NIH's new Application Submission System & Interface for Submission Tracking (ASSIST) is available for the electronic preparation and submission of multi-project applications through Grants.gov to NIH. Applications to this FOA must be submitted electronically using ASSIST or an institutional system-to-system solution; paper applications will not be accepted. ASSIST replaces the Grants.gov downloadable forms currently used with most NIH opportunities and provides many features to enable electronic multi-project application submission and improve data quality, including: pre-population of organization and PD/PI data, pre-submission validation of many agency business rules and the generation of data summaries in the application image used for review.

It is critical that applicants follow the Multi-Project (M) Instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts) and where instructions in the Application Guide are directly related to the Grants.gov downloadable forms currently used with most NIH opportunities. Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

Part 1. Overview Information
Part 2. Full Text of the Announcement

Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

The Office of Rare Diseases Research (ORDR) within the National Center for Advancing Translational Sciences (NCATS) along with the ICOs listed in Part I at the National Institutes of Health (NIH) invites applications in response to this Funding Opportunity Announcement (FOA) for the Rare Diseases Clinical Research Consortia (RDCRC) component of the Rare Diseases Research Network (RDCRN). The RDCRCs are intended to advance the diagnosis, management, and treatment of rare diseases. Each RDCRC will promote highly collaborative, multi-site, patient-centric, translational and clinical research. It is strongly encouraged that the RDCRC study outcome measures include those that address unmet clinical trial readiness needs that will move the field of research forward from its current state.

RDCRCs may address clinical trial readiness by supporting studies that validate clinical research tools that can include biomarkers or clinical outcome assessment measures that are fit-for-purpose within a defined context of use relevant to the clinical trials. Clinical trial readiness studies may also propose to expand the knowledge of disease natural history necessary for clinical trial design, and can include 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. The RDCRC will target at least three rare diseases/disorders/syndromes/conditions/manifestations (referred to in this document as rare diseases). The use of animal models is not permitted. The RDCRCs will provide an outstanding environment for the career enhancement of the next generation of rare diseases researchers. In addition, patient and stakeholder (parent, caregiver, support and advocacy group) experiences, perspectives, needs and priorities must be meaningfully incorporated into decisions and activities of the RDCRC.

It is the intent of the NIH to not support individual RDCRCs for more than 15 years (three awards) after awards made under this FOA. Duration of funding will be determined by the grant number.

Background

The Rare Diseases Act of 2002 (Public Law 107-280) defines a rare disease as a condition affecting fewer than 200,000 individuals in the United States. Collectively there are an estimated 7,000 diseases or conditions that fall into this category; cumulatively there are approximately 25 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 indicate 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 therapy have recently led to promising and potentially transformative treatments, there are several challenges in bringing effective treatments to more people living with rare diseases. First, making a diagnosis can be challenging with many patients experiencing a "diagnostic odyssey" of many months or even years because of limited knowledge of the range of disease manifestations and of genotype-phenotype studies. Second, there are often no high quality natural history datasets documenting how the disease affects patients' functioning, and how it progresses over time. Third, there are often no adequate clinical or biological markers to support the clinical development of new therapeutics. Fourth, the relatively small number of patients and clinicians caring for them lead to challenges to the design and implementation of clinical trials. 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. In addition, the global burden associated with rare disease necessitates international coordination and collaboration.

To facilitate progress in addressing these challenges the Rare Diseases Act of 2002 directed the ORDR 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 institutes (NCATS, NCRR, OD, NICHD, NINDS, NIAMS, NHLBI, NIDDK, NIDCR, NIMH, NCI, NIAID and NEI), led by the Office of Rare Diseases Research at NCATS, have partnered to support the RDCRN. The Network 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 31 individual consortia that conducted research on 238 individual disorders, leading to a greater understanding of rare diseases.

This FOA seeks RDCRC applications for rare diseases research relevant to the mission of the participating NIH ICs. 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).

Scope

The Rare Diseases Clinical Research Network (RDCRN) is a cooperative network composed of multiple Rare Diseases Clinical Research Consortia (RDCRC) and a Data Management and Coordinating Center (DMCC) (see RFA-TR-18-021) to facilitate clinical research in rare diseases carried out by the RDCRCs. This FOA invites applications for the RDCRCs.

Each RDCRC application must indicate at least three different rare diseases, defined as:

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

Each RDCRC must propose at least two clinical research projects but no more than five. One clinical research project must be a longitudinal study. Options for additional clinical research projects include, but are not restricted to, natural history studies, biomarker studies and other clinical trials readiness studies. Knowledge from such clinical studies should be essential to direct subsequent clinical trials and can be invaluable for the targeted rare diseases.

The use of animal models is not permitted. Clinical research, as it is defined by the NIH consists of:

1) 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. It includes: (a) mechanisms of human disease, (b) therapeutic interventions, (c) clinical trials, or (d) development of new technologies; or

2) Epidemiological and behavioral studies or;

3) Outcomes research and health services research.

Studies based entirely on publicly available or deidentified data or specimens (thus falling under 45 CFR 46.101(b), Exemption 4) are not considered clinical research by this definition.

One of the Clinical Research Projects must be longitudinal in nature (e.g., Natural History Studies). Clinical research supported under this FOA includes mechanistic studies designed to understand a biological or behavioral process, the pathophysiology of a disease, or the mechanism of action of an intervention.

Projects must be focused only on rare diseases. In this document, rare disease is defined as one that affects fewer than 200,000 people in the United States.

Any interventional clinical trials proposed as part of a RDCRC must be Phase I, or early stage proof-of-concept trials.

Areas of research can include, but are not limited to, the following:

Clinical studies aimed at clinical trial preparation, including natural history studies

Early-stage clinical trials

Biomarkers

Development of patient reported outcome measures

Genotype/Phenotype studies

Mechanistic trials/target engagement trials

Diagnostic studies

New treatment modalities

Repurposing of drugs

Prevention studies

Newborn Screening/other screening

Patient-centered outcome measure

Patient and stakeholder experiences, perspectives, needs and priorities must be meaningfully incorporated into decisions and activities of the RDCRC.

The research problems proposed should require substantial collaborative efforts to solve, and thus are best carried out in a multi-site RDCRC setting. Applicants are encouraged to emphasize new ideas, novel approaches, and state-of-the-art technologies to address the needs for effective treatments and other strategies to improve the lives of individuals with rare diseases.

Applications must include multidisciplinary collaborative efforts, those involving patients, clinicians, researchers, bioinformaticians and others with appropriate expertise, along with stakeholders.

RDCRC applicants must also propose resource development, career enhancement and outreach activities that will enhance rare diseases research on a national or international level.

Consortia with research agendas at varying stages of scientific development within the research program are encouraged to apply. Early stage consortia 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 that would benefit from a RDCRC effort) are encouraged to apply.

Applications will be considered nonresponsive if:

• Any of the structural elements listed above are missing
• There are fewer than three rare diseases included
• It is not a multiple-site RDCRC
• There is not at least one longitudinal project
• The projects are not clinical research
• There is no inclusion of patient or stakeholder group
• Seek support for single-component basic, translational, clinical studies or Phase III clinical trials

Applicants seeking support for projects that are outside of the scope of the FOA (e.g., single-component 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.

It is imperative that RDCRC applicants carefully review the DMCC FOA (RFA-TR-18-021) to fully understand the resources and services that will be provided to the network by the DMCC and to coordinate efforts.

General Description of the Required Structural Elements of each RDCRC:

The structural requirements of an RDCRC under this FOA are:

• Administrative Core
• Clinical Research Projects, minimum 2, maximum 5
• Pilot/Feasibility Core
• Career Enhancement Core

Administrative Core

The RDCRC Administrative Core is responsible for the overall administration of the RDCRC (including policy, procedure, and funds allocation) and the integration of all activities within and among the RDCRC sites. This includes coordinating communication among the RDCRC sites and integrating participating researchers into a cohesive RDCRC environment, even if geographically dispersed. Additionally, the Administrative Core will serve as the point of coordination with the RDCRN via the DMCC and the patient and stakeholder communities.

The Administrative Core will include a Clinical Team Liaison who is a clinical investigator. The Clinical Team Liaison will ensure a mutually supportive interaction between the scientists conducting clinical research. An Administrative Coordinator should be identified in the application who will be responsible for assisting the RDCRC Director (PD/PI of the application) with day-to-day administrative details and program coordination.

The Administrative Core will also coordinate and support RDCRN-wide efforts to develop and monitor best practices for clinical and research data handling and use, including the use of Common Data Elements (CDEs).

The Administrative Core is expected to establish and maintain a website to communicate the RDCRC mission and the availability of career enhancement opportunities provided through the Career Enhancement Core, and to provide access to information about RDCRN-wide resources provided by the DMCC.

Clinical Research Projects

The RDCRCs are intended to advance the diagnosis, management, and treatment of rare diseases with a focus on clinical trial readiness. A minimum of two but no more than five multi-site clinical research projects are required. One of the projects must be longitudinal in nature (e.g., Natural History Studies). If a clinical research project is proposed, it need not include an intervention. See Section IV.2 for additional guidance on projects that propose a clinical trial. Epidemiological, behavioral and health outcomes research studies in rare diseases are also encouraged.

Each of the proposed clinical research projects should address problems that require substantial collaborative research effort and a multi-site RDCRC environment to solve, benefit from NIH programmatic input, and are more substantial than a stand-alone grant. Collectively, the projects should involve synergistic teams with experience in rare diseases or disease/disorder/syndrome/condition/manifestation along with complementary expertise. Collaborations should be arranged to bring the best expertise to bear on a problem while ensuring input from all patients and stakeholders (parents, caregivers, support and advocacy groups).

Pilot/Feasibility Core

A Pilot/Feasibility 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 encouraged.

Pilot/Feasibility projects must not be described in the current application and if described will not be considered in the review of the application.

The selection and initiation of future pilot/feasibility projects are contingent upon approval by the NIH and the assigned 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): Updated Notice https://grants.nih.gov/grants/guide/notice-files/NOT-OD-15-129.html

Career Enhancement Core

As nationally recognized consortia in rare diseases research, the RDCRCs are expected to play a leadership role in career enhancement new researchers for the rare diseases field and contribute to the development of future research leaders. Each RDCRC should provide a Career Enhancement Program to provide support for career enhancement-related expenses for predoctoral, postdoctoral and/or clinical fellow as well as support for activities that enhance the institution's environment for the education of students/post-docs and early-stage investigators in rare diseases research.

Leveraging existing career enhancement programs and exploring sponsorship opportunities are encouraged. This program may propose activities that enhance the career enhancement environment through specialized coursework, a seminar program, retreats for presentation of students/post-doc research, journal clubs or other activities that contribute to the preparation of junior investigators for careers in rare diseases research. Exposure to research at other RDCRCs is also encouraged through exchange programs, short-term career enhancement opportunities or visits to learn new research approaches.

RDCRC Governance (RDCRC-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.

RDCRN Formation and Governance (Network-specific)

The awards funded under this FOA will be cooperative agreements (see Section VI.2. Cooperative Agreement Terms and Conditions of Award). Close interactions among awardees and NIH will be required to manage this complex network.

The RDCRN will consist of all the awarded RDCRCs and the DMCC. The RDCRN governance will rest with the Network Steering Committee, with advice from an External Scientific Panel (ESP). The Network Steering Committee may establish subcommittees and working groups to facilitate development, implementation, and monitoring of specific Network functions as needed.

The Network Steering Committee is composed of:

• The RDCRC PD(s)/PI(s) and patient advocate group representative(s) from each RDCRC
• The PD(s)/PI(s) of the DMCC
• NIH Program Director(s)/Scientist(s) from participating institutes

The Network Steering Committee 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 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 ESP will be named by NIH program officials and will serve in advisory capacity by reviewing RDCRN activities and making recommendations to the Network Steering Committee and the NIH regarding process and substantive issues that arise during Network operations.

Leadership

The RDCRC PD/PI(s) should develop and maintain a RDCRC environment that fosters collaborative, patient-oriented, multi-site, multi-disciplinary research collaborations and career enhancement. The RDCRC PD/PI(s) cannot serve as the Program Director/Principal Investigator of a project in another active RDCRN award. However, other than this restriction, collaborations among RDCRCs are encouraged. The minimum cumulative effort of the principal investigator(s) of a consortium should be at least 2.1 person months per year.

Coalition of Patient Advocacy Groups (CPAG)

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

Rare Diseases Clinical Research Network (RDCRN) Data

Advancing rare disease research by freely sharing high-value data is a critical goal of the program. 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 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 requirements. RDCRN participants will be required to share their data within the DMCC.

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

Each RDCRC must be willing to work towards being a member of a network that supports GDPs across sites, encourages the use of CDEs, and has a commitment to community engagement, sharing of data and other resources within the network and to both the scientific communities and the general public.

Data Management Services

The DMCC Data Management Core will provide Cloud Computing Services and Engineering Support provisioned by the Information Resources Technology Branch (ITRB) within the National Center for Advancing Translational Sciences (NCATS). These activities do not constitute a basis for inclusion of intramural investigators in the RDCRC application as described in section III.1.

NCATS' ITRB will provide access to various public cloud services, and high-performance computing services for the needs of the awardees. This enables the awardees to offer their systems, projects and research in a secure environment with simplified implementation, deployment and operational reliability. Through these services, NCATS ITRB will enable the awardees to gain a self-service capability. NCATS ITRB will provide the following:

• Infrastructure as a Service (IaaS) on any of the major public cloud providers via NCATS' Federated Authorization Service
• If requested, access to NCATS' Federated Authorization Software as a Service (SaaS) to any of the awardees systems and applications
• If requested, various Common Cloud Engineering and Support Services.

IaaS Services

NCATS ITRB will provide the awardee with a cloud instance on any of the following public cloud service providers: Amazon Web Services, Microsoft Azure or Google Cloud Platform. This instance would be co-managed by the awardee and NCATS ITRB. Access to the awardees cloud instance would be managed using NCATS' Federated Authorization System and the awardees would have complete rights to all services provided by the Cloud Service Provider.

Federated Authorization Services SaaS

If requested, at no cost to the awardee, NCATS ITRB would provide access to NCATS' Federated Authorization Service. The awardee could use NCATS' Authorization Service to provide for federated access to any of their systems and applications.

Cloud Engineering Support

If requested, NCATS will provide access to and administrative support for various common cloud services including configuration, patching, backups, and user account management. These services include but are not limited to: Automated Configuration Management Services; Continuous Integration Services; Automated Deployment Services; Code Analysis Services; Log Aggregation and Analysis; Usage and Performance Monitoring Services; Aggregated Search Services; Cache management services; Message Queue and Notification services.

Cloud-based High Performance Computing

If requested, NCATS ITRB can also provide a cloud based elastic HPC service designed to automate and scale, giving the scientists the ability to model and deploy their HPC applications in a cloud that can provide the scale and performance needed. The cloud HPC provides resources without undue access restrictions, while addressing the security concerns surrounding cloud deployments. The cloud HPC solution addresses use cases that deal with various storage, hypervisor and network services. The cloud HPC offers higher utilization and operational savings while providing a high speed, secure and federated access.

Regulatory Requirements

Data Safety Monitoring Board (DSMB)

If DSMB services are required they may be requested from the DMCC only if no alternate source exists. To be eligible for the DMCC services, clinical trials or pilot studies must be of greater than minimal risk, and include one or more of the following:

1) Protocol designs that allow for modifications to the trial or statistical procedures of the trial after its initiation, such as an adaptive design;

2) Plan to evaluate novel technology or an intervention for which prior data (e.g., pre-clinical toxicology or from a related compound) suggest the intervention under study has the potential to induce a potentially severe or unacceptable toxicity;

3) Objective to provide definitive information about the effectiveness or safety of the intervention (e.g., a Phase 3 or efficacy trial, such as a trial intended to support product registration);

4) Ethics-driven need to stop the study early if the primary question is addressed, for futility, or for other pre-specified reasons.

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). In addition, a Food and Drug Administration (FDA) Investigational Device Exemption (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 if the IRB determines they are needed. 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 specifics interests include:

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 Cancer Institute (NCI)

The NCI seeks clinical research teams studying rare cancers. Examples include, but are not limited to, the following rare cancers: carcinoid, primary CNS-lymphoma, sarcomas, thyroid cancer, urinary cancers. chordoma, bone, cholangiocarcinoma, rasopathies.

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 and kidney disorders. Below are some examples of rare diseases that may be appropriate. Examples of 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, kidney and urologic diseases include porphyrias, inherited bone marrow failure syndromes or hemoglobinopathies, inherited and acquired systemic amyloidosis, minimal change disease, autosomal recessive polycystic kidney disease), primary hyperoxaluria, and renal disease associated with cystinosis or tuberous sclerosis.

National Heart, Lung and Blood Institute (NHLBI)

The NHLBI seeks applications studying rare lung diseases with a special interest in: lymphangioleiomyomatosis, pulmonary alveolar proteinosis, Hermansky Pudlak Syndrome, diseases of mucociliary clearance, and other rare lung diseases currently being studied in ongoing, established consortia.

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, and fungi. 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 that are inappropriate or exaggerated reactions of the immune system to substances that cause no symptoms in the majority of people.

NIAID research is focused on the development of new approaches for the diagnosis, prevention, and treatment of allergic diseases.

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, adults, families, and populations. Many disorders that affect children and their families are rare and/or neglected diseases. NICHD has supported research in at least 80 rare disorders. Many of these diseases have a genetic basis, and many affect neurodevelopment. NICHD encourages applications in rare disorders, including (but not limited to):

• Metabolic disorders (e.g., urea cycle disorders, organic acidemias, amino acidopathies, fatty acid oxidation disorders, mitochondrial disorders, or neurotransmitter disorders);
• Storage diseases (e.g., gangliosidoses, mucopolysaccharidoses, mucolipidoses, peroxisomal disorders, glycogen storage disorders, other lysosomal storage diseases);
• Muscular dystrophies and related neuromuscular disorders;
• Skeletal dysplasias and other congenital structural malformations;
• Genomic disorders and genetic syndromes (e.g., Angelman, Fragile X, Prader-Willi, Rett, Williams, Smith-Magenis, Cornelia de Lange, and DiGeorge/velocardiofacial syndrome; copy number variations such as 18q, 1p36, and other microdeletion or microduplication disorders);
• Sex chromosome disorders (e.g., Turner syndrome, Klinefelter syndrome, XXYY, XXXY, XXX, XYY)
• Rare conditions detected by newborn screening or with the potential to be added to the Recommended Uniform Screening Panel (RUSP).

National Institute of Dental and Craniofacial Research (NIDCR)

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.

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.

Examples include:

• Rare tumors of the head and neck, including salivary gland cancers;
• 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; 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 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.

Pre-application Information Session

All applicants are strongly encouraged to contact NIH staff to discuss the alignment of their proposed work with the goals of this FOA 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 companion FOA. 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 web site for this FOA.

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

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

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:

o Hispanic-serving Institutions

o Historically Black Colleges and Universities (HBCUs)

o Tribally Controlled Colleges and Universities (TCCUs)

o Alaska Native and Native Hawaiian Serving Institutions

o 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)

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)
• 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 Institutions) 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 SF 424 (R&R) 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. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• System for Award Management (SAM) (formerly CCR) 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.
• eRA Commons - Applicants must have an active DUNS number and SAM registration in order to complete the eRA Commons registration. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration. 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 DUNS number and 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 underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

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 SF424 (R&R) Application Guide.

The minimum cumulative effort of the PD/PI(s) should be at least 2.1 person months per year.

The RDCRC PD/PI(s) cannot serve as the Program Director/Principal Investigator of a project in another active RDCRN award.

This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.

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. 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 NOT-OD-11-101).

A button to access the online ASSIST system is available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

Most applicants will use NIH's ASSIST system to prepare and submit applications through Grants.gov to NIH. Applications prepared and submitted using applicant systems capable of submitting electronic multi-project applications to Grants.gov will also be accepted.

It is critical that applicants follow the Multi-Project (M) Instructions in the SF424 (R&R) Application Guide, except where instructed in this funding opportunity announcement to do otherwise and where instructions in the Application Guide are directly related to the Grants.gov downloadable forms currently used with most NIH opportunities. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

For information on Application Submission and Receipt, visit Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications.

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:

B. Duane Price, Ph.D.
Telephone: 301-435-0829
Email: b.duane.price@nih.gov

Component Types Available in ASSIST	Research Strategy/Program Plan Page Limits
Overall	12 pages
Admin Core	6 pages
Clinical Res Project	12 pages
Clinical Res Project	12 pages
Clinical Res Project	12 pages
Clinical Res Project	12 pages
Clinical Res Project	12 pages
Pilot-Feasibility	6 pages
Career Enhancement	6 pages

Additional page limits described in the SF424 Application Guide and the Table of Page Limits must be followed.

The following section supplements the instructions found in the SF424 (R&R) 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
• Clinical Research Projects: required, minimum 2, maximum 5
• Pilot/Feasibility Core: required; maximum of 1
• Career Enhancement Core: required; maximum of 1

When preparing your application in ASSIST, use Component Type 'Overall'.

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

Complete entire form.

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

Follow standard instructions.

Facilities and Other Resources:

Each RDCRC must provide a statement that addresses how the institutional commitment will be established and sustained, and how the RDCRC research effort will be prioritized within the institution.

Describe institutional commitment to tenured faculty positions, dedicated space and other resources, and sufficient time release to allow the investigators to pursue the goals of the RDCRN.

Describe institutional commitment that promotes the mission of team-based research.

Describe how the environment and infrastructure of the RDCRC are beneficial in accomplishing the goals of the projects.

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.

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

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.

Specific Aims: Describe the overall goals of the RDCRC for the performance period of the grant. Describe the research objectives or the RDCRN for promoting understanding of rare diseases 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.
• Describe the group of rare diseases to be included (minimum of three) and how the diseases relate to one another and the rationale for this grouping.
• Clearly state the unmet research/clinical needs these projects address, and how the projects and cores contribute to the overall goals and objectives of the RDCRC in advancing understanding of the diseases, improving clinical trial readiness, developing and testing therapies, advancing patient care and reducing disease burden.
• Describe how the RDCRC will be effective in significantly accelerating progress toward effective treatments or other improvements in the lives of individuals with the targeted rare diseases through coordinated and synergistic research and infrastructure activities.
• Explain the strategy for achieving the goals defined for the overall program and how each clinical research project and core relates to that strategy. The program should be viewed as interrelated clinical research projects, each of which is not only individually meritorious but is also complementary to the other projects and related to the overall theme developed for the RDCRC.
• Provide justification in the application that (a) the proposed projects are such that they require an intensive collaborative effort to succeed and (b) key personnel will collaborate effectively.
• Justify how the structure and administration of the RDCRC enable the individually meritorious components (i.e. clinical research projects, pilot studies, and career enhancement opportunities) to have greater clinical and scientific impact than what each component would accomplish individually.
• Briefly describe the clinical research projects and cores and the organizational structure of the RDCRC.
• Indicate prior collaborative arrangements among proposed senior key personnel.
• Describe how the RDCRC will work collaboratively with the DMCC.
• Describe how the RDCRC will engage in the use of RDCRN-wide data standards and data sharing.
• Describe how the RDCRC will engage in sharing of data and other resources within the network and to both the scientific communities and the general public.
• Describe patient or stakeholder participation across the planned objectives (e.g., in addressing clinical design, recruitment, and education). The proposed stakeholder's activities should be appropriate for the level of stakeholder capabilities.
• Describe the nature of the approach for the RDCRC of clinical investigators, institutions, and relevant organizations to include patient or stakeholder groups in the RDCRC.
• Explain how combined resources create capabilities that are more than the sum of the parts.
• Describe plans for the RDCRC to collaborate and otherwise contribute to the RDCRN, through participating in the annual meeting, workshops, career enhancement, collaborative efforts, or other RDCRN-wide activities and initiatives.
• Describe interactions with other organizations or industry.
• Describe how you will utilize the NCATS ITRB Cloud Computing Services and Engineering support to achieve your mission.

Renewal applications from existing RDCRCs -

• Document achievement of the goals of the prior funding period.
• Describe inclusion of patient or stakeholder groups by providing examples of previous and/or ongoing collaborations.
• For consortia that have been continuously funded for longer than 10 years, 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 regard to clinical trial readiness should be addressed.
• For consortia that have been continuously funded for longer than 14 years, 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 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/or 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 Director.
• 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.
• Co-funding or matching funds from other sources (including industry) are 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.

For the RDCRC, the institution that submits the U54 application must 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. Also 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 are recommended.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

The data sharing plan is required and should describe the following:

• Data to be shared
• Availability of individual participant data
• Availability of data standards and data dictionaries
• Availability of other documents
• Timing of data availability (start and end dates)
• Individuals that the data be shared with (e.g. members of the RDCRN, patients and stakeholders)
• Method used to share the information with patients and stakeholders
• Type of analyses the data will be available for (e.g., all analysis, limited analysis)
• Mechanism by which the data will be made available
• Remediation of data impacted by the EU General Data Protection Regulation (EU GDPR)

Other resources:

What other resources (for example, molecular data from biosamples, analytical results and research tools) from this RDCRC will be publicly available?

When will other resources be made available?

All applications, regardless of the amount of direct costs requested for any one year, must address a Data Sharing Plan.

Appendix:

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 (Overall)

When involving NIH-defined human subjects research, clinical research, and/or 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, 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 SF424 (R&R) Application Guide must be followed.

Delayed Onset Study

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

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

Administrative Core

When preparing your application in ASSIST, use Component Type 'Admin Core.'

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

Complete only the following fields:

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

Enter Human Embryonic Stem Cells in each relevant component.

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.

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.

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

Budget 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.

Specific Aims: Describe the goals of the Administrative Core and how these goals will contribute to substantial and sustained support of the RDCRC. The specific aims should address plans for communication and coordination across the RDCRC and the DMCC.

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

RDCRC Scientific and Administrative Leadership

Describe plans for organizational and administrative management of the RDCRC. Explain the methods that will be used for monitoring progress and effective use of the shared resources. Explain the plans for internal quality control of on-going research, management of day-to-day activities, management of contractual agreements (if applicable), and a plan for resolution of disputes. Describe how the Core Lead's leadership capabilities adequately provide for administrative management. Describe plans for allocation of funds as applicable.

Describe a plan for communication (meetings, conference calls etc.) and participation of all personnel within the RDCRC. The description of the Administrative Core of an RDCRC should detail how the activities and contribution of the collaborating investigators and institutions will be coordinated.

The RDCRC Administrative Core must include a Clinical Team Liaison who ensures a mutually supportive interaction between scientists conducting clinical research. Describe the qualifications of the clinical investigator and the plan to promote clinical research.

An Administrative Coordinator should be identified on the application who will be responsible for assisting the RDCRC Director (PD/PI of the application) with the day-to-day administrative details, program coordination.

Applicants are encouraged to form the strongest teams possible to address the proposed research questions, 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.

Data Management and Coordination with DMCC

Describe the plan to work collaboratively with DMCC Administrative Core to coordinate efforts across RDCRN with the DMCC Data Management Core, Clinical Research and Engagement and Dissemination Cores.

Identify a representative from the RDCRC who will participate in the development and facilitation of RDCRN wide Good Data Practices (GDP) of clinical and research data and other coordinated efforts to facilitate data sharing standards across the network.

Describe plans for identifying and utilizing (if available) or developing Common Data Elements (CDEs). These should be listed in the administrative CDE's. Potential CDE resources may include but are not limited to NBSTRN, NINDS CDE, BD2K, NLM, https://www.nlm.nih.gov/cde/, https://cde.drugabuse.gov, https://cdebrowser.nci.nih.gov/cdebrowserClient/cdeBrowser.html#/search, Neuro-QOL

The RDCRC should leverage DMCC core support, however, the Administrative Core should provide support for any RDCRC-specific needs that extend beyond the scope of the DMCC (e.g. biostatistical support). Describe the biostatistical support for the RDCRC. The biostatistician from RDCRC will provide statistical support for protocol development and assist in study designs and statistical data analysis. The biostatistician in collaboration with DMCC will also assist in the collection of epidemiologic information and quality assurance for database of pooled data for the RDCRC.

If working groups will be established, indicate their specific functions, composition and to whom they report.

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.

External Advisory Committee (EAC)

Describe how an External Advisory Committee (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: Only letters of support specific to the Administrative Core should be attached to this section.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide.

Appendix:

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 NIH-defined human subjects research, clinical research, and/or 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

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

Single IRB for Multisite Projects

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

Clinical Research Project

When preparing your application in ASSIST, use Component Type 'Clinical Res Project'.

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 Project)

Complete only the following fields:

Applicant Information

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

PHS 398 Cover Page Supplement (Clinical Research Project)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Clinical Research Project)

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

Vertebrate Animals: Answer only the 'Are Vertebrate Animals Used?' question.

Project Narrative: Do not complete.

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

List all performance sites that apply to the specific component.

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

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

In the Project Director/Principal Investigator section of the form, use Project Role of 'Other' with Category of 'Project Lead' and provide a valid eRA Commons ID in the Credential field.

In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.

Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.

If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.

Budget (Clinical Research Project)

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

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

PHS 398 Research Plan (Clinical Research Project)

Research Strategy:

Clearly state the project's overall objective and explain its relevance to the central theme of the RDCRC. In addition, a compelling case should be presented in support of interrelated and/or complementary projects and collaborating investigators that will yield results beyond those achievable if each project were pursued separately and without formal interaction among the participating investigators.

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 advancing treatments for the targeted rare disease/disorder/syndrome/condition/manifestation.

If the clinical research project includes an interventional 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, if applicable.

The preclinical rationale should provide evidence that the rigor of preclinical efficacy data and the level of effect of the agent are both sufficient to warrant clinical testing (for guidance, see https://grants.nih.gov/grants/guide/notice-files/NOT-NS-11-023.html).

The approach section should describe how regulatory requirements will be met in a timely manner, and indicate drug/biologic availability for use in a trial and agreement of all participating clinical/corporate partners.

Describe the inclusion of patients or stakeholders in the work proposed.

Clinical trials

It is strongly encouraged that clinical studies utilize established CDEs whenever possible to ensure comparability with other clinical trials (e.g., NIH CDEs: https://www.nlm.nih.gov/cde/; Longitudinal Pediatric Data Resource: https://lpdr-lvl1.nbstrn.org/; NINDS CDEs: https://www.commondataelements.ninds.nih.gov/#page=Default).

Any interventional clinical trials proposed as part of a RDCRC must be Phase 1, or early stage proof-of-concept trials. 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.

• Examples of relevant clinical trials or studies 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 at 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;
• Studies to identify inclusion and exclusion criteria to be applied in a subsequent definitive clinical trial.

As noted previously, when clinical trials are proposed, there should be strong evidence provided in support of the potential value and feasibility of the study, including a clear preclinical rationale if applicable, unimpaired regulatory status, evidence of drug/biologic availability for use in a trial, and agreement of all participating clinical/corporate partners.

Under current regulations, NCATS will support clinical trial (CT) activities through the end of phase II for all diseases or conditions, and through the end of phase III for a rare disease or condition. If proposing such trials, contact NIH IC Scientific/Research contacts. (See Section VII. Agency Contacts). Although clinical trials can be supported through RDCRC, clinical trials are NOT a required component of an RDCRC.

Letters of Support: Only letters of support specific to each Clinical Research Project should be attached to this section. Provide letters of collaboration from individuals who will contribute in a substantive, meaningful way to the scientific development or execution of the clinical research project, whether or not salaries are requested.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide.

Appendix:

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 Project)

When involving NIH-defined human subjects research, clinical research, and/or 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

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

Single IRB for Multisite Projects

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

Pilot/Feasibility Core

When preparing your application in ASSIST, 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 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 Core)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Pilot/Feasibility 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

Facilities and other resources:

Identify support the Core receives from the institution, such as large gifts, dedicated space, direct support of infrastructure core personnel, and dedicated equipment, including support for research infrastructure-related functions such as directing or managing the Core, and similar activities. This information may be presented in tabular form.

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

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

The Pilot/Feasibility Core budget may include equipment, supplies, support contracts, and other necessary expenses. (Equipment as used herein means tangible personal property (including information technology systems) having a useful life of more than one year and a per-unit acquisition cost which equals or exceeds the lesser of the capitalization level established by the non-Federal entity for financial statement purposes, or $5,000. Exceptions require identification, justification and NIH pre-approval for that specific equipment. Since cloud computing services and engineering support are being provided by the RDCRN DMCC Engagement and Dissemination Core, applicant justification must include rationale for non-use.)

All items should be fully justified for allocation of RDCRC funds within the Budget Justification. Any budget requested for support of the Pilot/Feasibility Core Director must match the effort associated with the Pilot/Feasibility Core work conducted by the Pilot/Feasibility Core Director.

Applicants should budget funds to support developmental projects that stimulate clinical trial readiness in targeted rare disease research. These funds may be used by investigators for projects of high scientific merit, that are related to the overall goals of the RDCRC and that have the potential to move the field forward in an impactful manner.

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 Core)

Specific Aims: Describe the specific goals of the Pilot/Feasibility Core.

Research Strategy:

Describe in detail how the program of pilot/feasibility projects will be established and how it will enable innovative pilot/feasibility studies aimed at advancing the diagnosis, clinical trial readiness, management or treatment of one or more rare diseases.

• Clearly describe the solicitation and selection processes including eligibility criteria for pilot/feasibility projects.
• Describe the review criteria for the pilot/feasibility projects and the peer review process for pilot/feasibility project selection such that the program ensures 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 in an impactful manner
• Are milestone driven, with clear go/no go criteria
• Are time limited (At least 1 year but no more than 2 years second year must be contingent on meeting year one milestones).
• 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.
• Describe how the progress of the pilot/feasibility projects will be evaluated for consideration for a second year of support.
• Pilot/Feasibility projects must not be described in the current application and if described will not be reviewed.

Programs must abide by the requirements outlined in the "delayed onset studies" referenced below.

Letters of Support:

Only letters of support specific to the Pilot/Feasibility Core should be attached to this section. Letters from high-level institution official(s) (e.g., Dean of the School of Medicine, President, and Vice President for Research) should state the institutional support. There is no cost sharing requirement under this FOA. Indication of institutional commitment to the success of the program will be considered positively in the programmatic evaluation of applications. Examples for such support may include ensuring adequate access to facilities.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide.

Appendix:

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 Core)

When involving NIH-defined human subjects research, clinical research, and/or 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

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

Career Enhancement

When preparing your application in ASSIST, 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.

Specific names provided for Other Attachments must be no more than 50 characters including spaces.

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 needs to allocate a budget for career enhancement support, as appropriate, and all other core activities.

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: Describe the specific goals of the Career Enhancement Core

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. 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 students/post-docs 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, which would enhance the career enhancement of new researchers for the rare diseases field and contribute to the development of future research leaders. Career enhancement activities that go beyond the RDCRC to enhance the experiences of student(s)/post-doc(s) in other laboratories or at other institutions are also encouraged.

Describe how the student(s)/post-doc(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 program activities intended to develop the working knowledge needed for student(s)/post-doc(s) to select among and prepare for the next step in varied career options available in the rare disease workforce.

Exploring sponsorship opportunities is encouraged. The Career Enhancement Program may propose activities that enhance the environment through specialized coursework, a seminar program, retreats for presentation of student(s)/post-doc(s) research, journal clubs or other activities that contribute to the preparation of investigators for careers in rare diseases research. Exposure to research at other RDCRCs is also encouraged through exchange programs, short-term career enhancement opportunities or visits to learn new research approaches.

Student(s)/post-doc(s) Candidates:

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 student(s)/post-doc(s) with clinical expertise due to the significant need for well-trained clinical researchers in the rare diseases field. Do not name prospective student(s)/post-doc(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 student(s)/post-doc(s), the academic and research background needed to pursue the proposed career enhancement, and, as appropriate, plans to accommodate differences in preparation among student(s)/post-doc(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 student(s)/post-doc(s) level, and explain how the programs will synergize, if applicable, whether student(s)/post-doc(s) are expected to transition from one support program to another, and how the career enhancement faculty, pool of potential student(s)/post-doc(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 renewals applications provide aggregate data 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.

For renewal applications: 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: Only letters of support specific to the Career Enhancement Core should be attached to this section. Letters from high-level institution official(s) (e.g., Dean of the School of Medicine, President, and Vice President for Research) should state the institutional support. There is no cost sharing requirement under this FOA. Indication of institutional commitment to the success of the program will be considered positively in the programmatic evaluation of applications. Examples for such support may include ensuring adequate access to facilities.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide.

Appendix:

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.

See Part 1. 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.

Part I. Overview Information 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 Policy on Late Application Submission.

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 the SF424 (R&R) Application Guide.

This initiative is not subject to intergovernmental review.

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

Pre-award costs are allowable only as described in the NIH Grants Policy Statement.

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.

Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide. Paper applications will not be accepted.

For information on how your application will be automatically assembled for review and funding consideration after submission go 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 Applying Electronically. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Guidelines for Applicants Experiencing System Issues. 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 Component of the SF424(R&R) Application Package. 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 DUNS number it provides on the application is the same number used in the organization's profile in the eRA Commons and for the System for Award Management (SAM). Additional information may be found in the SF424 (R&R) 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.

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 may participate in this program as PDs/PIs in accord with the Terms and Conditions provided in this FOA. Intellectual property will be managed in accord with established policy of the 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.

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 a "Common Data Element (CDE) Resource Portal" (http://cde.nih.gov/) 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.

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 FOA. 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.

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.

Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

In addition, for applications involving clinical trials:

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 RDCRC 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 RDCRC proposed).

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

• To what extent will the RDCRC facilitate clinical trial readiness?
• Is there strong evidence that this will be a successful RDCRC, with each of the projects and cores not only individually scientifically meritorious but also complementary to the other components?
• Is there justification in the application that: (a) the proposed projects require an intensive collaborative effort to succeed and (b) key personnel will collaborate effectively?
• Are there appropriate plans for the RDCRC to collaborate and otherwise contribute to the RDCRN, through participating in the annual meeting, workshops, career enhancement, collaborative efforts, or other RDCRN-wide activities?
• Is there an appropriate plan to incorporate RDCRN-wide data standards to all data collected?
• Is there a sufficient plan to sharing of data and other resources within the network and to both the scientific communities and the general public?
• If the RDCRC is multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate?
• Is there a strong collaborative relationship among the investigators at the various sites and across the RDCRC and with CPAGS?
• Are patient and stakeholder experiences, perspectives, needs and priorities being meaningfully incorporated into decisions and activities of the RDCRC?
• Is there evidence of institutional commitment to the establishment and growth of the RDCRC?
• Is the physical distribution of RDCRC investigators and core resources conducive to the synergy necessary for a successful RDCRC?
• Will existing NIH-supported core facilities be shared with the RDCRC?
• Do the institutional administration and environment provide opportunities for RDCRC growth?
• If applicable, are there sufficient commitment and support on the part of institutions associated with the RDCRC through RDCRC agreements?

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the Clinical Research Projects 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 Clinical Research Projects 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 Clinical Research Project that by its nature is not innovative may be essential to advance a field.

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

In addition, for applications involving 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?

Are the Project Director(s)/Principal Investigator(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 career enhancement? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

In addition, for applications involving clinical trials

With regard to the proposed leadership for the project, do the Project Director(s)/Principal Investigator(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?

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?

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the 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 children, justified in terms of the scientific goals and research strategy proposed?

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?

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

In addition, for applications involving clinical trials

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

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

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

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

Reviewers will provide an overall impact score for each Core to reflect their assessment of the likelihood for the core to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria.

• Does the application clearly describe and justify the proposed Administrative Core operational plan and organizational structure?
• Is the proposed Administrative Core adequate to accomplish the objectives of the RDCRC?
• How well does the Administrative Core fit into the central focus of the RDCRC?
• Does the application describe adequate plans for internal quality control of on-going research, management of day-to-day program activities, management of contractual agreements, fair, effective communication and cooperation among program leaders and/or program investigators, and a plan for resolution of disputes, and allocation of funds, as applicable?
• Do the Core Leader's leadership capabilities adequately provide for administrative management of the core?
• Does the Administrative Core promote strategies to ensure a robust scientific approach across the RDCRC?
• Are data management and coordination with the DMCC adequately addressed?
• Is the proposed plan for promoting awareness of disorders within the RDCRC to the community adequate?

• Does the application describe the plan for ensuring that the proposed projects are related to the targeted rare diseases within the RDCRC, promotes clinical trial readiness and have the potential to move the field forward?
• Does the application adequately address the program for pilot/feasibility projects?
• Is the solicitation, review and selection process rigorous and unbiased?
• Does the application adequately address how the program will ensure that the pilot/feasibility projects leverage existing resources and infrastructure?
• Does the application adequately address how the program will ensure that the pilot/feasibility projects are milestone driven?
• Does the application adequately address how the pilot/feasibility projects will be evaluated and managed at the end of the first year?

• Is the Career Enhancement Program administration, including the qualifications of the core leader and the proposed oversight and monitoring, adequate?
• Are the proposed faculty appropriate for the student(s)/post-doc(s) and do they have a strong record of research and mentoring?
• Are the proposed career enhancement activities, including those unique to clinical research with rare diseases and those focused on workforce development appropriate?
• Is the nomination and selection process appropriate for the proposed Career Enhancement Program?
• Is the institutional environment, including the institutional support and the proposed interaction with existing Career Enhancement Programs appropriate?
• Is the plan to review and determine the quality and effectiveness of the Career Enhancement Program adequate? For renewal applications, has the program been successful in meeting the goals of the Career Enhancement Program?

As applicable for the project/core 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

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)?

For research that involves human subjects but does not involve one of the six 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 six 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.

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 children 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.

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

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.

Not Applicable.

Was there satisfactory achievement of the goals of the prior funding period? Do the investigators describe inclusion of patient or stakeholder groups by providing examples of previous and/or ongoing collaborations? Do the investigators describe the value of additional knowledge to be gained from continuing ongoing natural history studies with regard to clinical trial readiness? For consortia that have been continuously funded for longer than 10 years, do the applicants adequately justify continued funding for the RDCRC, including the value of additional knowledge to be gained? For consortia that have been in existence for longer than 14 years, is there a satisfactory sustainability plan?

Not Applicable.

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.

Not Applicable.

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).

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: 1) Data Sharing Plan; 2) Sharing Model Organisms; and 3) Genomic Data Sharing Plan .

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.

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

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:

• 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.
• Will receive a written critique.

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

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the National Center for Advancing Translational Science Advisory Council. 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.

After the peer review of the application is completed, the PD/PI will be able to access his or her 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.

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.

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 grantee's business official.

Awardees must comply with any funding restrictions described in Section IV.5. 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 FOA 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 of all trials whether required under the law or not. For more information, see http://grants.nih.gov/ClinicalTrials_fdaaa/

Institutional Review Board or Independent Ethics Committee Approval: Grantee institutions must ensure that the application as well as all protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the awardee 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).

Awardee-selected projects that involve human subjects require prior approval by NIH prior to initiation.

• The awardee institution will provide NIH with written study protocols that address risks and protections for human subjects in accordance with NIH's Instructions for Preparing the Human Subjects Section of the Research Plan.
• The awardee 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.
• The selection and initiation of new pilot/feasibility projects are contingent upon approval by NIH staff and 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): Updated Notice https://grants.nih.gov/grants/guide/notice-files/NOT-OD-15-129.html

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, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person's race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency. HHS recognizes that 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 FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/index.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html; and https://www.hhs.gov/civil-rights/for-providers/laws-regulations-guidance/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

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 the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, 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 45 CFR Part 75.205 "Federal awarding agency review of risk posed by applicants." This provision will apply to all NIH grants and cooperative agreements except fellowships.

Cooperative Agreement Terms and Conditions of Award

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 (DHHS) grant administration regulations at 45 CFR Part 75, 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 awardees 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 award 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 awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

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

RDCRC (Individual Consortium)

The PD(s)/PI(s) will have the primary responsibility for defining objectives and approaches, and to plan, conduct, analyze, and publish results, interpretations, and conclusions of their studies. The PD(s)/PI(s) will serve as RDCRC Director(s) and will be responsible for the integration and management of activities within the RDCRC.

The PD(s)/PI (s) will be responsible for organizing 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. The role of these Committees will include the oversight, review, and evaluation of the RDCRC, and the selection and prioritization of projects that will use resources and services that are provided through the RDCRN.

Awardees will retain custody of and have 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.

RDCRN (Network)

The PD(s)/PI(s) of each RDCRC/DMCC will also serve as members of the RDCRN Steering Committee and are required to participate in its activities, including regular conference calls and 1-2 annual RDCRN face-to-face meetings.

Awardees agree to participate in the overall coordination of NIH research efforts in Rare Diseases. This participation may include collaboration and consultation with other NIH awardees, the appropriate sharing of information, data, and research materials, and participation in NIH efforts to standardize and harmonize pre-clinical and clinical data collection.

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

An agency program official or IC program director will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.

A Project Scientist(s) from the funding IC will work closely with the PD/PI, the Steering Committee, and the PIs of all projects/cores in order to ensure proper conduct of the RDCRC.

The assigned Project Scientist will be responsible for: (1) overseeing the activities of the RDCRC, along with the other entities delineated above, to ensure that studies are properly conducted and completed in a timely fashion; (2) providing advice and guidance to ensure that the RDCRC functions and operates in accordance with NIH policies and procedures, and is consistent with the mission of the NIH to improve public health; (3) serving as a point of contact for investigators with the NIH; and (4) disseminating information from the Institute and communicating with Institute leadership to ensure that the RDCRC operates smoothly.

Milestones:

Milestones are goals that are quantifiable for measuring success of each project/core and should have quantitative criteria associated with them (see Section IV.2 for details). Milestones should also be included for each of the Overall DMCC Specific Aims and should inform annual evaluations of progress of the RDCRC as a whole.

Prior to funding an application, the Project Scientist 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 milestones will be specified prior to award.

Progress towards achievement of the final set of milestones will be evaluated by the Project Scientist and program staff. Program staff may consult with independent experts as necessary. If justified, future milestones may be revised based on data and information obtained during the previous project period. If, based on the progress report, a project does not meet the milestones, funding for the project may be reduced or discontinued.

Areas of Joint Responsibility include:

None; all responsibilities are divided between awardees 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 award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. It will have three members: 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 awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.t Applicable

Multi-site clinical studies:

Any third-party collaboration must be governed by a research collaboration agreement (e.g. CTA, RCA, MOU, etc.) with terms that ensure the collaboration is conducted in accordance with the Cooperative Agreement, applicable NIH policies and procedures.

Any third party involvement in the study, including access to any study data; study results; using the name of the study; or the name/logo of the NIH or any NIH institute, is permitted only after concurrence by the Program Official who may consult with others at NIH including the Technology Advancement Office.

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

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.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees 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 $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.

In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, 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 (currently 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 45 CFR Part 75 Award Term and Conditions for Recipient Integrity and Performance Matters.

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 registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact Center Telephone: 800-518-4726
Email: support@grants.gov

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-945-7573

R. Tiina K. Urv, Ph.D.
National Center for Advancing Translational Sciences (NCATS)
Telephone: 301-827-2746
Email: urvtiin@mail.nih.gov

William Merritt, Ph.D.
National Cancer Institute (NCI)
Telephone: 240-276-6137
Email: merrittw@mail.nih.gov

Lora Reineck, M.D.
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0222
Email: lora.reineck@nih.gov

Linda Griffith, M.D., Ph.D.
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-627-3525
Email: LGriffith@niaid.nih.gov

James Witter, M.D., Ph.D.
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Telephone: 301-594-1963
Email: witterj@mail.nih.gov

Tracy King, M.D.
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-402-1822
Email: tracy.king@nih.gov

Jason Wan, Ph.D.
National Institute of Dental and Craniofacial Research (NIDCR)
Telephone: 301-594-9898
Email: jasonwan@nidcr.nih.gov

Cindy Roy, Ph.D.
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone: 301-594-8805
Email: cindy.roy@nih.gov

Jill A. Morris, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-5745
Email: jill.morris@nih.gov

B. Duane Price, Ph.D.
National Center for Translational Sciences (NCATS)
Telephone: 301-435-0829
Email: b.duane.price@nih.gov

Laura Gray
National Center for Advancing Translational Sciences (NCATS)
Telephone: 301-451-4238
Email: laura.gray@nih.gov

Shane Woodward
National Cancer Institute (NCI)
Telephone: 240-276-6303
Email: woodwars@mail.nih.gov

Anthony Agresti
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-827-8014
Email: agrestia@nhlbi.nih.gov

Jason Lundgren
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240- 669-2973
Email: lundgrenj@mail.nih.gov

Andrew Jones
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Telephone: 301-435-0610
Email: jonesan@mail.nih.gov

Bryan Clark
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-435-6975
Email: clarkb1@mail.nih.gov

Dede Rutberg
National Institute of Dental and Craniofacial Research (NIDCR)
Telephone: 301-594-4798
Email: rutbergd@mail.nih.gov

Pamela Love
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone: 301-435-6198
Email: lovepa@mail.nih.gov

Tijuanna Decoster
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-9231
Email: decostert@ninds.nih.gov

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 principals, 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 45 CFR Part 75.