NIDCR Drug, Biologic, Device and/or Procedure Intervention Clinical Trial Planning and Implementation Cooperative Agreement (UG3/UH3 Clinical Trial Required)

NIDCR Drug, Biologic, Device and/or Procedure Intervention Clinical Trial Planning and Implementation Cooperative Agreement (UG3/UH3 Clinical Trial Required) is sponsored by National Institute of Dental and Craniofacial Research (NIDCR). Supports planning and implementation of clinical trials testing drugs, biologics, devices, or procedures to improve dental, oral, or craniofacial diseases.

PAR-25-057: NIDCR Drug, Biologic, Device and/or Procedure Intervention Clinical Trial Planning and Implementation Cooperative Agreement (UG3/UH3 Clinical Trial Required) This funding opportunity was updated to align with agency priorities. Carefully reread the full funding opportunity and make any needed adjustments to your application prior to submission. Department of Health and Human Services Part 1.

Overview Information Participating Organization(s) National Institutes of Health ( NIH ) Components of Participating Organizations National Institute of Dental and Craniofacial Research ( NIDCR ) Funding Opportunity Title NIDCR Drug, Biologic, Device and/or Procedure Intervention Clinical Trial Planning and Implementation Cooperative Agreement (UG3/UH3 Clinical Trial Required) UG3 / UH3 Exploratory/Developmental Phased Award Cooperative Agreement Notices of Special Interest associated with this funding opportunity January 28, 2026 - NIH Removing AIDS Application Due Dates from NOFOs.

See Notice NOT-OD-26-029 . March 31, 2025 - This funding opportunity was updated to align with agency priorities. Carefully reread the full funding opportunity and make any needed adjustments to your application prior to submission.

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 Funding Opportunity See Section III. 3. Additional Information on Eligibility.

Assistance Listing Number(s) Funding Opportunity Purpose This Notice of Funding Opportunity (NOFO) will support UG3/UH3 phased, cooperative agreement research applications to plan and implement clinical trials within the mission of the National Institute of Dental and Craniofacial Research (NIDCR).

Studies appropriate for this NOFO are those testing a drug, biologic, device, or procedure to improve dental, oral, or craniofacial diseases or conditions, including trials for any phase of testing for a Food and Drug Administration (FDA)-regulated product.

Awards made under this NOFO will initially support a one-year milestone-driven planning phase (UG3), with possible transition to a clinical trial implementation phase (UH3) of up to five years. Progression to the UH3 phase is based on an administrative review and is dependent on success in meeting UG3 milestones, NIDCR program priorities, and availability of funds.

The UG3/UH3 application must be submitted as a single application with the final design of the UH3 clinical trial including detail about the study population, intervention(s), and outcome(s) described in the application, following the instructions described in this NOFO.

The UG3 planning phase permits both scientific and operational planning activities, though the planning phase cannot be used to test for intervention safety or efficacy or assess the study’s primary outcome. The UH3 phase of the award will support the conduct of one investigator-initiated clinical trial.

Applications designed to test behavior change interventions or those used as tools to understand mechanisms of behavior change will not be supported by this NOFO. Open Date (Earliest Submission Date) 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 instructions in the Research (R) Instructions in the How to Apply - Application Guide , except where instructed to do otherwise (in this NOFO or in a Notice from NIH Guide for Grants and Contracts ). Conformance to all requirements (both in the Application Guide and the NOFO) 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.

There are several options available to submit your application through Grants. gov to NIH and Department of Health and Human Services partners. You must use one of these submission options to access the application forms for this opportunity.

Use the NIH ASSIST system to prepare, submit and track your application online. Use an institutional system-to-system (S2S) solution to prepare and submit your application to Grants. gov and eRA Commons to track your application.

Check with your institutional officials regarding availability. Workspace to prepare and submit your application and eRA Commons to track your application. 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 Improving health through the generation of robust data from well-designed and executed clinical trials is a high priority for the National Institute of Dental and Craniofacial Research (NIDCR).

To meet this goal, the NIDCR offers this NOFO to support investigator-initiated clinical trials. This NOFO utilizes a phased, milestone-driven, cooperative agreement mechanism that includes a one-year UG3 planning phase, followed by potential transition to up to a five-year UH3 clinical trial implementation phase.

Progression to the UH3 phase is based on an administrative review following submission of a detailed Transition Package request and is dependent on success in meeting UG3 milestones, NIDCR program priorities, and availability of funds. Prospective applicants should note that initial funding of the UG3/UH3 cooperative agreement does not guarantee support of the UH3 clinical trial implementation phase.

Each UG3/UH3 award will support an individual project, and the UG3 planning and UH3 implementation activities must be submitted as a single application.

Clinical trials appropriate for this NOFO are those proposing diagnostic, prevention, or treatment approaches to test a drug, biologic, device, or procedure for dental, oral, or craniofacial diseases or conditions, including trials for any phase of testing for a Food and Drug Administration (FDA)-regulated product.

The NIDCR is committed to identifying effective preventive, diagnostic, and treatment approaches for dental, oral, or craniofacial diseases and conditions. To advance these efforts, the Institute has maintained a clinical trial program for many years and is continuing its support of well-designed clinical trials that test interventions and have the potential to improve dental, oral and craniofacial health across the lifespan.

A clinical trial is defined by NIH as 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.

Clinical trial designs may be used to establish efficacy or effectiveness of strategies for the prevention, diagnosis, management and/or treatment of dental, oral, or craniofacial diseases and conditions. Further, clinical trials determine whether interventions are safe, feasible, and acceptable to patients.

Clinical studies to evaluate clinical or laboratory tests, techniques or tools (e.g., new imaging techniques, diagnostic tests or surgical planning tools) would meet the definition of a clinical trial if the test or tool would be used for making a medical decision about a study participant, and that decision could affect a health outcome.

Applications designed to test behavior change interventions or those used as tools to understand mechanisms of behavior change will not be supported by this NOFO. Each UG3/UH3 Clinical Trial Cooperative Agreement award will support the planning and implementation of a single clinical trial.

The UG3/UH3 funding mechanism supports projects in two phases; awards made under this NOFO will initially support a one-year milestone-driven planning phase (UG3), with possible transition to a clinical trial implementation phase (UH3) of up to five years.

Projects funded under this NOFO must be driven by well-defined milestones to be completed during the UG3 planning phase and those to be completed during the clinical trial UH3 implementation phase. The UG3 study development activities and UH3 study implementation plans should be well-developed and described in the grant application.

The final design, study population and sample size including clinical site(s), intervention(s), and outcome(s) of the UH3 clinical trial should be detailed in the UG3/UH3 grant application. Initial funding of the planning phase cooperative agreement does not guarantee support of the clinical trial implementation phase.

The NIDCR will be substantially involved with the UG3/UH3 awardees as a partner in providing overall scientific and operational guidance, consistent with the Cooperative Agreement mechanism. Trials may be supported by a coordinating center, central laboratories and/or other specialized services.

Applicants are encouraged to utilize resources (e.g. CTSAs, electronic health records, administrative databases, patient registries, etc.) to increase the efficiency of trial operations. If the application proposes a clinical trial with an investigational drug, biologic or device, the investigators must have received approval for the appropriate investigational application to the FDA prior to transition to the UH3 phase.

Monitoring the degree to which a study intervention is delivered as it was intended (i.e., with consistency or fidelity) is expected for clinical trials research. Fidelity monitoring will ensure the intervention is being delivered in a standardized manner across clinical sites and among interventionist personnel. Fidelity monitoring procedures should be described in the grant application or developed during the UG3 planning phase.

Design, Analysis, and Sample Size for Studies to Evaluate Group-Based Interventions: Investigators who wish to evaluate the effect of an intervention on a health-related biomedical or behavioral outcome may propose a study in which (1) groups or clusters are assigned to study arms and individual observations are analyzed to evaluate the effect of the intervention, or (2) participants are assigned individually to study arms but receive at least some of their intervention in a real or virtual group or through a shared facilitator.

Such studies may propose a parallel group- or cluster-randomized trial, an individually randomized group-treatment trial, a stepped-wedge design, or a quasi-experimental version of one of these designs. In these studies, special methods may be warranted for analysis and sample size estimation. Applicants should show that their methods are appropriate given their plans for assignment of participants and delivery of interventions.

Additional information is available at https://researchmethodsresources. nih. gov/ .

Examples of clinical trials that might be planned with the UG3 award and implemented with the UH3 award include but are not limited to: Interventions to understand demographics and/or sex as a biological variable in dental care recommended and/or received; Interventions to understand potential sex as a biological variable differences in dental, oral and craniofacial diseases; Clinical trials testing tissue regeneration therapies to repair or replace dental, oral or craniofacial tissues; Clinical trials involving chemotherapeutic, pharmacologic, gene therapy, cell-based therapies or other interventions to prevent and/or treat oral and craniofacial diseases or disorders; Clinical trials testing new preventive or treatment therapies for dental, oral, or craniofacial diseases (e.g., dental caries, periodontal diseases, head and neck cancer, orofacial pain conditions, salivary gland dysfunction), especially in populations with high unmet need; Clinical trials testing the ability of diagnostic criteria, reliable markers, oral biosensors/biodevices, and/or imaging techniques to diagnose and assess the onset and progression of oral disease; Clinical trials testing surgical interventions that may improve oral health outcomes in people with craniofacial anomalies or other congenital or acquired conditions affecting dental, oral or craniofacial structures; Clinical trials focusing on the treatment of HIV/AIDS associated oral complications; Clinical trials to determine impactful innovations to dental practice that reduce the risk of highly transmissible and virulent pathogens and ensure the safety of personnel and patients in dental practices; Clinical trials testing therapies to prevent or treat dental, oral, or craniofacial sequelae of systemic treatments or conditions in medically complex patients, such as those with craniofacial anomalies, Sjogren's disease, a history of head and neck cancer treatment, orofacial pain conditions, or congenital or acquired immune dysfunction; Clinical trials to optimize opioid risk mitigation clinical tools, such as those encouraging the use of prescription drug monitoring programs (PDMPs), counseling, and other reminders prior to prescribing opioids for pain management; Interventions that test or implement medical condition and risk behavior screening in dental care settings (such as opioid use disorder (OUD) screening) and facilitate appropriate referral to treatment; and Clinical trials testing pain management strategies for temporomandibular dysfunction and other orofacial pain conditions.

UG3 Clinical Trial Planning Phase The UG3 planning phase will provide one year of support for operational and scientific planning activities. Operational planning activities include, at minimum, finalizing the protocol and preparing other documents to implement the clinical trial (e.g., data collection instruments, Manual of Procedures, quality management plan, data management plan).

Allowable scientific planning activities include small-scale data collection to assess the feasibility and/or acceptability of a planned intervention and associated study procedures (e.g., acceptability of mode of intervention delivery; feasibility of proposed data collection procedures; preliminary testing of intervention training and fidelity monitoring procedures) and assessment of the study population to determine recruitment potential for the future trial.

The UG3 phase cannot be used to test for intervention safety or efficacy or assess the study’s primary outcome.

Activities supported during the UG3 phase may include, but are not limited to, the following, expressed as UG3 milestones: Demonstration that the necessary study population is available at the clinical sites; Collection of any data to determine feasibility of study procedures and/or study intervention; Finalization of a clinical protocol following International Conference on Harmonisation (ICH) E6 Good Clinical Practice Consolidated Guidance, prepared using the NIDCR interventional protocol template or the NIH-FDA Phase 2 and 3 IND/IDE clinical trial protocol template if proposing a Phase II or Phase III clinical trial that requires an investigational new drug (IND) or investigational device exemption (IDE) application; Finalization of plans to obtain study agent(s), administer or deliver the study intervention, train interventionalists, and monitor intervention delivery; Completion of the Manual of Procedures (MOP), which should include a detailed description of study procedures to ensure consistency of data collection across sites and processes for validation and quality control of any non-standard clinical or laboratory/mechanistic testing that will be performed; Finalization of the statistical analysis plan; Completion of data collection instruments (case report forms) that are ready to be programmed into an electronic data management system; Completion of the consent form(s) and assent form(s), if applicable; Completion of the quality management and data management plans; Completion of the Clinical Investigators Brochure (IB) or equivalent, if applicable; Submission of regulatory documents to the FDA for FDA-regulated interventions; Finalization of a Study Accrual and Retention Plan (SARP), including a timeline for study participant accrual and retention goals and strategies should enrollment or retention not meet specified metrics; and Finalization of agreements for use of resources available within CTSAs, patient registries, community partner sites, etc. Milestones and UG3/UH3 Transition All applications must describe well-defined milestones that must be completed during the UG3 planning phase and annual milestones that must be completed during the UH3 clinical trial implementation phase.

A milestone is defined as a scheduled event in the project timeline, signifying the completion of a major project stage or activity. Milestones must be objective, measurable, and achievable. The Terms and Conditions for an award under this NOFO will include milestones that are mutually agreed upon by the awardee institution and NIDCR.

All UG3 awards will need to meet all UG3 milestones to have an opportunity to transition to the UH3 implementation phase. Toward the completion of the UG3 planning phase, the UG3 awardee will be required to submit a detailed Transition Package to request transition to the UH3 clinical trial implementation phase.

The Transition Package requests will undergo administrative review by NIH staff to determine whether an award will be made for the UH3 implementation phase. Transition decisions are based on success in meeting UG3 phase milestones, NIDCR program priorities, and availability of funds. The quality of the study-related documents and plans are given key consideration when the NIDCR considers the transition to the UH3 phase.

Prospective applicants should note that initial funding of the UG3/UH3 cooperative agreement does not guarantee support of the UH3 clinical trial implementation phase. UH3 Clinical Trial Implementation Phase The UH3 funding period will provide up to five years of support to conduct the clinical trial in accordance with activities planned in the UG3 phase.

Continued funding during the UH3 phase will be dependent upon meeting annual UH3 milestones, and it is expected that the clinical trial will be completed within the UH3 grant period. The NIDCR expects clinical trials supported during the UH3 phase to be hypothesis driven, with well-defined milestones, and have the potential for high impact within the research mission of the NIDCR.

The trial outcome measure(s) must be clinically meaningful and important to stakeholders including patients and health care providers. The clinical trial must meet all applicable NIH, FDA, and Office for Human Research Protections (OHRP) policy requirements.

UH3 activities may include the following operational activities, expressed as UH3 milestones: Finalization of data management system(s) Completion of regulatory approvals Registration of clinical trial in ClinicalTrials.

gov Enrollment of the first study participant Enrollment and randomization of 25%, 50%, 75% and 100% of the projected study population Completion of data collection Completion of primary outcome data analyses Reporting of results in ClinicalTrials. gov The proposed clinical trial must meet all applicable NIH and Office for Human Research Protections (OHRP) policy requirements, and FDA requirements should be followed where applicable.

Awardees are required to comply with the NIDCR Clinical Terms of Award for any planning phase activities that involve human subjects and all UH3 studies. It is recommended that applicants use the NIDCR tools and templates for development of the clinical trial documents, located in the NIDCR Toolkit for Clinical Researchers .

Potential applicants are encouraged to review the NIDCR interventional protocol template or the NIH-FDA Phase 2 and 3 IND/IDE clinical trial protocol template if proposing a Phase II or Phase III clinical trial that requires an investigational new drug (IND) or investigational device exemption (IDE) application.

These protocol templates have further information about elements that should be included in a clinical trial and described in the Research Strategy and Protocol Synopsis sections of the grant application.

Applications proposing to test products must contain information ensuring that the products are produced according to Good Manufacturing Practice (GMP), a system for ensuring that products are consistently produced and controlled according to quality standards.

Applications that propose multi-site studies with multiple domestic sites are subject to the NIH Single IRB policy as indicated in NOT-OD-16-094 and the Revised Common Rule cooperative research provision 45 CFR 46. 114 . Delayed onset studies will not be supported by this NOFO.

See Section VIII. Other Information for award authorities and regulations. Investigators proposing NIH-defined clinical trials may refer to the Research Methods Resources website for information about developing statistical methods and study designs.

Section II. Award Information Cooperative Agreement: A financial assistance mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, NIH scientific or program staff will assist, guide, coordinate, or participate in project activities.

See Section VI. 2 for additional information about the substantial involvement for this NOFO. Application Types Allowed The OER Glossary and the How to Apply Application Guide provide details on these application types.

Only those application types listed here are allowed for this NOFO. Required: Only accepting applications that propose clinical trial(s). Need help determining whether you are doing a clinical trial?

Funds Available and Anticipated Number of Awards The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications. Application budgets are limited to less than $400,000 in direct costs for the UG3 phase; Application budgets for the UH3 phase are not limited but need to reflect the actual needs of the proposed project.

If the budget exceeds direct costs of $500,000 or more in any year, applicants must follow the NIDCR policy for Grant Applications Requesting $500,000 or More in Direct Costs for Any Project Year . The total project period may not exceed one year for the UG3 phase and five years for the UH3 phase. NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from this NOFO.

Section III.

Eligibility Information Higher Education Institutions Public/State Controlled Institutions of Higher Education Private Institutions of Higher Education 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 (Other than Small Businesses) 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 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 Non-domestic (non-U.S.) Entities (Foreign Organizations) 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 must complete and maintain the following registrations as described in the How to Apply- Application Guide to be eligible to apply for or receive an award.

All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. Failure to complete registrations in advance of a due date is not a valid reason for a late submission, please reference the NIH Grants Policy Statement Section 2.

3. 9. 2 Electronically Submitted Applications for additional information.

System for Award Management (SAM) – Applicants must complete and maintain an active registration, which requires renewal at least annually . The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.

NATO Commercial and Government Entity (NCAGE) Code – Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM. Unique Entity Identifier (UEI) - A UEI is issued as part of the SAM. gov registration process.

The same UEI must be used for all registrations, as well as on the grant application. eRA Commons - Once the unique organization identifier is established, organizations can register with eRA Commons in tandem with completing their Grants. gov registrations; all registrations must be in place by time of submission.

eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application. Grants. gov – Applicants must have an active SAM registration in order to complete the Grants.

gov registration. Program Directors/Principal Investigators (PD(s)/PI(s)) All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons.

If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Eligible Individuals (Program Director/Principal Investigator) 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 their organization to develop an application for 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 How to Apply-Application Guide. This NOFO does not require cost sharing as defined in the NIH Grants Policy Statement Section 1. 2 Definition of Terms .

3. Additional Information on Eligibility Applicant organizations may submit more than one application, provided that each application is scientifically distinct. The NIH will not accept duplicate or highly overlapping applications under review at the same time, per NIH Grants Policy Statement Section 2.

3. 7. 4 Submission of Resubmission Application .

This means that the NIH will not accept: A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application. A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.

An application that has substantial overlap with another application pending appeal of initial peer review (see NIH Grants Policy Statement 2. 3. 9.

4 Similar, Essentially Identical, or Identical Applications ). Section IV. Application and Submission Information 1.

Requesting an Application Package The application forms package specific to this opportunity must be accessed through ASSIST, Grants. gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.

gov Workspace are available in Part 1 of this NOFO. See your administrative office for instructions if you plan to use an institutional system-to-system solution. 2.

Content and Form of Application Submission It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide except where instructed in this notice of funding opportunity to do otherwise. 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. All page limitations described in the How to Apply- Application Guide and the Table of Page Limits must be followed. Instructions for Application Submission The following section supplements the instructions found in the How to Apply- Application Guide and should be used for preparing an application to this NOFO.

All instructions in the How to Apply - Application Guide must be followed. SF424(R&R) Project/Performance Site Locations All instructions in the How to Apply- Application Guide must be followed. SF424(R&R) Other Project Information All instructions in the How to Apply- Application Guide must be followed.

SF424(R&R) Senior/Key Person Profile All instructions in the How to Apply- Application Guide must be followed. All instructions in the How to Apply- Application Guide must be followed. For the initial UG3/UH3 application, a complete detailed budget is required for both the UG3 phase and the UH3 phase.

The applicant should estimate the costs for the UH3 phase based on the scope of work described in the application for the UH3 phase. Budget justifications must be included. The length of the project period should reflect the actual needs of the project.

The maximum project period is 6 years; project periods of less than 6 years will be accepted. If parts of the costs of the trial are to be provided by sources other than NIH, these contributions must be presented in detail in the budget justification. These outsourced costs do not constitute cost sharing as defined in the current NIH Grants Policy Statement and should not be presented as part of the requested budget.

Data and Safety Monitoring Board (DSMB) expenses and activities will be provided by NIDCR if the DSMB is convened by NIDCR. All instructions in the How to Apply-Application Guide must be followed. PHS 398 Cover Page Supplement All instructions in the How to Apply- Application Guide must be followed.

All instructions in the How to Apply- Application Guide must be followed, with the following additional instructions: Provide the overall goals for the entire application and indicate separately Specific Aims to be accomplished in the UG3 phase and in the UH3 phase. Clearly label them as UG3 Specific Aims and UH3 Specific Aims. The significance, biological and clinical relevance of the proposed study must be stated clearly.

It should be supported by the following: A clear statement of the question(s) the study will address and its importance. The scientific rationale and clinical need for the study, including an assessment of previous preclinical and/or clinical studies and their quality (if applicable). The potential for the study results to impact knowledge or clinical practice.

If the proposed study is a Phase III clinical trial , information about the generalizability of potential findings to US populations. Present a compelling argument of how the proposed trial will shift clinical practice or inform health care policy. The application should describe any novel theoretical concepts, approaches or methodologies, instrumentation or interventions that will be used in the proposed clinical trial.

The Approach section should have a clear demarcation of the UG3 and UH3 portions of the application. Describe the study development activities planned for the UG3 phase. Address the feasibility of recruiting participants who are eligible for the proposed research.

For an application proposing a multi-site study, applicants are expected to provide evidence that each recruiting center has access to sufficient study participants who meet the eligibility criteria. Provide an overview of the proposed study design that must justify the selected trial elements provided in the Protocol Synopsis, including: Provide a translation of the clinical question into a statistical hypothesis.

Rationale for the selected trial design/intervention model (e.g., single-group, parallel, cross-over, factorial) and allocation method. Justification for the selected study Phase. For example, there should be adequate evidence from previous studies that an intervention should be tested in a Phase III, multi-center trial.

Rationale for selection of the intervention to be tested and a description of how and at what frequency the intervention will be administered. Methods to be used to ensure masking or minimize bias if complete masking is not possible. Justification for selection of the primary and secondary outcome measures and a description of how the outcome variables will be collected and the criteria for measuring the outcomes.

Description of the study population, including the sample size, pertinent demographic information, required health status or disease condition, and geographic location. Explain why the study population is an appropriate group to address the study objectives. Do not duplicate information described in Section 2 (Study Population Characteristics) of the Study Record: PHS Human Subjects and Clinical Trials Information form.

Description of the proposed effect size of the study expressed in terms of a clinical outcome (e.g., 25% reduction in caries increment). Discuss potential biases