of the alimentary tract include rare forms of intestinal failure such as tufting enteropathy. Examples of rare endocrine diseases include acromegaly, hypoparathyroidism, pseudohypoparathyroidism, familial hypocalciuric hypercalcemia, thyroid hormone resistance. Examples of rare metabolic diseases include aminoacidopathies, cystic fibrosis, lysosomal storage diseases, lipodystrophy, monogenic diabetes, monogenic obesity, fatty acid oxidation and urea cycle defects. Examples of rare hematologic, urologic, and kidney diseases include congenital dyserythropoietic anemias, inherited bone marrow failure syndromes or hemoglobinopathies, inherited and acquired systemic amyloidosis, autosomal recessive polycystic kidney disease, and renal disease associated with cystinosis or tuberous sclerosis.

National Human Genome Research Institute (NHGRI)

NHGRI encourages the sharing of aggregate sequence variant interpretations to ClinVar; leveraging ClinGen's patient registry, GenomeConnect; and participating in relevant ClinGen gene and variant curation activities. More information can be found on at clinicalgenome.org. In addition, NHGRI is interested in supporting pharmacogenomic research and studies to advance the treatment of rare diseases/conditions through genetic/genomic testing to improve drug efficacy and effectiveness and to reduce drug adverse effects in patients of diverse populations. More details about the institute’s vision and priority areas can be found in the 2020 NHGRI Strategic Vision (https://www.genome.gov/2020SV).

National Institute on Aging (NIA)

The NIA, Division of Aging Biology (DAB) is interested in studying aging in the context of rare diseases and geroscience-based interventions. Areas of research could include, but are not limited to:

• Biology of aging in rare diseases such as understanding the aging process in different rare diseases; identification and in-depth investigation of disease-specific biomarkers and the epigenetic clock that could provide insights into the predictors of accelerated aging in rare diseases.
• Functional impact of aging phenotypes such as frailty, sarcopenia, and cognitive decline in rare diseases.
• Interventions (nutrition, physical activity, use of geroprotectants) to delay aging in patients with rare diseases in different stages of life.
• Genetic interaction between rare disease alleles and hallmarks of aging.

The NIA, Division of Geriatrics and Clinical Gerontology (DGCG) is interested in studying topics related to the following progeroid syndromes, but are not limited to:

• Down Syndrome
• Werner Syndrome
• Cockayne Syndrome
• Wiedemann-Rautenstrauch Syndrome

The NIA, Division of Neuroscience (DN) is interested in studying basic and clinical research including genetic determinants of rare diseases in the aging population; specific areas of interest include but are not limited to:

• Rare heterogeneous premature-ageing diseases, including telomere biology disorders (TBDs).
• Rare age-related genetically driven circadian dysregulation and expression changes.
• Cardiac amyloidosis caused by rare genetic factors and their relationship to amyloidosis found in Alzheimer’s Disease and Related Dementias.
• Rare age-related mitochondrial disorders.
• Rare age-related neurotransmitter disorders.
• Rare age-related genetically driven frailty factors including the identification of biomarkers that may reveal therapeutic targets for age-related diseases.
• Rare age-related genetic resilience factors found in the oldest old that may reveal therapeutic approaches to age-related diseases.
• Rare cytoskeleton disorders that impact the central nervous system.
• Rare age-related metabolic, endocrine, digestive, hematologic, kidney, and storage disorders that impact the central nervous system.
• Rare arthritic, rheumatic, musculoskeletal, skin, and neuromuscular disorders that may impact the central nervous system.
• Rare age-related resilience factors in genetically predisposed cohorts such as frontotemporal dementias and other rare Alzheimer’s disease-related dementias.

National Institute of Neurological Disorders and Stroke (NINDS)

The NINDS seeks to support clinical research on rare neurological and neuromuscular conditions. Examples include (but are not limited to): cerebrovascular disorders, neurometabolic disorders, neuromuscular and neurodegenerative disorders, movement disorders, epilepsies and paroxysmal disorders, channelopathies, mitochondrial diseases, and childhood developmental and/or genetic syndromes, including those that involve rare genetic forms of autism or neurodevelopmental disabilities. Applicants proposing a clinical trial should contact the Scientific/Research Contact listed in Section VII. Agency Contacts below for guidance to meet NS-specific policies for clinical trials. Applicants seeking support for projects that are outside of the scope of the NOFO (e.g., single-site, basic, translational, clinical studies or Phase III clinical trials) should contact the Scientific/Research Contact listed in Section VII. Agency Contacts below for guidance on other, more appropriate funding opportunities.

Applications Not Responsive to this NOFO: 

The following types of studies are not responsive to this NOFO. Applications proposing such studies will be considered non-responsive, will be withdrawn from review, and not considered for funding. 

• Single site clinical studies
• Phase III Clinical Trials as part of Clinical Research Projects
• There are fewer than three rare diseases included
• There is not at least one longitudinal study
• There are either less than two or more than four research projects submitted
• There is no patient advocacy group involved
• Basic sciences studies
• Applications that propose any type of animal studies within the RDCRC. The use of in vitro models must be relevant to clinical endpoints (i.e., testing drugs, validating biomarkers versus more basic research) 

Pre-application Information Session 

All applicants are strongly encouraged to contact NIH ICO staff to discuss the alignment of their proposed work with the goals of this NOFO and the RDCRN. A technical assistance teleconference will be held for potential applicants. NIH staff will be available to answer questions related to this and the associated DMCC NOFO. Time, date, and dial-in information for the call will be announced in an NIH Guide Notice. 

Note: For more information, please refer to the Questions and Answers website for this NOFO (https://ncats.nih.gov/research/research-activities/RDCRN/applicant-information).

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

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

Section II. Award Information

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

Section III. Eligibility Information

1. Eligible Applicants

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Local Governments

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

Federal Governments

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

Other

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

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

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

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

Applicant organizations

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

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

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

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

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support. Individuals from diverse backgrounds, including underrepresented racial and ethnic groups, individuals with disabilities, and women are always encouraged to apply for NIH support. See, Reminder: Notice of NIH's Encouragement of Applications Supporting Individuals from Underrepresented Ethnic and Racial Groups as well as Individuals with Disabilities, NOT-OD-22-019. 

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

The RDCRC PD/PI(s) should have documented experience in conducting research on a disorder that qualifies as a rare disease (within the definition of this NOFO) and must have demonstrated experience in managing large multi-component clinical research programs. 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. The minimum effort of the PD(s)/PI(s) across RDCRC projects and/or cores should be at least 2.0 person months per year. If there are multiple PDs/PIs each individual must meet the minimum requirement. 

2. Cost Sharing

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

3. Additional Information on Eligibility

Number of Applications

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

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

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

Section IV. Application and Submission Information

1. Requesting an Application Package

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

2. Content and Form of Application Submission

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

Letter of Intent

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

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

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

The letter of intent should be sent to:

NCATS Letters of Intent
Telephone: 301-827-9549
Email: [email protected] 

Page Limitations

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

Instructions for the Submission of Multi-Component Applications

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

The application should consist of the following components: 

• Overall: required
• Administrative Core: required; maximum of 1
• Pilot/Feasibility Governance Core: required; maximum of 1
• Career Enhancement Core: required; maximum of 1
• Clinical Research Projects: required; minimum of 2, maximum of 4 

Overall Component

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

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

SF424(R&R) Cover (Overall)

Complete entire form.

PHS 398 Cover Page Supplement (Overall)

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

Research & Related Other Project Information (Overall)

Follow standard instructions.

Other Attachments:

Justification for Rare Disease Status (Required) 

• 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 FDA, 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 (COA) 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. 

Project/Performance Site Locations (Overall)

Enter primary site only.

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

Research and Related Senior/Key Person Profile (Overall)

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

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

Budget (Overall)

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

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

PHS 398 Research Plan (Overall)

Introduction to Application: For Resubmission and Revision applications, an Introduction to Application is required in the Overall component.

Specific Aims: Describe the overall goals of the RDCRC for the performance period of the grant. Describe the research objectives of the RDCRC for promoting understanding of rare diseases, facilitating early and timely diagnosis and establishing clinical trial readiness.

Research Strategy: This section should describe the major theme of the RDCRC, its goals and objectives, background information, the overall importance of the research and provide a sense of the overall significance of the RDCRC, i.e., how the RDCRC infrastructure and any results and resources it generates will impact the encompassed rare diseases in the near- and long-term if the goals and objectives are achieved.

• Describe the rationale for the overall proposed program including the rationale for why these rare diseases were chosen for study (minimum of three). 
• Briefly describe the clinical research projects and cores and provide a figure of the organizational structure of the RDCRC. 
• Clearly state the unmet research/clinical needs these projects address, and how the RDCRC will accelerate progress toward effective treatments or other improvements in the lives of individuals with the targeted rare diseases through coordinated and collaborative research and infrastructure activities. 
• Describe how the projects and cores contribute to the overall goals and objectives of the RDCRN in advancing understanding of the diseases, facilitating early diagnosis, improving clinical trial readiness, developing and testing therapies, advancing patient care and reducing disease burden. 
• Describe the justification for why the RDCRN infrastructure is needed to advance research for the selected rare diseases and why standard NIH grant support mechanisms (e.g., R01s) are insufficient. 
• Describe the RDCRC PD(s)/PI(s) expertise in rare diseases and experience managing large multi-component clinical research programs. 
• For multi-PD/PI applications, describe their complementary and integrated expertise, and comment on their leadership approach, governance, and organizational structure. 
• Indicate prior collaborative relationships among proposed senior key personnel at the various sites and across the RDCRC. 
• Describe the leaders and collective teams for each core and how their skills complement each other to contribute to the overall team. 
• Describe the nature of the ongoing relationships with patient advocacy group(s) and the approach of patient or stakeholder participation across the planned objectives (e.g., in addressing clinical design, recruitment, and education). Describe how patient and stakeholder experiences, perspectives, needs, and priorities will be meaningfully incorporated as partners into decisions and activities of the RDCRC. 
• Describe how the RDCRC will work with the DMCC and leverage the shared network tools provided by NIH. 
• Describe plans for the RDCRC to collaborate and otherwise contribute to the RDCRN, through participating in network-wide committees, workshops, meetings, career enhancement, collaborative efforts, or other RDCRN-wide activities and initiatives. 
• Describe the rationale for choosing clinical sites to participate in the network. 
• Describe any relevant existing partnerships with other rare disease organizations or industry. 

Renewal applications from existing RDCRCs: 

• For RDCRC that have been previously funded, document achievement of the goals of the prior funding period. 
• For RDCRC that have been previously funded, justify the need for continued funding for the RDCRC and the value of additional knowledge to be gained. Specifically, the value of continuing ongoing natural history studies with a focus on clinical trial readiness should be addressed. 
• Describe inclusion of patient or stakeholder groups by providing examples of previous and/or ongoing collaborations. 
• For RDCRC that have been previously funded, a sustainability plan should be proposed. The plan should address maintenance of the critical functions of the RDCRC and preparing for the end of NIH funding. Applicants are encouraged to creatively engage in the scientific and operational problems that need to be addressed for the RDCRC to be a sustainable success. This includes plans for continued relationships with patient and family groups, infrastructure support for critical components of the RDCRC, and data sharing (for current data and beyond). A timeline should be included that illustrates the transition process and out years beyond the NIH funding period.  

Letters of Support: 

Applicants must provide letters from the appropriate high-ranking institutional official(s) from the lead institution and partnering institutions that: 

• Commit the institution(s) to the RDCRC goals, indicating that the program will be integral to their broad vision of clinical research in rare diseases. 
• Defines the position, authority, and reporting responsibility (on the institution's organizational chart) for the RDCRC PD(s)/PI(s). 
• Defines the financial and other resource support for the RDCRC that will be provided by the applicant institution(s). There are no dollar requirements, but specific commitment is required. Some examples include financial support, adequate space, release time agreements, tenured or tenure-track positions for clinical/translational faculty, FTEs for clinical support or ancillary personnel, core consolidation, and maintenance. Specific commitments to cores and other components can be summarized in a table. 
• Defines the authority or influence that the RDCRC PD(s)/PI(s) has, and/or will have over the different components of the Center, facilities, and space, as well as decision-making authority for hiring and/or approving new faculty and support personnel. 
• Commit to notify NIH program staff of adverse events in all clinical studies supported by the Center that are serious, unexpected, and related to participation in research. A reiteration to notify NIH program staff of all unanticipated problems as outlined in OHRP guidance (http://www.hhs.gov/ohrp/policy/advevntguid.html) on studies supported by RDCRC resources would satisfy this requirement. These notifications include all adverse events as noted above as well as other reportable unanticipated problems. 

Applicants should provide letters from the appropriate high-ranking institutional official(s) from the partnering institutions that: 

• Leveraging funds from other sources (including industry) is encouraged, as long as these funds do not limit faculty research, communications, and implementation at any point and there are methods in place 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 with an external collaborator must meet NIH requirements for conducting human subject’s research. 
• For the RDCRC, the institution that submits the U54 application should receive a formal written agreement(s) from the other participant organization(s) and submit them with the application. This agreement should clearly delineate the institutional commitment of the participating organization(s) (in the ways outlined above) to the RDCRC Program. 
• These letters should be clear expressions of commitment consistent with achieving the goals of the program. 

Applicants may provide letters of support specific to the cores or projects if they do not duplicate other letters of support. Please label each core- or project- specific letters of support with the subcomponent it is supporting. 

Also, only include letters of collaboration from individuals and groups who will contribute in a substantive, meaningful way to the scientific development or execution of the overall RDCRC, whether or not salaries are requested. Supporting letters from patient or stakeholder groups should be included. 

Resource Sharing Plan:
Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the How to Apply - Application Guide.

Other Plan(s): 

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

• All applicants planning research (funded or conducted in whole or in part by NIH) that results in the generation of scientific data are required to comply with the instructions for the Data Management and Sharing Plan. All applications, regardless of the amount of direct costs requested for any one year, must address a Data Management and Sharing Plan. . The Data Management and Sharing (DMS) Plan must be provided in the Overall component. Applicants should develop the DMS Plan taking the following into consideration:

NIH expects that datasets from the RDCRN will be widely shared with the scientific community for research, while carefully observing standards of patient privacy, confidentiality, and management of health information. Information such as study protocols, descriptions, bioinformatics tools, and publications are expected to be made available through an open access section of a database such as the RDCRN and other public web sites, and publication in the scientific literature.

In addition, the RDCRN DMCC will work with each RDCRC to ensure that data to be shared meets all quality control standards, uses RDCRN-wide data standards, provides all appropriate metadata, and identifies all data use limitations. Individual RDCRCs will then be responsible for submitting the data into the NCATS Governed RDCRN-DR, along with a university signing official signature, within a time frame dictated by the applicable NIH data sharing policies, their funding IC, and NCATS. The investigative team of the RDCRC Administrative Core has the responsibility for certifying that submitted data is compliant with regulations and was obtained under the informed consent of the participants.

Appendix:

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

PHS Human Subjects and Clinical Trials Information (Overall)

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

If you answered “Yes” to the question “Are Human Subjects Involved?” on the R&R Other Project Information form, there must be at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record within the application. The study record(s) must be included in the component(s) where the work is being done, unless the same study spans multiple components. To avoid the creation of duplicate study records, a single study record with sufficient information for all involved components must be included in the Overall component when the same study spans multiple components.

Study Record: PHS Human Subjects and Clinical Trials Information

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

All applications must follow the instructions G.500 PHS Human Subjects and Clinical Trials Information with additional instructions specific to this NOFO.

Section 2 - Study Population Characteristics

A goal of this initiative is to support studies that lead to findings that are applicable to all people affected by the rare disease being studied. Therefore, it is important that the sex/gender, race, ethnicity, and age of the participants appropriately represent the population of people living with the studied condition in the U.S. Applications may request personnel effort, support for study participant travel/meals and other budget items within the overall budget cap to ensure that this goal of appropriate inclusion is met. 

In sections 2.4 Inclusion of Women and Minorities and 2.5 Recruitment and Retention Plan of the Human Subject form applications must address the following points in addition to the G.500 instructions. 

2.4 Inclusion of Women and Minorities

• Provide data if available on the demographics of individuals affected by the condition under study in the catchment area for the clinic sites proposed in the application. 
• Provide annual targets for enrollment including numbers by sex/gender, race, and ethnicity. 
• Identify the person/people in the research team that will carry out the proposed outreach and their qualifications or relevant abilities such as fluency in languages other than English and/or cultural sensitivity. 

2.5 Recruitment and Retention Plan

• Describe how the proposed recruitment and retention plan is designed to overcome obstacles to study participation. Strategies to overcome obstacles include but are not limited to the following: 
  • Broaden the eligibility criteria as appropriate so as not to exclude potential participants for reasons that are unlikely to affect the outcomes of the study. 
  • Minimize the burden of participating in the study by reducing the frequency and/or duration of clinic visits and overall time required. 
  • Select study sites with ample numbers and diversity of potential study participants. 
  • Select study sites that minimize the travel of study participants. 
  • Provide support for study participant transportation, accommodations and parking as needed. 
  • Provide daycare for family members during study visits. 
  • Allow for clinic visits in evenings or during weekends. 
  • Integrate remote data collection such as smartphone apps or wearables into the study design while also taking into consideration the need for access to broadband communication networks in rural areas. 
  • Establish recruitment, enrollment and/or data collection sites in the community at locations that are convenient, familiar, and trusted by potential study participants. 
  • Have validated translations of consent forms and other relevant study documents available in languages that help ensure achievement of the planned enrollment. 
  • Include study personnel who are bilingual and culturally sensitive to the planned enrollment population. Consider enlisting the help of community ambassadors to build trust in the communities of potential study participants. 
• In addition to the primary plan for recruiting sex/gender, racial, and ethnic group members, provide alternative/back-up strategies to be used if enrollment significantly deviates (more than 20% of any category for each annual milestone) from the planned numbers according to sex/gender, race, or ethnicity. Back-up plans may, for example, propose to add research sites with access to additional individuals that are understudied in the enrollment. 
• Describe what other research studies may be competing for recruitment of the same patient population at the same clinic sites that are proposed in the application. Describe plans for communicating to potential study participants the options available to them. 

Section 4 - Protocol Synopsis

4.3 Statistical Design and Power

Applicants should provide a Statistical Analysis Plan (SAP) for the proposed research project(s). This may include details on the analyses specified in the study protocol, including a description of how the statistical analysis of the primary, secondary and other endpoints will be performed, how the sample size was determined, how missing data will be handled, plans for interim analyses for safety, etc. 

Delayed Onset Study

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

PHS Assignment Request Form (Overall)

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

Administrative Core 

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

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

SF424 (R&R) Cover (Administrative Core) 

Complete only the following fields: 

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

PHS 398 Cover Page Supplement (Administrative Core) 

Enter Human Embryonic Stem Cells in each relevant component. 

Research & Related Other Project Information (Administrative Core) 

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

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

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

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

List all performance sites that apply to the specific component. 

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

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

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

Budget (Administrative Core) 

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

The Administrative Core budget should include travel for the RDCRC PD(s)/PI(s) and one Scholar to attend an annual two-day in-person meeting in the Washington DC metro area. 

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply. 

PHS 398 Research Plan (Administrative Core) 

Specific Aims:  The RDCRC Administrative Core is responsible for the overall administration of the RDCRC (including policy, procedure, and funds allocation). 

Research Strategy:  

• Describe the Administrative Core Team's leadership experience with multisite clinical research programs and how it will adequately provide for administrative management. 
• Applicants are encouraged to form the strongest teams possible to promote strategies to ensure a robust scientific approach, which can include both domestic and international sites and investigators. Because close partnership with the patients and stakeholders has been shown to be critical to the success of the RDCRCs, applicants are encouraged to include patient advocates in the leadership team of the Administrative Core. 
• Describe plans for the organization and administrative management of the RDCRC. The plan should include management of day-to-day activities, establishing policies and procedures that dovetail with those of the RDCRN, funds allocation, and establishing contracts with all participating RDCRC sites, monitoring progress of RDCRC program milestones. 
• Describe the skills and experience of the Administrative Core PI and how it is related to the management of multisite clinical research programs and rare disease research. 
• Describe the skills and experience of the Administrative Coordinator to assist the RDCRC PD(s)/PI(s) and Administrative Core PI with the day-to-day administrative details and program coordination. 
• Describe a plan for communication (meetings, conference calls etc.) and participation of all personnel within the RDCRC. Provide details of how the activities and contribution of the collaborating investigators, institutions and patient advocacy groups will be coordinated. 
• Describe how 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). 
• Describe how the Administrative Core will coordinate and manage regulatory and clinical documents in collaboration with the NIH and the DMCC (e.g., Investigational New Drug Application (IND), single Institutional Review Board (IRB), clinical protocols, consent forms). Describe how the Administrative Core will manage and monitor quality control of ongoing research projects. 
• Describe how the Administrative Core will work collaboratively with the DMCC to develop and utilize clinical trial readiness metrics for both regulatory requirements and clinical research components to evaluate their progress in clinical trial readiness. 
• Describe how the Administrative Core will coordinate data and biospecimen sharing and storage across all clinical sites. 
• Describe how the Administrative Core will coordinate with the DMCC to develop and maintain a RDCRC communication plan. 
• Describe how the Administrative Core will establish data sharing and data use agreements within the RDCRC for all clinical sites, and between the primary recipient institute and the DMCC. 
• Describe how the Administrative Core will collaborate with the DMCC to establish and promulgate RDCRN data management and sharing standards and policies within the RDCRC. 
• Describe how the Administrative Core will collaborate with the DMCC to index biosamples and other resources within the RDCRC in a "virtual repository" management system.      
• Identify the individual(s) with statistical expertise in rare disease research (e.g., small sample size power analysis, analysis of longitudinal data, qualitative studies, innovative study design, platform clinical trials) who will coordinate and leverage DMCC core support. 
• Identify the individual(s) with bioinformatic expertise who will collaborate with the DMCC to facilitate the use of research tools (e.g., RedCap, Ambra, Complion) within the RDCRC. 
• Describe the plan for promoting awareness of disorders within the RDCRC research program to the scientific, clinical, and patient/stakeholder communities in collaboration with the RDCRN. 
• If working groups will be established, indicate their specific functions, composition and to whom they report. 
• Describe how an EAC consisting of scientific, clinical, and patient group representation that will be composed of at least five members will be established and will function. 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. 

Letters of Support: Any letters of support should be included in the Overall Component.

Appendix: 

Only limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions. 

PHS Human Subjects and Clinical Trials Information (Administrative Core) 

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

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

Study Record: PHS Human Subjects and Clinical Trials Information 

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

Delayed Onset Study 

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

Pilot/Feasibility Governance Core 

When preparing your application, use Component Type ‘Pilot/Feasibility.’ 

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

SF424 (R&R) Cover (Pilot/Feasibility Governance Core) 

Complete only the following fields: 

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

PHS 398 Cover Page Supplement (Pilot/Feasibility Governance Core) 

Enter Human Embryonic Stem Cells in each relevant component. 

Research & Related Other Project Information (Pilot/Feasibility Governance Core) 

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

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

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

Project /Performance Site Location(s) (Pilot/Feasibility Governance Core) 

List all performance sites that apply to the specific component. 

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

Research & Related Senior/Key Person Profile (Pilot/Feasibility Governance Core) 

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

Budget (Pilot/Feasibility Governance Core 

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

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply. 

PHS 398 Research Plan (Pilot/Feasibility Governance Core) 

Specific Aims: State the goals of the Pilot/Feasibility Governance Core concisely and summarize the expected outcome(s).    

Research Strategy:  

• Describe in detail how the pilot/feasibility core will organize and administer the process for selecting pilot and/or feasibility project establishment. Specific pilot/feasibility projects must not be described in the current application and if described will not be reviewed. 
• Pilot projects should be at least 1 year but not more than 2 years in duration. If 2-year awards are allowed, the second year must be contingent on year 1 progress. No new pilot/feasibility projects may be initiated in the final year of the award.   
• Clearly describe the solicitation processes, including multiple avenues of outreach for projects. Describe the eligibility criteria for the investigators and the scope of projects that are being sought. 
• Describe how the review criteria for pilot/feasibility project selection will ensure that pilot/feasibility projects: 
  • Have scientific merit. 
  • Are related to the overall goals and activities of the RDCRC. 
  • Have the potential to advance the field of research. 
  • Leverage existing resources and infrastructure within the RDCRC and RDCRN and the corresponding rare disease community, if available. 
• Describe funding caps for individual pilot/feasibility projects, including any planned caps on F&A costs. 
• Describe how diversity will be addressed in the review process. 
• Describe the selection process, including any involvement of the assigned NIH PS. 
• Applicants should also describe their plans for awarding and overseeing selected pilot/feasibility projects, including: 
  • The process for ensuring that NIH prior approval requirements are met. 
  • The process for issuing new subawards if pilot recipients are not already at a RDCRC institution. 
  • Reporting pilot awards to the DMCC. 
  • How the progress of the pilot/feasibility projects will be evaluated for consideration for a second year of support (if applicable).   

Letters of Support: Any letters of support should be included in the Overall Component.  

Appendix: 

Only limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.    

PHS Human Subjects and Clinical Trials Information (Pilot/Feasibility Governance Core) 

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

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

Study Record: PHS Human Subjects and Clinical Trials Information 

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

Delayed Onset Study 

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

  Career Enhancement Core 

When preparing your application, use Component Type ‘Career Enhancement.’ 

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

SF424 (R&R) Cover (Career Enhancement Core) 

Complete only the following fields: 

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

PHS 398 Cover Page Supplement (Career Enhancement Core) 

Enter Human Embryonic Stem Cells in each relevant component. 

Research & Related Other Project Information (Career Enhancement Core) 

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

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

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

Project /Performance Site Location(s) (Career Enhancement Core) 

List all performance sites that apply to the specific component. 

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

Research & Related Senior/Key Person Profile (Career Enhancement Core) 

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

Budget (Career Enhancement Core) 

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

The Career Enhancement Core is limited to $100,000 direct costs per year. Award recipients may choose to leverage other sources for additional support; however, NIH will not provide support greater than $100,000 direct costs per year for this activity. 

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply. 

PHS 398 Research Plan (Career Enhancement Core) 

Specific Aims: State the goals of the proposed Career Enhancement Core concisely and summarize the expected outcome(s).            

Research Strategy:  

Program Leadership and Administration: 

• Describe the strengths, leadership and administrative skills, career enhancement experience, scientific expertise, and active research of the Career Enhancement Core Leader. Describe the Core Leader’s commitment and track record of training and career development of women, under-represented minorities, and people with disabilities. Relate these strengths to the proposed management of the Career Enhancement Program. 
• Describe the planned strategy and administrative structure to be used to oversee and monitor the Career Enhancement Program. 

Program Faculty: 

• Describe the RDCRC faculty who will be available to serve as preceptors/mentors and provide guidance and expertise appropriate to the level of Career Enhancement candidates proposed in the application. 
• Describe the complementary expertise and experiences of the proposed RDCRC Faculty, including active research and other scholarly activities in which the faculty are engaged, as well as experience mentoring and career enhancement individuals at the proposed career stage(s). 

Proposed Career Enhancements: 

• Provide an overview (objectives, design, and direction) of the proposed Career Enhancement Program aimed at the career enhancement of new researchers for the rare diseases field and development of future research leaders. Career enhancement activities that go beyond the RDCRC to enhance the experiences of Career Enhancement candidate(s) in other laboratories or at other institutions are also encouraged. 
• Describe how the Career Enhancement candidate(s) will be prepared to address technical challenges unique to clinical research with rare diseases, such as partnering with patients, stakeholders, and/or multidisciplinary teams to leverage existing resources. Describe training in clinical trial design and statistical approaches that address the challenges of small sample sizes common to rare diseases. 
• Describe program activities intended to develop the working knowledge needed for Career Enhancement candidate(s) to select among and prepare for the next step in varied career options available in the rare disease workforce. 
• The Career Enhancement Program should promote support of scholars and fellows from other public or private funding organizations. Describe strategies to help publicize the availability of fellowships, train junior/new investigators to apply for fellowships and provide feedback on their applications. Track the success of fellowship applications and report annual progress on these activities. 
• The Career Enhancement Program may propose activities that enhance the environment through specialized coursework, a seminar program, retreats for presentation of Career Enhancement candidate(s) research, journal clubs or other activities that contribute to the preparation of investigators for careers in rare diseases research. Explore ways to publicize and provide access to these activities to scholars and fellows within the RDCRC’s institutions, at other RDCRCs and other institutions. Exposure to research at other RDCRCs is also encouraged through exchange programs, short-term career enhancement opportunities or visits to learn new research approaches. 

Career Enhancement Candidates: 

• The Career Enhancement Core could provide direct support for scholars/fellows, leverage existing training programs (e.g., Institutional Training or Career Development Awards; T32, T35, K12) and/or facilitate funding of fellowships from other public or private funding organizations. If direct support is proposed, describe the nomination and selection process to be used to select candidates who would be supported by funds from the Career Enhancement Core. 
• Applicants are encouraged to place a high priority on the recruitment of Career Enhancement candidate(s) with clinical expertise due to the significant need for well-trained clinical researchers in the rare diseases field. Describe strategies to recruit students/fellows with clinical training; for example, outreach/presentations to medical school classes or summer fellowship opportunities. Do not name prospective Career Enhancement candidate(s) in the application or contact them in advance of the review. 
• Describe for whom the Career Enhancement Program is intended, including the career enhancement level(s) of the Career Enhancement candidate(s) the academic and research background needed to pursue the proposed career enhancement, and, as appropriate, plans to accommodate differences in preparation among Career Enhancement candidate(s). 

Institutional Environment: 

• The sponsoring institution must assure support for the career enhancement environment of the RDCRC as proposed in the Career Enhancement Core, including assurance that sufficient time will be allowed for the Career Enhancement Core Leader and other RDCRC Faculty to contribute to the proposed career enhancement. 
• Describe existing research career enhancement, student development, or career development programs in which the RDCRC faculty are eligible to participate as mentors. Differentiate the proposed Career Enhancement Program from existing career enhancement programs at the same Career Enhancement candidate(s) level, and explain how the programs will synergize, if applicable, whether Career Enhancement candidate(s) are expected to transition from one support program to another, and how the career enhancement faculty, pool of potential Career Enhancement candidate(s), and resources are sufficiently robust to support the proposed Career Enhancement Program in addition to existing career enhancement programs. 

Program Evaluation: 

• Describe a plan to review and determine the quality and effectiveness of the Career Enhancement Program. 

For renewal applications: 

• Provide aggregate data that demonstrates the impact of Career Enhancement activities on participant's professional development. Aggregate data should address groups identified as underrepresented in the biomedical and clinical sciences, examples of their accomplishments while supported by the RDCRC and how RDCRC support has enhanced their careers in rare disease research. 
• Highlight how Career Enhancement activities have evolved in response to changes in relevant scientific and technical knowledge, educational practices, and to evaluation of the Career Enhancement Program. 

Letters of Support: Any letters of support should be included in the Overall Component. 

Appendix: 

Only limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.    

PHS Human Subjects and Clinical Trials Information (Career Enhancement Core) 

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

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

Study Record: PHS Human Subjects and Clinical Trials Information 

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

Delayed Onset Study 

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

Clinical Research Projects 

When preparing your application, use Component Type ‘Clinical Research Projects.’ 

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

SF424 (R&R) Cover (Clinical Research Projects) 

Complete only the following fields: 

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

PHS 398 Cover Page Supplement (Clinical Research Projects) 

Enter Human Embryonic Stem Cells in each relevant component. 

Research & Related Other Project Information (Clinical Research Projects) 

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

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

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

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

List all performance sites that apply to the specific component. 

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

Research & Related Senior/Key Person Profile (Clinical Research Projects) 

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

Budget (Clinical Research Projects) 

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

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply. 

PHS 398 Research Plan (Clinical Research Projects) 

Specific Aims:  State the goals of the proposed Clinical Research Projects concisely and summarize the expected outcome(s).       

Research Strategy:  

• Clearly describe the hypothesis or hypotheses to be tested for the project and explain its relevance to the central theme of the RDCRC. 
• Describe how the individual clinical research project's achievement will address the central objectives of the RDCRC.   
• Highlight why the implementation of the project will be facilitated by a RDCRC environment.    
• Specify the overall biomedical significance of the work proposed. 
• Specify the gaps filled by each project in the long-term goal of advancing early diagnosis and treatments for the targeted rare disease/disorder/syndrome/condition. 
• Describe how the perspectives of patients and stakeholders will be included in the work proposed. 
• Describe the source of common data elements that will be used in the study and how they will ensure comparability with other clinical research and clinical trials (e.g., NIH CDE (https://cde.nlm.nih.gov/home), Longitudinal Pediatric Data Resource, NINDS CDEs (https://commondataelements.ninds.nih.gov/)).  

If a clinical research project includes an NIH-defined clinical trial: 

• Describe the potential value of the study and the feasibility of successfully completing the study within the duration of the award, including the preclinical rationale. 
• 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. 
• Describe how regulatory requirements will be met in a timely manner. 
• Indicate drug/biologic availability for use in a trial document agreement of all participating clinical/corporate partners. 

If clinical trials involving the testing of new investigational therapeutics, new indications for FDA-approved drugs, or other medical interventions under a research protocol will be performed indicate: 

• Status of IND/IDE or timeline for obtaining an IND 
• Name and organization of the IND/IDE holder 
• Date the IND/IDE was filed with the FDA 
• FDA IND/IDE number 
• Any comments from the FDA regarding this protocol 

Letters of Support: Any letters of support should be included in the Overall Component. 

Appendix: 

Only limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.    

PHS Human Subjects and Clinical Trials Information (Clinical Research Projects) 

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

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

Study Record: PHS Human Subjects and Clinical Trials Information 

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

Delayed Onset Study 

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

Foreign Institutions 

Foreign (non-U.S.) institutions must follow policies described in the NIH Grants Policy Statement, and procedures for foreign institutions described throughout the SF424 (R&R) Application Guide.  

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

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

4. Submission Dates and Times

Part I. contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies) using ASSIST or other electronic submission systems. Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications.

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

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

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

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

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

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, unless otherwise agreed upon by the FDA.  See Section IV.2 for additional guidance on projects that propose a clinical trial. If not exempt, 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.    

7. Other Submission Requirements and Information

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

For information on how applications will be automatically assembled for review and funding consideration after submission, refer to: http://grants.nih.gov/grants/ElectronicReceipt/files/Electronic_Multi-project_Application_Image_Assembly.pdf.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit How to Apply - Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

All PD(s)/PI(s) and component Project Leads must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile form. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH.

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

See more tips for avoiding common errors.

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

In order to expedite review, applicants are requested to notify the NCATS Referral Office by email at [email protected] when the application has been submitted. Please include the NOFO number and title, PD/PI name, and title of the application

Applications Involving the NIH Intramural Research Program

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. 

Use of Common Data Elements in NIH-funded Research

Many NIH ICs encourage the use of common data elements (CDEs) in basic, clinical, and applied research, patient registries, and other human subject research to facilitate broader and more effective use of data and advance research across studies. CDEs are data elements that have been identified and defined for use in multiple data sets across different studies. Use of CDEs can facilitate data sharing and standardization to improve data quality and enable data integration from multiple studies and sources, including electronic health records. NIH ICs have identified CDEs for many clinical domains (e.g., neurological disease), types of studies (e.g., genome-wide association studies (GWAS)), types of outcomes (e.g., patient-reported outcomes), and patient registries (e.g., the Global Rare Diseases Patient Registry and Data Repository). NIH has established the NIH CDE Repository to assist investigators in identifying NIH-supported CDEs when developing protocols, case report forms, and other instruments for data collection. The Portal provides guidance about and access to NIH-supported CDE initiatives and other tools and resources for the appropriate use of CDEs and data standards in NIH-funded research. Investigators are encouraged to consult the Portal and describe in their applications any use they will make of NIH-supported CDEs in their projects. 

Prior Consultation with Scientific/Research Staff

Consultation with the appropriate Institute or Center (IC) staff at least 10 weeks prior to the application due date is strongly encouraged for all applicants considering submission of the Rare Diseases Clinical Research Consortia (RDCRC) for Rare Diseases Clinical Research Network (U54 Clinical Trials Optional) application, including new applications. If requested, IC staff will consider whether the proposed clinical trial meets the goals and mission of the Institute/Center, and whether it addresses one or more high priority research areas. IC staff will not evaluate the technical and scientific merit of the proposed project; technical and scientific merit will be determined during peer review using the review criteria indicated in this NOFO. During the consultation phase, if the proposed RDCRC does not meet an IC's programmatic needs, applicants will be strongly encouraged to consider other funding opportunities.

Post Submission Materials

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

Section V. Application Review Information

1. Criteria

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

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

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).

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

Significance

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

Specific to this NOFO:

• To what extent is there sufficient rationale provided for the rare diseases chosen? Consider whether these rare diseases can be reasonably grouped together to move the individual fields forward.   
• To what extent do the clinical projects and cores demonstrate a focus on unmet research/clinical needs for the targeted rare diseases? 
• To what extent will the proposed RDCRC accelerate progress toward effective treatments or other improvements in the lives of individuals with the targeted rare diseases through coordinated and collaborative research and infrastructure activities? 
• To what extent are the clinical projects and cores individually meritorious and complementary to the overarching goals of the RDCRN? If successful, how might the proposed RDCRN advance understanding of the diseases, facilitating early diagnosis, improving clinical trial readiness, developing and testing therapies, advancing patient care and reducing disease burden? 
• To what extent is there sufficient justification for the need for the RDCRN center infrastructure over completing the research via traditional grant mechanisms? 

In addition, for applications involving clinical trials

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

Investigator(s)

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

Specific to this NOFO:

• To what extent is the PD(s)/PI(s) rare disease expertise and experience appropriate for managing large multi-component clinical research programs in rare diseases addressed? 

In addition, for applications involving clinical trials

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

Innovation

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?

In addition, for applications involving clinical trials

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

Approach

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

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

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

Specific to this NOFO:

• To what extent are patient and stakeholder experiences, needs and priorities meaningfully incorporated as partners into decisions and activities of the RDCRC? 
• To what extent are the plans to work with the DMCC and leverage the shared network tools provided by the NIH appropriate? 
• To what extent are the plans for the RDCRC to collaborate and otherwise contribute to the RDCRN meaningful? 
• To what extent are the plans adequate to ensure and maintain collaborative relationships across multiple research sites and the RDCRC? 

In addition, for applications involving clinical trials

Does the application adequately address the following, if applicable

Study Design

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

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

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

Data Management and Statistical Analysis

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

Environment

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

Specific to this NOFO:

• To what extent is the rationale for choosing clinical sites adequate and justified? To what extent does the overall RDCRC include a diverse set of sites? 
• To what extent is the institutional commitment appropriate for supporting a rare diseases research center? 

In addition, for applications involving clinical trials

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

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

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

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

Scored Review Criteria - CORES 

As applicable for the Pilot/Feasibility Governance and Career Enhancement Cores, reviewers will provide an assessment of its strengths and weaknesses and provide a score of acceptable, acceptable with concerns, or unacceptable. The following items should be evaluated while determining scientific and technical merit, and in providing an overall Impact Score for the Core. 

Administrative Core 

Review Criteria for the Administrative Core 

Significance: 

• To what extent will the Administrative Core promote strategies to ensure robust and impactful scientific outcomes for the RDCRC? 

Team: 

• To what extent do the skills and experience of the Administrative Core PI provide the needed knowledge and experience to facilitate the requirements of the Administrative Core? 
• To what extent do the skills and experience of the proposed Administrative Coordinator provide them with the ability to assist the RDCRC PD(s)/PI(s) and the Administrative Core PI with day-to-day administrative details and program coordination? 
• To what extent does the leadership experience and expertise provide the Administrative Core with the management and coordination skills needed for success for a large RDCRC? 
• To what extent is there sufficient collaboration between the bioinformatics and statistical staff, and the DMCC, to ensure appropriate access to the DMCC resources described? 
• To what extent is there appropriate effort and expertise for the Administrative Core team to support the RDCRC, including statistical and informatics expertise in rare disease research? 

Communication: 

• To what extent is there an appropriate plan for promoting awareness of disorders within the RDCRC to the scientific, clinical, and patient/stakeholder communities? 
• To what extent will there be coordination with the DMCC for coordinating outreach and communication? 
• How effectively will the communication plan ensure participation and coordination between the collaborating investigators, institutions, patient advocacy group(s) and the DMCC? 

Approach: 

• To what extent does the Administrative Core make adequate provisions to meet the needs of the RDCRC and to work collaboratively with the RDCRN DMCC? 
• To what extent will the plans for organizational and administrative management lead to success in accomplishing the objectives of the RDCRC? Consider:  
  • The management of day-to-day activities. 
  • Establishing policies and procedures that dovetail with those of the RDCRN. 
  • Funds allocation and establishing contracts with all participating RDCRC sites. 
  • Monitoring progress of RDCRC program milestones. 
• Considering both RDCRC activities and RDCRN activities, to what extent is the collaboration with the DMCC Cores sufficient to integrate the RDCRC into the network? 
• To what extent will the Administrative Core collaborate with the DMCC on the management and coordination of regulatory and clinical documents? Is the proposed timeline for having all agreements with all RDCRC clinical sites in place acceptable and timely? Is there an appropriate timeline for having data use and data sharing agreements in place with the DMCC and is the plan acceptable and timely? Are there appropriate plans for monitoring the quality of ongoing research? 
• To what extent will the Administrative Core collaborate with the DMCC to develop and utilize clinical trial readiness metrics for both regulatory requirements and clinical research components to evaluate their progress in clinical trial readiness? 
• To what extent will the Administrative Core collaborate with the DMCC to: 
  • Facilitate an environment that provides equitable access to information and resources to all participants? 
  • Promulgate data management and sharing standards and policies across the RDCRC? 
  • Include the use of RDCRN standardized data sharing and data use agreements? 
  • Index biosamples and other resources within the RDCRC in a "virtual repository" management system? 
• To what extent is the institutional environment, including institutional support, appropriate? 

Pilot/Feasibility Governance Core 

Review Criteria for the Pilot/Feasibility Governance Core 

• To what extent is the strategy for soliciting and selecting pilot/feasibility projects clearly described? How will the applicant ensure that the solicitation, review, and selection processes are rigorous and unbiased? 
• To what extent does the application adequately describe the plan for ensuring that the proposed projects have scientific merit, relationship to the overall goals and activities of the RDCRC, potential to advance the field of research, leverage of existing resources and infrastructure, address diversity and the selection process? 
• To what extent does the application adequately address how recipients will award and oversee pilot/feasibility projects, including how they will ensure that NIH prior approval requirements are met, how new subawards will be issued if needed, how awards will be reported to the DMCC, and how the progress of projects will be evaluated for a second year of funding (if applicable)? 
• To what extent is the institutional environment, including institutional support, appropriate? 

Career Enhancement Core 

Review Criteria for the Career Enhancement Core 

• To what extent is the Career Enhancement Program administration, including the qualifications of the core leader and the proposed oversight and monitoring, appropriate? 
• To what extent are the proposed faculty appropriate for the Career Enhancement candidate(s) and do they have a strong record of research and mentoring? 
• To what extent are the proposed career enhancement activities, including those unique to clinical research with rare diseases and those focused on workforce development, appropriate? 
• If strategies are proposed to promote fellowship funding from other public/provide funding organizations, are the plans for facilitating grant writing, refining applications, tracking, and reporting on fellowship success well considered and described? 
• If direct support for Career Enhancement candidate(s) is proposed, to what extent is the nomination and selection process appropriate for the proposed Career Enhancement Program? 
• To what extent is the institutional environment, including the institutional support and the proposed interaction with existing Career Enhancement Programs, appropriate? 
• To what extent is the plan to review and determine the quality and effectiveness of the Career Enhancement Program adequate? 
• For renewal applications, to what extent has the program been successful in meeting the goals of the Career Enhancement Program? 

Scored Review Criteria - Clinical Research Projects 

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

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

Specific to this NOFO: 

• To what extent does the research project target gaps to be filled for advancing early diagnosis and treatments for the targeted rare disease/disorder/syndrome/condition? 

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

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

Specific to this NOFO: 

• To what extent does the investigative team at each clinical site have appropriate experience in the field of rare disease research and expertise required to conduct the proposed research? 

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

Innovation 
Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed? 

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

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

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address: 
1) the protection of human subjects from research risks, and  
2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of individuals of all ages (including children and older adults), justified in terms of the scientific goals and research strategy proposed? 

Specific to this NOFO: 

• To what extent are the approaches proposed appropriate for rare diseases research? 
• To what extent is the study design(s) appropriate for rare diseases research? 
• If applicable, to what extent are plans for statistical analysis appropriate for rare diseases research? 

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

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

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

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

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

Specific to this NOFO: 

• Is the environment for the project conducive to completing the project in terms of access to the populations? 

In addition, for applications involving clinical trials 
If proposed, are the administrative, data coordinating, enrollment, and laboratory/testing centers, appropriate for the trial proposed? 

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

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

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

Additional Review Criteria - Overall, Clinical Research Projects, and Cores

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

Study Timeline

Specific to applications involving clinical trials

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

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

Protections for Human Subjects

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

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

Inclusion of Women, Minorities, and Individuals Across the Lifespan

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

Vertebrate Animals

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

Biohazards

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

Resubmissions

Not Applicable

Renewals

For Renewals, the committee will consider the progress made in the last funding period. For consortia that have been previously funded, how well were the goals of the prior funding period achieved? How strong is the justification for continued support? What is the value of continuing ongoing natural history studies, and will these studies facilitate clinical trial readiness? How well have patient or stakeholder groups been included in previous and/or ongoing collaborations?

Revisions

Not Applicable

Additional Review Considerations - Overall, Clinical Research Projects and Cores

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

Applications from Foreign Organizations

Not Applicable

Select Agent Research

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

Resource Sharing Plans

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

Authentication of Key Biological and/or Chemical Resources:

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

Budget and Period of Support

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

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by the National Center for Advancing Translational Sciences, in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

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

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

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted. Following initial peer review, recommended applications will receive a second level of review by the appropriate national Advisory Council or Board. The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.

3. Anticipated Announcement and Award Dates

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

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

Section VI. Award Administration Information

1. Award Notices

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement. This request is not a Notice of Award nor should it be construed to be an indicator of possible funding.

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

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

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

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

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

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

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

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

Prior Approval of Pilot Projects

Recipient-selected projects that involve clinical trials or studies involving human subjects require prior approval by NIH prior to initiation.

• The recipient institution will comply with the NIH Guidance on Changes That Involve Human Subjects in Active Awards and That Will Require Prior NIH Approval.
• The recipient institution will provide NIH with specific plans for data and safety monitoring, and will notify the IRB and NIH of serious adverse events and unanticipated problems, consistent with NIH DSMP policies.

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

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

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

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

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

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to System for Award Management (SAM.gov) requirements. SAM.gov requires Federal agencies to review and consider information about an applicant in the designated integrity and performance system (currently SAM.gov) prior to making an award. An applicant can review and comment on any information in the responsibility/qualification records available in SAM.gov. NIH will consider any comments by the applicant, in addition to the information available in the responsibility/qualification records in SAM.gov, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 2 CFR Part 200.206 “Federal awarding agency review of risk posed by applicants.” This provision will apply to all NIH grants and cooperative agreements except fellowships.

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (HHS) grant administration regulations at 2 CFR Part 200, and other HHS, PHS, and NIH grant administration policies. 

The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the recipients is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the recipients for the project as a whole, although specific tasks and activities may be shared among the recipients and NIH as defined below. 

The PD(s)/PI(s) will have the primary responsibility for: 

• Defining objectives and approaches to plan, conduct, analyze, and publish results, interpretations, and conclusions of their studies. 
• Serving as RDCRC Director(s) and responsible for the integration and management of activities within the RDCRC including ensuring data sharing and data use agreements are aligned with RDCRN requirements. 
• Implementing a Local Executive Committee for day-to-day management of the RDCRC, and an External Advisory Committee, with scientific, clinical, and patient or stakeholder representation.  
• Partnering with patient advocacy group(s) and ensuring that a representative from the patient advocacy group(s) represents the RDCRC on the CPAG steering committee.  
• Attending two RDCRN meetings per year (one in-person and one virtual). 
• Collaborating with the DMCC to use network resources and data standards. 
• Ensuring clinical trials using RDCRC resources receive prior approval from the NIH awarding institute/center and are managed through an appropriate agreement between the RDCRC and funding source which requires all parties to adhere to NIH clinical trial policies and regulations. 
• Participating in the overall coordination of NIH research efforts in Rare Diseases including collaboration and consultation with other NIH recipients, the appropriate sharing of information, data, and research materials, and participating in NIH efforts to standardize and harmonize pre-clinical and clinical data collection. 
• Ensuring results of the research projects are published in a timely manner. 
• Retaining custody of and having primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies. 

NIH staff have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below: 

One or more designated NIH program staff members will have substantial involvement as Project Scientists in the awards under this NOFO. The specific roles of the substantially involved NIH staff members include the following activities: 

• Overseeing the activities of the RDCRC to ensure studies are properly conducted and completed in a timely manner. 
• Serving as a non-voting member of the Network SC and/or CPAG SC. 
• Providing status updates on other RDCRN activities that may be relevant to the individual RDCRC study goals or milestones. 
• Assisting the NCATS RDCRN Program Director as well as the Network SC in avoiding unwarranted duplication of effort across the RDCRN. 
• Monitoring the operations of the RDCRC for progress towards milestones and making recommendations on overall project directions.  
• Informing the NCATS RDCRN Program Director as well as the Network SC of any challenges or delays in project progress. 
• Ensuring proper collaboration between the RDCRC and the other members of the RDCRN. 
• Enlisting additional technical experts as necessary from within the NIH, and other government agencies, to review scientific progress and administrative requirements to ensure compliance with NIH policies and procedures.   

An agency PO will be responsible for the scientific and programmatic stewardship of the award and will be named in the award notice. The PO will be responsible for negotiating the final set of approved RDCRC award milestones and coordinating with the NCATS RDCRN Program Director on the RDCRN milestones. 

Areas of Joint Responsibility include: 

The RDCRN will consist of all the awarded RDCRCs, their affiliated patient advocacy groups, the DMCC, and NIH program representatives. All responsibilities are divided between recipients and NIH staff as described above. 

Dispute Resolution: 

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between recipients and NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual recipient. This special dispute resolution procedure does not alter the recipient's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and HHS regulation 45 CFR Part 16. 

External Collaborations:

External collaborations may entail providing financial support; participating directly in a study; supplying study resources; or receiving special access to study results, data, findings, or intellectual property. External collaborations may concern only the original scope of the study or may extend to enlargements of the scope or ancillary additions through further procedures, data collection, or analyses, and may involve one, some, or all centers in a collaborative clinical trial. 

Examples of types and mechanisms of external collaborations include: 

• In-kind support of materials, e.g., drugs, devices, reagents. 
• In-kind support of services, e.g., laboratory services. 
• Financial support through a conditional gift to an NIH Gift Fund. 
• Financial support through a charitable third party that works in collaboration with the NIH ICO and that manages, accounts for, and distributes funds to study investigators in accordance with ICO program plans. 
• Financial support provided directly to an ICO supported investigator for use in accordance with study plans. 

Any external collaboration must be governed by a research collaboration agreement (e.g., Clinical Trials Agreement (CTA), Research Collaboration Agreement (RCA), Memorandum of Understanding (MOU), etc.) with terms that ensure the collaboration is conducted in accordance with the Cooperative Agreement, applicable NIH policies and procedures.   

Any external collaborator in the study, including but not limited to, access to any study data; study results; using the name of the study, is permitted only after concurrence by the PO who may consult with others at NIH including the Technology Advancement Office. 

3. Data Management and Sharing

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

Sharing Human Data via the RDCRN Data Repository (RDCRN-DR)
 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). Fulfilling this expectation by the recipient will be among the terms and conditions of the award. Established by NCATS, and supported by other NIH Institutes, the RDCRN-DR is a secure informatics platform for scientific collaboration and data-sharing that enables the effective communication of detailed research data, results, tools, and supporting documentation. All human subject's data collected and/or derived for a project funded under this NOFO are expected to be submitted to the RDCRN-DR. Investigators funded under this NOFO are expected to use RDCRN technologies to submit data in accordance with the RDCRN-DR Data Sharing Terms and Conditions, outlined in the following checklist: 

This checklist outlines the basic elements that need to be incorporated in the informed consent language, the contractual language established between the RDCRC Administrative Core and its sites, and the RDCRC policies that govern data sharing, use, and publication within the RDCRC and with external users. 

• 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. The Informed Consent should also describe: 
  • Sharing data with the Administrative Core of the RDCRC as a limited data set. 
  • Sharing data with the DMCC. 
  • Sharing data with other researchers for future studies. 
  • Allowing the transfer of data, without identifiers, to a federal data repository maintained by the NCATS. 
  • Options for restricting data sharing that the investigators deem necessary to offer the participant (e.g., as mandated by the IRB). 
• A subcontract between an Administrative Core and clinical sites must include language that: 
  • Makes explicit that each site agrees to enter data in a data capture system maintained by the DMCC unless otherwise specified by the sponsoring NIH institute, acknowledging that the data entered into the DMCC may meet the definition of a limited data set. 
  • Allows the AC to collate participant data in the form of a limited data set from all protocols that the site participates in. 
  • Gives the AC the authority to distribute and share data with the DMCC and the NIH.  
  • Gives the AC the authority to share the data with other third parties as governed by specific data use agreements. 
  • Gives the AC the authority to transfer the data, without direct identifiers, to a Federal data repository maintained by the NIH. 
  • References the Data Management & Sharing Plan as written in the grant application and any Data Sharing Policy between RDCRC sites and the Administrative Core. 
    Suggested language: Pursuant to this agreement, as outlined in the Data Management & Sharing Plan of award [NIH award number] [Site] will enter [RDCRC] data in a data capture system hosted in the NCATS cloud and maintained by the DMCC on behalf of the [RDCRC] unless otherwise specified by the sponsoring NIH institute. The Administrative Core of [RDCRC] has the authority to collect information from [Site] in the form of a limited data set for the purpose of combining the data across the sites of each protocol. The Administrative Core has the authority to manage the data with the support of the RDCRN DMCC and further share the data with third parties as governed by data use agreements that the Administrative Core will prepare and execute according to the policies of the [RDCRC]. Further, the Administrative Core has the authority to transfer [RDCRC] data to Federal data repositories to fulfill their obligation to the sponsor(s), in doing so, the Administrative Core will utilize the services of the RDCRN DMCC. 
• A Data Sharing Policy between all participating sites of an RDCRC should be consistent with the RDCRN Template Document (linked above) and guidelines published by the RDCRN and the NIH. This policy should facilitate data sharing and outline the mechanisms of data sharing within the RDCRC and with external partners. The policy should clearly state the intention to transfer patient-level information, stripped of identifiers, to a federal data repository. 
• A Data Use Policy, consistent with the template and guidelines published by the RDCRN, that includes a publication policy outlining how data collected in RDCRC studies is to be used, disseminated, and attributed. 

A Data Management and Sharing Plan, formulated in accordance with these RDCRN Data Sharing Terms and Conditions, must be included in the grant application. It is expected that the investigator’s data sharing plan will specify the following elements: (1) description of what data will be collected including clinical data, diagnostic data, and physiological measurements such as MRI, (2) description of what biospecimens will be collected, (3) description of the data that will be derived from the biospecimens such as genotyping, sequence, metabolomic measures, proteomic measures, etc., (4) what data and/or biospecimens will be made available for deposit in databases or in a repository accessible to the research community, (5) a timetable for deposition of the data and/or biomaterials, and a specified time interval after which those data and materials can be released to the research community. 

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

Progress reports should briefly describe status of pilot projects, including data and safety monitoring, and should notify NIH of serious adverse events and unanticipated problems.

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

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

In accordance with the regulatory requirements provided at 2 CFR Part 200.113 and Appendix XII to  2 CFR Part 200, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period. The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (Responsibility/Qualification in SAM.gov, formerly FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in Appendix XII to 2 CFR Part 200 – Award Term and Condition for Recipient Integrity and Performance Matters.

Section VII. Agency Contacts

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

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

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

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: [email protected] (preferred method of contact)
Telephone: 301-480-7075

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: [email protected]

Tiina K. Urv, Ph.D.
National Center for Advancing Translational Sciences (NCATS)
Telephone: 301-827-2746 
Email: [email protected] 

Jill A. Morris, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-5745
Email: [email protected]

Marilyn Miller, Ph.D.
National Institute on Aging (NIA)
Phone: (301)496-9350
E-mail: [email protected]

Melissa Parisi, MD, PhD
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-435-6880
Email: [email protected]

Marrah Lachowicz-Scroggins, PhD
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-827-8229
Email: [email protected]

Faye H Chen, Ph.D.
NIAMS - NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
Phone: 301-594-5055
E-mail: [email protected]

Zubaida Saifudeen, PhD
NIDCR - NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH
Phone: (301) 827-3029
E-mail: [email protected]

Ruth Florese, Ph.D.
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 301-761-6284
Email:  [email protected] 

Cindy Roy, Ph.D
NIDDK - NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
Phone: 301-594-8805
E-mail: [email protected]

Rongling Li
NHGRI - NATIONAL HUMAN GENOME RESEARCH INSTITUTE
Phone: 301.480.2487
E-mail: [email protected]

Holly Lynn Storkel
NIDCD - NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS
Phone: 301.451.6842
E-mail: [email protected]

Marilyn Moore-Hoon, Ph.D.
National Center for Advancing Translational Sciences (NCATS)
Telephone: 301-827-9549 
Email: [email protected] 

Steve Elsberg
National Center for Advancing Translational Sciences (NCATS)
Telephone: 301-435-0528 
Email: [email protected]

Chief Grants Management Officer
National Institute of Neurological Disorders and Stroke (NINDS)
Email: [email protected]

Jeni Smits
National Institute on Aging (NIA)
Phone: none
E-mail: [email protected]

Margaret Young
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-642-4552
Email: [email protected]

Taylor Svilar
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-402-8545
Email: [email protected]

Erik Edgerton
NIAMS - NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
Phone: 301-594-7760
E-mail: [email protected]

Gabriel Hidalgo, MBA
NIDCR - NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH
Phone: 301-827-4630
E-mail: [email protected]

Sam Ashe
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 301-435-4799
Email:  [email protected]

Pamela Love
NIDDK - NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
Phone: (301) 435-6198
E-mail: [email protected]

Deanna L Ingersoll
NHGRI - NATIONAL HUMAN GENOME RESEARCH INSTITUTE
Phone: 301-435-7858
E-mail: [email protected]

Samantha Tempchin
National Institute on Deafness and Other Communication Disorders (NIDCD)
Telephone: 301-435-1404
Email: [email protected]

Section VIII. Other Information

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

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