Rare Diseases Clinical Research Network (U54)

Rare Diseases Clinical Research Network (U54) is sponsored by National Institutes of Health. Consortia for rare disease research; MS not rare but EBV-MS links may fit collaborative neuroinfectious models.

Expired PAR-25-438: Rare Diseases Clinical Research Consortia (RDCRC) for the Rare Diseases Clinical Research Network (RDCRN) (U54 Clinical Trial Optional) This notice has expired. For NIH, in limited situations, applications may be accepted on a case-by-case basis for a short period after expiration to accommodate NIH late or continuous submission policies . Contact the eRA Service Desk for any submission issues.

Check the NIH Guide for active opportunities and notices. Department of Health and Human Services Part 1.

Overview Information Participating Organization(s) National Institutes of Health ( NIH ) Components of Participating Organizations National Center for Advancing Translational Sciences ( NCATS ) National Heart, Lung, and Blood Institute ( NHLBI ) National Human Genome Research Institute ( NHGRI ) National Institute of Allergy and Infectious Diseases ( NIAID ) National Institute of Arthritis and Musculoskeletal and Skin Diseases ( NIAMS ) Eunice Kennedy Shriver National Institute of Child Health and Human Development ( NICHD ) National Institute of Dental and Craniofacial Research ( NIDCR ) National Institute of Diabetes and Digestive and Kidney Diseases ( NIDDK ) National Institute of Neurological Disorders and Funding Opportunity Title Rare Diseases Clinical Research Consortia (RDCRC) for the Rare Diseases Clinical Research Network (RDCRN) (U54 Clinical Trial Optional) U54 Specialized Center- Cooperative Agreements June 17, 2025 - Notice of Change to Application Due Dates for PAR-25-438, "Rare Diseases Clinical Research Consortia (RDCRC) for the Rare Diseases Clinical Research Network (RDCRN) (U54 Clinical Trial Optional)".

See Notice NOT-TR-25-010 . April 4, 2024 - Overview of Grant Application and Review Changes for Due Dates on or after January 25, 2025. See Notice NOT-OD-24-084 .

August 31, 2022 - Implementation Changes for Genomic Data Sharing Plans Included with Applications Due on or after January 25, 2023. See Notice NOT-OD-22-198 . August 5, 2022 - Implementation Details for the NIH Data Management and Sharing Policy.

See Notice NOT-OD-22-189 . Funding Opportunity Number (FON) Companion Notice of Funding Opportunity See Section III. 3.

Additional Information on Eligibility . Assistance Listing Number(s) 93. 350, 93.

855, 93. 866, 93. 853, 93.

172, 93. 846, 93. 837, 93.

233, 93. 838, 93. 839, 93.

840, 93. 121, 93. 865, 93.

847 Notice of Funding Opportunity Purpose The objective of this Notice of Funding Opportunity (NOFO) is to invite new and renewal applications for the Rare Diseases Clinical Research Consortia (RDCRC) that comprise the Rare Diseases Clinical Research Network (RDCRN).

The RDCRCs are intended to advance and improve diagnosis, management, and treatment of numerous, rare diseases through highly collaborative, multi-site, patient-centric, translational, and clinical research. Special emphasis will be placed on the early and timely identification of individuals with rare diseases and clinical trial readiness.

Funding Opportunity Goal(s) NCATS' mission is to turn research observations into health solutions through translational science. We work to develop or enhance the development, testing, and implementation of diagnostics and therapeutics for a wide range of diseases and conditions.

Key approaches include understanding what’s similar across diseases to spur multiple treatments at a time, developing models that better predict a person’s reaction to treatment, enhancing clinical trials so results more accurately reflect the patient population, and leveraging real-world data and data science approaches to address public health needs.

Facilitating these approaches are our robust partnerships with other government agencies, including other NIH institutes, centers, and offices; industry; academia; nonprofit organizations; and patients, patient advocates, and other communities. NCATS' vision is to bring more treatments for all people more quickly. Open Date (Earliest Submission Date) Letter of Intent Due Date(s) Dates have been removed per NOT-TR-25-010 .

Renewal / Resubmission / Revision (as allowed) AIDS - New/Renewal/Resubmission/Revision, as allowed All applications are due by 5:00 PM local time of applicant organization. Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

Required Application Instructions It is critical that applicants follow the Multi-Project (M) Instructions in the How to Apply - Application Guide , except where instructed to do otherwise (in this NOFO or in a Notice from the NIH Guide for Grants and Contracts ). Conformance to all requirements (both in the How to Apply - Application Guide and the NOFO) is required and strictly enforced.

Applicants must read and follow all application instructions in the How to Apply - Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the How to Apply - Application Guide , follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

Part 1. Overview Information Part 2. Full Text of Announcement Section I.

Notice of Funding Opportunity Description Section II. Award Information Section III. Eligibility Information Section IV.

Application and Submission Information Section V. Application Review Information Section VI. Award Administration Information Section VII.

Agency Contacts Section VIII. Other Information Part 2. Full Text of Announcement Section I.

Notice of Funding Opportunity Description The Division of Rare Diseases Research Innovation (DRDRI), within the National Center for Advancing Translational Sciences (NCATS), along with the Institutes, Centers, and Offices (ICOs) listed in Part I at the National Institutes of Health (NIH), invites applications in response to this Notice of Funding Opportunity (NOFO) for the Rare Diseases Clinical Research Consortia (RDCRC) component of the Rare Diseases Research Network (RDCRN).

The RDCRCs were established with the intent of advancing the diagnosis, management, and treatment of rare diseases. Each RDCRC will promote highly collaborative, multi-site, and patient-centric translational and clinical research.

The lived perspective of patients, and their needs and priorities, must be meaningfully incorporated into decisions and activities of the proposed RDCRC, with related patient advocacy groups having an active partnership role within the RDCRC. Each RDCRC must address specific unmet clinical research needs that will move the field of research forward from its current state of knowledge.

This includes activities such as earlier diagnosis of individuals with targeted rare diseases and facilitating more rapid development of new treatments through a program in clinical trial readiness. The Rare Diseases Act of 2002 (Public Law 107-280 ( https://www. gpo.

gov/fdsys/pkg/PLAW-107publ280/content-detail. html )) defines a rare disease as a condition affecting fewer than 200,000 individuals in the United States. Collectively there are estimated to be over 10,000 diseases or conditions that fall into this category; cumulatively, there are approximately 25 – 30 million people in the United States who are affected by rare diseases or conditions.

Many of these disorders lead to significant morbidity and mortality. These facts highlight that rare diseases are a significant public health concern. Despite advances in our understanding of the causes and mechanisms of many diseases, effective treatments are available for fewer than 5% of rare diseases.

Although advances in technologies such as gene-based therapies have recently led to promising and potentially transformative treatments, these are currently limited to a few rare diseases. Bringing effective treatments to more people living with rare diseases is a risk-filled venture for numerous reasons.

First, making a diagnosis can be challenging with many patients experiencing a "diagnostic odyssey" of years because of limited knowledge of the range of disease manifestations and of genotype-phenotype correlations. Second, many rare diseases have a spectrum of phenotypes, and there are often no high-quality natural history datasets documenting how the disease affects patients' functioning and how it progresses over time.

Third, the relatively small number of patients and clinicians caring for them leads to challenges in the design and implementation of clinical trials. Fourth, there are often no sensitive and specific outcome measures or biomarkers that are appropriate for use in clinical trials or that are clinically relevant to patient needs.

Fifth, the data quality and the rigor of scientific studies are often lacking and usage of data standards and adherence to FAIR principles for data management vary across rare disease research making collaborations difficult.

Finally, the resources available for therapeutics development are limited, making it critical to find frameworks for leveraging partnerships among patient groups, industry, academic investigators, and federal funding agencies. The global burden associated with rare diseases necessitates international coordination and collaboration.

To facilitate progress in addressing these challenges, the Rare Diseases Act of 2002 directed the DRDRI to support regional "RDCRCs of Excellence" for clinical research, career enhancement, and demonstration of diagnostic, prevention, control, and treatment methods for rare diseases.

Since the inception of this legislation, numerous NIH ICOs (NCATS, NCRR, OD, NICHD, NINDS, NIAMS, NHLBI, NIDDK, NIDCR, NIMH, NCI, NIAID and NEI), led by the DRDRI at NCATS, have partnered to support the RDCRN.

The RDCRN was established to be a collaborative and coordinated network of investigators and patient groups committed to the investigation of rare diseases working in partnership with leaders in technology to enhance communication and sharing of resources through a multidisciplinary approach. To date, this program has successfully supported 33 individual RDCRCs that have conducted research on nearly 250 individual disorders.

The research conducted within the RDCRN has contributed to the Food and Drug Administration (FDA) approval for eleven treatments for rare diseases. Organization of the RDCRN The RDCRN is a cooperative network composed of multiple Consortia (RDCRCs) and a Data Management and Coordinating Center (DMCC) established to coordinate RDCRN activities and to support and facilitate clinical research in rare diseases conducted by the RDCRCs.

The RDCRN functions as a collaborative network with each RDCRC establishing and maintaining an environment that fosters collaborative, patient-oriented, multi-site, multi-disciplinary research collaborations and career enhancement. The activities of the RDCRN are coordinated, facilitated, and supported by the DMCC.

Patient advocacy group partners specific to the RDCRC participate in individual RDCRC activities as well as participating in Coalition of Patient Advocacy Group (CPAG) activities. The RDCRN governance consists of three committees: the Network Steering Committee (SC), the CPAG SC and the Joint Leadership Team (JLT). These committees are described in detail in the "Governance" section.

The committees consist of the PIs of each funded RDCRC, their affiliated patient advocacy groups, the DMCC, and NIH program representatives including the NCATS RDCRN Program Director, Program Officials (PO) and Project Scientists (PS). All recipients of an RDCRC and their teams are members of the RDCRN, and as such are part of a national rare diseases research resource.

Each RDCRC will be expected to actively participate in network activities, including meetings of the Steering committee, biennial RDCRC meetings, and various relevant workgroups (e.g., bioinformatics, engagement, dissemination of information).

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

In this document, a rare disease is defined as one that affects fewer than 200,000 people in the United States (per the Rare Diseases Act 2002). Each RDCRC application must indicate at least three different rare diseases that may share, but are not limited to, common pathways/mechanisms of action/organ system, and may be defined as: Conditions - a particular state of being that limits/restricts something else.

Disorders - abnormal physical or mental conditions or ailments. Syndromes - a group of symptoms that occur together, or a condition characterized by a set of associated symptoms. Diseases - a disorder of structure or function that affects a specific location and is not simply a result of physical injury.

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

Applicants are encouraged to emphasize new ideas, novel approaches, and state-of-the-art technologies to address the needs for early diagnosis and effective treatments along with other strategies to improve the lives of individuals with rare diseases. Applicants with research agendas at varying stages of scientific development within the research program are encouraged to apply.

This includes groups that would be considered early-stage RDCRC with many knowledge gaps that need to be addressed (e.g., groups that do not yet have established registries, groups with poorly defined natural history data that would benefit from an RDCRC effort). Each RDCRC must form partnerships with patient advocacy groups.

These groups must participate as active members of the RDCRC with meaningful roles within the RDCRC and as members of the RDCRN CPAG. The platform for the DMCC resides within the NCATS Information Technology Resources Branch (ITRB) provided cloud resource. All software licenses belong to NCATS.

This is an NCATS-furnished infrastructure that the award recipient will use as a platform on which to build the data management and coordination center. This protects the integrity of the data and allows the RDCRN DMCC system to stay in the same location regardless of future DMCC award recipients.

Overall, the goal of the DMCC is to provide support to each individual RDCRC, and to coordinate and support the activities of the RDCRN as a whole. The structural requirements of the DMCC are: Administrative Core to facilitate network operation, governance, and communication. Data Management Core to build and maintain a robust, secure data infrastructure.

Clinical Research Core to provide guidance in developing best practices in clinical research, protocol development and good data practices using the FAIR principles. Engagement and Dissemination Core to promote patient engagement and broad research dissemination.

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

The RDCRCs will collaborate with the DMCC to establish and promulgate coordinated RDCRN data management and data sharing standards and policies within the RDCRC. It is imperative that RDCRC applicants carefully review the DMCC NOFO to fully understand the resources and services that will be provided to the network participants by the DMCC.

Applicants should ensure planned activities involve coordination with the DMCC and do not replicate efforts. Coalition of Patient Advocacy Groups (CPAG) The RDCRN CPAG was established to promote collaboration between rare disease patient and stakeholder organizations and the RDCRN to facilitate better access to, and earlier benefit from, research conducted on rare diseases. Each RDCRC must be actively engaged with the CPAG.

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

The structural requirements of an RDCRC under this NOFO are: Pilot/Feasibility Governance Core 2-4 Clinical Research Projects An individual with demonstrated experience in the management of multisite clinical research programs, along with rare disease research should be identified as PI for the Administrative Core.

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

Each Administrative Core should have identified statistical and bioinformatics team members to work collaboratively with the DMCC to coordinate and leverage DMCC core support and meet the needs of the RDCRC that extend beyond the scope of the DMCC: Biostatistician - Individuals with demonstrated strong statistical experience working with rare diseases research as well as clinical trial design and implementation.

Bioinformatics - Individuals with demonstrated skills in managing RDCRN established data standards, FAIR data principles, and biological data, especially when the data sets are small and complex.

The Administrative Core of each RDCRC will be responsible for the following activities: Administrative Support for RDCRC Management of RDCRC Agreements and Regulatory and Clinical Documentation Coordination of Activities with DMCC Management and Sharing of Data and Biospecimens Collaborating with the DMCC in the Engagement and Dissemination of Information Coordination of Patient Advocacy Groups Participation Administrative Support for RDCRC The Administrative Core is responsible for the overall management of day-to-day program activities for the RDCRC.

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

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

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

The Administrative Core will be responsible for coordinating the required single IRB. The Administrative Core, in consultation with the DMCC, will establish RDCRN-specific data sharing and data use agreements within the RDCRC, for all clinical sites, and between the primary recipient institution and the DMCC.. Coordination of Activities with DMCC The RDCRC must not replicate services provided by the DMCC.

The Administrative Core will work collaboratively with the DMCC Cores (Administrative Core, Data Management Core, Clinical Research Core, and Engagement and Dissemination Core) to coordinate and support both RDCRC activities and RDCRN-wide efforts (e.g., develop and monitor best practices for clinical and research data handling and use as well as data sharing).

This includes the development and utilization of clinical trial readiness metrics for both regulatory requirements (e.g., protocols, IRBs) and clinical research components (e.g., natural history studies outcome measures, biomarkers) to evaluate their progress in clinical trial readiness.

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

It is important that the RDCRC is prepared to identify a point of contact for communications with DMCC and share the following information with the DMCC: Key contacts for individual research studies Patient advocacy group contacts Protocols and schedule of events List of diseases/disorders studied Consent documents and data use limitations List of data elements and data modalities List of sites and personnel Management and Sharing of Data and Biospecimens The Administrative Core will coordinate data sharing and biospecimen sharing, storage and tracking information across all clinical sites within the RDCRC and externally with agreements.

The DMCC will provide resources for tracking specimens and, via a “virtual repository,” indexing biospecimens.

Engagement and Dissemination of Information Design (determine logo, colors, photos, site layout, etc.) Review (attend regular meetings and reviews with team to build and finalize site) Highlight new publications Highlight ongoing studies Coordination of Patient Advocacy Group Participation The Administrative Core will establish communication and maintain engagement with all partnering patient advocacy groups.

Pilot/Feasibility Governance Core A Pilot/Feasibility Governance Core should be established to enable future innovative single- or multi-site pilot studies aimed at advancing the diagnosis, clinical trial readiness, management, and/or treatment of rare diseases. Pilot projects that extend RDCRC research collaborations beyond the RDCRN are allowed.

Pilot projects may be awarded to institutions that are not already RDCRC members; however, execution of new subawards may be required. The core should define the process by which pilot studies will be encouraged, assessed, and managed. Specific pilot/feasibility projects must not be described in the current application and if described will not be considered in the review of the application.

However, a plan for how pilots will be selected and how results will be disseminated must be included. Pilot projects may be clinical trials only with prior NIH institute approval, and policies may vary by institute.

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

htm . All pilot/feasibility projects must be documented within the DMCC’s network-tracking system once an award is made. The RDCRCs are expected to play a leadership role in career enhancement; attract new researchers for the rare diseases field; and contribute to the development of future research leaders.

Each RDCRC should provide a Career Enhancement Program to provide support for career enhancement-related activities, as well as support for development of the institution's environment for the education of Career Enhancement candidates in rare diseases research.

Examples of Career Enhancement candidates include, but are not limited to, the following: Doctoral/Medical students Postdoctoral fellow/researchers Early-stage investigators Investigators new to the rare disease field Leveraging existing career enhancement programs and exploring fellowship opportunities from other public and private funding organizations is encouraged.

This program may propose activities that expand the career enhancement environment through, for example, specialized coursework, a seminar program, retreats for presentation of Career Enhancement candidates’ research, mentoring programs, journal clubs, professional development programs, or other activities that contribute to the preparation of scholars and junior investigators for careers in rare diseases research.

Exposure to research at other RDCRCs is also encouraged through exchange programs or visits to learn new research approaches. The leads of the Career Enhancement program should collaborate with the DMCC to develop disease agnostic, rare disease specific activities that would benefit participants of the Career Enhancement program. Results of projects supported by the core should be shared with the RDCRN.

The RDCRC must coordinate with the DMCC to track Career Enhancement recipients and activities within the RDCRN. Clinical Research Projects The RDCRCs are intended to advance the diagnosis, management, and treatment of rare diseases with a focus on clinical trial readiness and early and timely diagnosis. A minimum of two but no more than four multi-site clinical research projects are required.

One of the projects must be longitudinal in nature with the intent of understanding the clinical course of the disease and helping inform future clinical trials (e.g., natural history studies). Clinical research supported under this NOFO includes mechanistic studies designed to understand a biological or behavioral process, the pathophysiology of a disease, or the mechanism of action of an intervention.

Epidemiological, behavioral, and health outcomes research studies in rare diseases are also encouraged. Projects should address any relevant ethical, legal or social implications as needed. Each of the proposed clinical research projects should address problems that require a substantial collaborative research effort as well as a multi-site RDCRC environment to solve and can benefit from NIH programmatic input.

The research projects should be more substantial than what can be accomplished in a single site project. Success of each project should move the field closer to the design and/or implementation of pivotal clinical trials or earlier diagnosis.

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

Any clinical trials proposed as part of a RDCRC must meet ICO-specific rules for clinical trials. Consultation with relevant ICO contact prior to proposing a clinical trial is highly encouraged . Such clinical trials should be designed to provide specific data that will be necessary to design a subsequent definitive efficacy trial.

The proposed clinical trial must address questions that, when answered, will optimize the design of a subsequent definitive clinical trial rather than simply address the clinical question with lower power. Small targeted clinical trials may be proposed if the project meets the criteria listed in the "Clinical Research - definitions and requirements" section.

Knowledge from such clinical studies should be essential to direct subsequent clinical trials and can be invaluable for the targeted rare diseases. See Section IV. 2 for additional guidance on projects that propose a clinical trial.

Although clinical trials can be supported through an RDCRC, clinical trials are NOT a required component of an RDCRC application.

Examples of research areas that propose to advance rare disease research include but are not limited to: Characterization of the rare disease cohort being studied, including demographic, genetic, phenotypic, imaging and laboratory data to identify disease subtypes, i.e., differentiate patients with similar morphological phenotypes but different genetic mutations and severity of outcomes.

Clinical studies aimed at clinical trial preparation, including natural history studies. Development of algorithms connecting clinical and patient-reported outcomes with laboratory, imaging, environmental and -omics data to aid decision-making for clinical management of the rare diseases being studied. Early-stage clinical trials.

Elucidation of genotype-phenotype interactions and multisystem phenotyping to develop reliable and valid predictive tools to determine who will respond to which treatments and when to intervene.

Encouragement of dissemination and implementation research for rare diseases including: Partnering with clinicians and patient communities to understand barriers to and facilitators of implementation of known treatments and interventions for rare diseases. Study of implementation strategies to increase adoption, feasibility, and sustainability of known effective evidence-based interventions for rare diseases.

Strategies to understand how to disseminate evidence-based assessments or diagnostics and clinical guidelines to relevant rare disease populations. Encouragement of innovative methods such as use of telemedicine and community-engagement approaches to improve the participation of participants with rare diseases located in remote locations or facing other barriers to participating in research (e.g., mobility challenges).

Evaluation of the contribution of external factors to differences in rare-disease risk, severity, and treatment response. Generation of data (laboratory, clinical and imaging data) to improve diagnosis and to distinguish subtypes of the rare disease being studied. Identification of molecular pathways that can lead to therapeutic targets.

Natural history of progression of rare disease being studied and clinical outcomes. New treatment modalities. Studies that will address evidence gaps that are required for a successful Recommended Uniform Screening Panel nomination for newborn screening.

Utilization of data science and other novel analytic techniques to study rare-disease risk, severity, and treatment response among specific populations (e.g., pregnant women, obese or low-weight patients, elderly patients). Validation of biomarkers that meet FDA requirements as a drug development tool for use in future Phase III Randomized Clinical Trials.

Clinical Research - Definitions and requirements For this NOFO, clinical trial readiness is the state of having validated clinical research tools and sufficient knowledge of disease natural history to design efficient clinical trials. Validated clinical research tools can include biomarkers or clinical outcome assessment measures that are fit-for-purpose within a defined context of use relevant to the clinical trials.

Knowledge of disease natural history necessary for clinical trial design can include, but is not limited to, characteristics for stratification or determining study inclusion and exclusion criteria, the stage of disease progression that may be responsive to treatment, and data needed for determining sample size through power calculations. Clinical research, as it is defined by the NIH ( https://grants. nih.

gov/grants/glossary. htm#ClinicalResearch ) is research with human subjects that is either: Patient-oriented research. Research conducted with human subjects (or on material of human origin such as tissues, specimens, and cognitive phenomena) for which an investigator (or colleague) directly interacts with human subjects.

Excluded from this definition are in vitro studies that utilize human tissues that cannot be linked to a living individual. This definition includes (a) mechanisms of human disease, (b) therapeutic interventions, (c) clinical trials, or (d) development of new technologies. Epidemiological and behavioral studies.

Outcomes research and health services research. In vitro studies with human biospecimens must be within the context of NIH-defined Clinical Research and relevant to clinical endpoints. Studies based entirely on publicly available or deidentified data or specimens (thus falling under 45 CFR 46.

101(b) ( https://www. hhs. gov/ohrp/regulations-and-policy/regulations/45-cfr-46/index.

html ), Exemption 4) are not considered clinical research by this definition. However, these types of studies can be included in pilot studies or as a part of larger clinical research projects.

A clinical trial, as defined by the NIH, is a research study in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes. NIH provides a decision tool to determine whether a study meets the NIH definition of a clinical trial ( https://grants. nih.

gov/ct-decision/index. htm ). If a clinical trial is included in the application, it must demonstrate potential value of the trial and the feasibility of successfully completing the trial within the duration of the award, including the preclinical rationale, if applicable.

The preclinical rationale should provide evidence that the rigor of preclinical efficacy studies and the level of effect of the agent are both sufficient to warrant clinical testing of the agent (for guidance, see https://grants. nih. gov/policy/reproducibility/index.

htm ). Clinical trials involving the testing of new investigational therapeutics, new indications for FDA-approved drugs, or other medical interventions under a research protocol should be performed under an IND or Investigational Device Exemption (IDE), unless otherwise agreed upon by the FDA.

Unless the investigational product or device is exempted from the FDA IND/IDE requirements, the applicant must provide the NIH with the name and organization of the IND/IDE holder, the date the IND/IDE was filed with the FDA, the FDA IND/IDE number, and any comments from the FDA regarding this protocol.

Studies will not be funded unless necessary regulatory approval has first been obtained; regulatory approval at the time of application is preferred.

Examples of relevant clinical trials include, but are not limited to, the following: Studies to optimize the intervention strategy: for example, studies designed to investigate dose-concentration, dose-response, or concentration-response relationships that may inform optimal dosage selection for definitive trials. Studies to assess the appropriate delivery system or parameter