Part 1. Overview Information

Key Dates

All applications are due by 5:00 PM local time of applicant organization. 

Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

It is critical that applicants follow the 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.

IMPORTANT: Per NOT-OD-24-086 updated application forms (FORMS-I) will be used for this opportunity. The updated forms are not yet available and will be posted 30 calendar days or more prior to the first application due date. Once posted, you will be able to access the forms using one of the following submission options:

1. NIH ASSIST
2. An institutional system-to-system (S2S) solution
3. Grants.gov Workspace

Part 2. Full Text of Announcement

Section I. Notice of Funding Opportunity Description

PURPOSE

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 accept applications for competing renewal of ongoing clinical trials supported by NIDCR or competitive revisions proposing to modify the scope of ongoing NIDCR-supported clinical trials. Extension of an ongoing clinical trial via a competing renewal will be considered when there is a need for additional time to complete the trial or when an extended period of follow-up is well justified to assess longer term outcomes. Competitive revisions will be considered when there is compelling justification for modifying the scope of an ongoing clinical trial.

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

Clinical trials that involve behavioral or social sciences research at other stages of the intervention-development process also are appropriate. For example, the addition of a theoretically-driven model on interpersonal processes that facilitate healthier behavior change and adherence to an existing clinical trial not premised on interpersonal relationships is an example of a competitive revision to a behavioral/social clinical trial. An application that proposes additional longitudinal follow-up to explore ongoing behavioral adherence to an intervention with overwhelming oral public health impact is an example of a competing renewal.

Prior to submitting applications to this NOFO, all applicants are strongly encouraged to consult with the Scientific/Research contacts for the ongoing clinical trial to determine whether a competing renewal or competitive revision application is of interest to NIDCR. Early contact (e.g., 12 weeks prior to submission) is encouraged. This period of time provides an opportunity for NIDCR staff to discuss the scope and goals, and to provide information and guidance to potential applicants.

BACKGROUND

The NIDCR is committed to identifying effective preventive, diagnostic, and treatment approaches for dental, oral, and 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 and 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, surgical planning tools, or enhancements to electronic health records) 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.

SCOPE

Each UH3 Clinical Trial Cooperative Agreement award will support the implementation of a single clinical trial. Competing renewal applications will be considered when there is rationale to support extension of an ongoing clinical trial, when additional time is needed to complete the trial or when an extended period of follow-up is well justified to assess longer term outcomes. Competing renewal applications should provide strong justification and a detailed timeline to support the need for additional time to complete the trial or to assess longer term outcomes. Competitive revision applications will be considered when there is a compelling rationale to modify the scope of the clinical trial. Any new aim(s) proposed in the grant application should be fully powered to test the hypothesis(es) and may require additional data collection, specimen collection, or procedures. The proposed modification may use some or all of the ongoing clinical trial population.

The NIDCR will be substantially involved with the UH3 awardees as a partner in providing overall scientific and operational guidance, consistent with the Cooperative Agreement mechanism. The NIDCR expects clinical trials 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.

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 submitted the appropriate investigational application to the FDA prior to submitting the grant application.

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.

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/.

Milestones

Projects funded under this NOFO must be driven by well-defined, annual milestones that must be completed during clinical trial implementation. 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. Continued funding during the UH3 project period will be dependent upon meeting annual UH3 milestones, and it is expected that the study will be completed within the UH3 project period.

Additional Information

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 trial implementation activities that involve human subjects. 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

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

Section III. Eligibility Information

1. Eligible Applicants

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Local Governments

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

Federal Governments

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

Other

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

Non-domestic (non-U.S.) Entities (Foreign 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

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.

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. Individuals from diverse backgrounds, including underrepresented racial and ethnic groups, individuals with disabilities, and women are always encouraged to apply for NIH support. See, Reminder: Notice of NIH's Encouragement of Applications Supporting Individuals from Underrepresented Ethnic and Racial Groups as well as Individuals with Disabilities, NOT-OD-22-019.

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

2. Cost Sharing

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

Number of Applications

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

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

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

Section IV. Application and Submission Information

1. Requesting an Application Package

The application forms package specific to this opportunity must be accessed through ASSIST, 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.

Letter of Intent

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

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

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

The letter of intent should be sent to:

Yasaman Shirazi, PhD
Telephone: 301-594-5593
Email: yasaman.shirazi@nih.gov

Page Limitations

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

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.

SF424(R&R) Cover

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.

R&R Budget

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

The applicant should estimate the costs for clinical trial implementation based on the scope of work described in the application. Budget justifications must be included. The length of the project period should reflect the actual needs of the project. The maximum project period is 5 years; project periods of less than 5 years will be accepted.

If parts of the costs of the trial are to be provided by sources other than NIDCR, 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.

R&R Subaward Budget

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.

PHS 398 Research Plan

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

Research Strategy

Significance:

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.
• For renewal applications, provide strong justification for why additional time is needed to complete the trial or why extended follow-up for longer term outcomes is important.
• For revision applications, provide a description of what additional knowledge will be gained in the modified study scope and compelling rationale for the proposed study scope modification.

Innovation:

• 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.

Approach:

• Address the feasibility of recruiting (or retaining if participants have already been enrolled in the trial) 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, cluster-randomized, 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.
  • For behavioral interventions, demonstration that an intervention engages the mechanism of action target(s) it intends to, and that target engagement can be measured.
  • 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 or challenges in the proposed trial and how they will be minimized and/or addressed.

       Progress of Ongoing Clinical Trial:

• Provide a summary of the ongoing clinical trial's progress including attainment of enrollment/randomization and retention targets, and the initial timeline for study completion. Describe any challenges or delays and corrective action strategies utilized by the team in the prior funding period. Describe any changes that have been made to the study design, sample size, or power calculations during the course of the prior funding period.
• For renewal applications, describe the reasons for why the trial was not completed in the prior funding period and why additional time is needed to complete the trial or to obtain longer term outcomes.
• For revision applications, provide a clear description of additional data collection, specimen collection, procedures, and/or study participants needed to attain the proposed aim(s) associated with the modified study scope.

Investigator(s):

• Without duplicating information in biosketches, describe the expertise of the study team and the team’s ability to develop, manage and implement the planned study and perform appropriate analyses of data collected.

Letters of Support: Letters of support may be included from research collaborators, clinical collaborators, patient organizations, or other groups with whom the investigators propose to work.

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

The following modifications also apply:

• All applications, regardless of the amount of direct costs requested for any one year, should address: A plan to make study materials and procedures manuals (data collection instruments, study protocols) available in the public domain.

Other Plan(s): 

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

• All applicants planning research (funded or conducted in whole or in part by NIH) that results in the generation of scientific data are required to comply with the instructions for the Data Management and Sharing Plan. All applications, regardless of the amount of direct costs requested for any one year, must address a Data Management and Sharing Plan.

Appendix: Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the How to Apply- Application Guide.

• No publications or other material, with the exception of blank questionnaires or blank surveys, may be included in the Appendix.

PHS Human Subjects and Clinical Trials Information

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

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

Study Record: PHS Human Subjects and Clinical Trials Information

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

Additional instructions are provided for the following sections:

• 2.5 Recruitment and Retention Plan
• 2.7 Study Timeline 
• 3.3 Data and Safety Monitoring Plan
• 4.3 Statistical Design and Power
• 5.1 Other Clinical Trial-related Attachments

Section 2 - Study Population Characteristics

2.5 Recruitment and Retention Plan

The filename "Study Accrual and Retention Plan" should be used to name this attachment, which addresses the feasibility of recruiting participants who are eligible for the clinical trial. Specifically, applicants must provide evidence that each recruiting center in the trial has access to a sufficient number of participants who meet the eligibility criteria as defined in the grant application. For multi-site applications, information must be provided for each participating site.

Describe the plan to recruit/enroll the population of interest for the clinical trial, including outreach activities and pre-study assessments of the ability of participating clinical sites to recruit the proposed target number of participants. The plan should include a timeline with goals for accrual of study participants. If there are known participant or study-related barriers to accrual or participation (based on literature or prior experience), please list these barriers and describe plans to address them to optimize success. Address contingency plans for participant accrual if enrollment significantly lags behind accrual benchmarks.

Describe the plan to meet the study’s retention targets. Include a discussion of strategies for retention of participants, including any methods to maximize flexibility for data collection after baseline (e.g., data collection independent of office visits). The plan should clearly state retention goals. 

2.7 Study Timeline 

The filename "Study Timeline and Milestone Plan" should be used to name this attachment, which should include both the Study Timeline and Milestone Plan.

1. Study Timeline

The UH3 timeline should include the estimated time to: a) open study to enrollment; b) complete data collection; and c) complete final data analysis. Provide a clear and appropriate timeline to ensure the study will be completed during the project period.

Applications that lack the Study Timeline are considered incomplete and will be withdrawn without peer review.

2. Milestone Plan

A milestone is defined as: a scheduled event in the project timeline that signifies the completion of a major project stage or activity. Milestones must be objective, measurable, and achievable. The study timeline must include clearly stated annual UH3 milestones that will be completed during the UH3 implementation phase. Applications should also address anticipated challenges to meeting milestones and propose potential mitigation or corrective action strategies. Milestones should address accrual goals for women, minorities, and individuals of all ages and any other identified requirements for completion of the approved research.

Milestones may be refined and finalized in consultation with NIDCR Program Staff at the time of the UH3 award, if granted. The Terms and Conditions for an award under this NOFO will include milestones that are mutually agreed upon by the investigators and NIDCR. Annual milestones will be carefully assessed, and future support of a trial funded under this NOFO is contingent upon meeting projected milestones, including meeting adequate participant enrollment/retention targets.

Milestones that may be completed during the clinical trial implementation include, but are not limited to:

• Finalization of clinical protocol, statistical analysis plan, and other study documents necessary to implement the study
• Finalization of a Study Accrual and Retention Plan (SARP), including a timeline for study participant accrual and retention goals 
• Finalization of the data management system
• Completion of regulatory approvals
• Study activation
• Registration of clinical trial in ClinicalTrials.gov
• Enrollment of the first participant
• Enrollment and randomization of 25%, 50%, 75% and 100% of the projected study population
• Completion of data collection time period
• Completion of primary and secondary outcome data analyses
• Reporting of results in ClinicalTrials.gov per the NIH Policy on the Dissemination of NIH-Funded Clinical Trial Information

Applications that lack the Milestone Plan are considered incomplete and will be withdrawn without peer review.

Section 3 - Protection and Monitoring Plans

3.3 Data and Safety Monitoring Plan

Applicants should refer to NIH's policy on data and safety monitoring (https://grants.nih.gov/policy/humansubjects/policies-and-regulations/data-safety.htm) and the NIDCR Clinical Terms of Award for research involving human subjects.

Describe the study-specific plan to ensure data and safety monitoring, including:

Provide an overall description of the monitoring plan to ensure adherence to the protocol, adequate documentation of the consenting process, and the quality and consistency of administering the study intervention(s). Include methods to monitor study intervention fidelity and systems to record, report and manage exceptions and deviations. If applicable, describe monitoring of participating facilities such as labs or pharmacies for adequate handling and storage of investigational product(s) and study specimens. Describe plans for handling any deficiencies that are uncovered and in cases of serious deficiencies, the appropriate reporting to relevant authorities, including but not limited to the IRB of record, Data and Safety Monitoring Board (DSMB) if one is assigned, FDA if applicable, institutional officials and the NIH.

Describe plans to ensure that validated systems and controls are in place to assure the integrity of the clinical trial data being collected; proposed methods and systems for data collection (e.g., paper or electronic data collection systems), data entry, data verification, data validation and adverse event reporting; and the process for locking the final trial dataset for analyses. Describe the data query process and query frequencies and any planned mitigation strategies in the event of noncompliance with data collection processes. 

Do not name members of any oversight board in the application. The NIDCR will appoint members of any oversight committees after consultation with the investigators.

Section 4 - Protocol Synopsis

4.3 Statistical Design and Power

In addition to the information requested in the SF424 (R&R) Application Guide instructions, describe the plans for handling missing data.

Section 5 Other Clinical Trial-related Attachments

5.1 Other Clinical Trial-related Attachments

The application must contain the following two attachments (Schedule of Events, Quality Management Plan), according to the instructions below. The information provided here will be considered by reviewers and is meant to supplement, not duplicate, information provided in the Research Plan or other sections of the Study Record: PHS Human Subjects and Clinical Trials Information form. The following documents must be uploaded as separate pdf files with the names indicated below.

1.Schedule of Events. The filename "Schedule of Events" should be used to name this attachment. Applicants are encouraged to use the sample format (Appendix A) in the NIDCR Interventional (Clinical Trial) Protocol Template.

Provide a schematic, table, or text description of the protocol-specified schedule of events for an individual study participant. It should capture each study visit/assessment time point and planned activity(ies) for each time point.

For example:

• Screening Visit (time point): Sign consent form, assess eligibility criteria, review medical/dental history, review concomitant medications;
• Baseline Visit (time point): Confirm eligibility, obtain informed consent if needed, randomize, obtain baseline clinical and/or laboratory assessment(s), collect biospecimens, obtain patient-reported outcomes;
• Interim Study Visit(s) (time points): Provide intervention(s), obtain clinical and/or laboratory assessment(s), collect biospecimens, obtain patient-reported outcomes;
• Final Study Visit (time point): Obtain final clinical and/or laboratory assessment(s), collect end-of-study biospecimens, obtain patient-reported outcomes.

2.Quality Management Plan. The purpose of the Quality Management Plan is to establish standard processes for all study-related activities, to assess and document adherence to all clinical trial procedures, and to ensure the quality of data collection procedures.

• Describe plans to standardize study processes, train study staff, and monitor adherence to the clinical protocol, standard operating procedures (SOPs), Good Clinical Practice (GCP), and the applicable regulatory requirement(s)
• Describe the methods and systems for data collection (e.g., Case Report Forms/CRFs), including timely data entry, and the frequency and processes of review to ensure complete, accurate, and consistent data collection.

Delayed Onset Study

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

Do not enter a delayed onset study, as the UH3 trial should not be considered a delayed onset study.

PHS Assignment Request Form

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

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

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

4. Submission Dates and Times

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

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

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

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

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

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

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

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

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

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

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile form. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this NOFO for information on registration requirements.

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

See more tips for avoiding common errors.

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

Requests of $500,000 or more for direct costs in any year

Applicants requesting $500,000 or more in direct costs in any year (excluding consortium F&A) must contact a Scientific/ Research Contact at least 6 weeks before submitting the application and follow the Policy on the Acceptance for Review of Unsolicited Applications that Request $500,000 or More in Direct Costs as described in the How to Apply - Application Guide.

Applicants requesting $500,000 or more in direct costs in any year must follow the NIDCR-specific instructions for applications requesting $500,000 or more in direct costs for any year to seek permission to submit the application.

Recipients or subrecipients must submit any information related to violations of federal criminal law involving fraud, bribery, or gratuity violations potentially affecting the federal award. See Mandatory Disclosures, 2 CFR 200.113 and NIH Grants Policy Statement Section 4.1.35.

Send written disclosures to the NIH Chief Grants Management Officer listed on the Notice of Award for the IC that funded the award and to the HHS Office of Inspector Grant Self Disclosure Program at grantdisclosures@oig.hhs.gov.

Post Submission Materials

Applicants are required to follow the instructions for post-submission materials, as described in the policy

Section V. Application Review Information

1. Criteria

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

For this particular announcement, note the following:

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

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following scored review criteria and additional review criteria (as applicable for the project proposed). An application does not need to be strong in all categories to be judged likely to have a major scientific impact.

Reviewers will evaluate Factors 1, 2 and 3 in the determination of scientific merit, and in providing an overall impact score. In addition, Factors 1 and 2 will each receive a separate criterion score. 

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

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.

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by NIDCR, in accordance with NIH peer review policies and practices, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

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

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

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

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 Section 2.5.1. Just-in-Time Procedures. This request is not a Notice of Award nor should it be construed to be an indicator of possible funding.

Prior to making an award, NIH reviews an applicant’s federal award history in SAM.gov to ensure sound business practices. An applicant can review and comment on any information in the Responsibility/Qualification records available in SAM.gov. NIH will consider any comments by the applicant in the Responsibility/Qualification records in SAM.gov to ascertain the applicant’s integrity, business ethics, and performance record of managing Federal awards per 2 CFR Part 200.206 “Federal awarding agency review of risk posed by applicants.” This provision will apply to all NIH grants and cooperative agreements except fellowships.

3. Anticipated Announcement and Award Dates

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 Section 2.4.4 Disposition of Applications.

Section VI. Award Administration Information

1. Award Notices

A Notice of Award (NoA) is the official authorizing document notifying the applicant that an award has been made and that funds may be requested from the designated HHS payment system or office. The NoA is signed by the Grants Management Officer and emailed to the recipient’s business official.

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

Recipients must comply with any funding restrictions described in Section IV.6. Funding Restrictions. Any pre-award costs incurred before receipt of the NoA are at the applicant's own risk.  For more information on the Notice of Award, please refer to the NIH Grants Policy Statement Section 5. The Notice of Award and NIH Grants & Funding website, see Award Process.

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

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

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

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

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

2. Administrative and National Policy Requirements

The following Federal wide and HHS-specific policy requirements apply to awards funded through NIH:

• The rules listed at 2 CFR Part 200, Uniform Administrative Requirements, Cost Principles, and Audit Requirements for Federal Awards.
• All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the terms and conditions in the Notice of Award (NoA). The NoA includes the requirements of this NOFO. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Recipients, and Activities.
• If a recipient receives an award, the recipient must follow all applicable nondiscrimination laws. The recipient agrees to this when registering in SAM.gov. The recipient must also submit an Assurance of Compliance (HHS-690). To learn more, see the Laws and Regulations Enforced by the HHS Office for Civil Rights website.
  • HHS recognizes that NIH research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research. For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this NOFO.

All federal statutes and regulations relevant to federal financial assistance, including those highlighted in NIH Grants Policy Statement Section 4 Public Policy Requirements, Objectives and Other Appropriation Mandates.

Recipients are responsible for ensuring that their activities comply with all applicable federal regulations.  NIH may terminate awards under certain circumstances.  See 2 CFR Part 200.340 Termination and NIH Grants Policy Statement Section 8.5.2 Remedies for Noncompliance or Enforcement Actions: Suspension, Termination, and Withholding of Support. 

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

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

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

• Providing scientific leadership for all aspects of the study, including planning, any modification of study design, conduct of the study, quality control, data analysis and interpretation, preparation of publications, dissemination of data, tools, and technologies, and collaboration with other investigators. The PD(s)/PI(s) agrees to accept close coordination, cooperation, and participation of NIDCR staff in those aspects of scientific and technical management of the study as stated in these terms and conditions;
• Adhering to the NIDCR Clinical Terms of Award requiring that studies be monitored commensurate with the degree of potential risk to study subjects and the complexity of the study;
• Upon implementation of the study, following the procedures required by the protocol regarding study conduct and monitoring, participant management, data collection, and quality control;
• Retaining custody of and having primary rights to the data developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies;
• Managing involvement of industry or any other third party in the study. Except for licensing of patents or copyrights, support or involvement of any third party will occur only following notification of and concurrence by the NIDCR;
• Managing procedures to comply with the requirements of 45 CFR Part 46 for the protection of human subjects and the NIH policy requirements for the inclusion of women, minorities, and children and Inclusion Across the Lifespan and, where applicable, for all participating institutions to comply with FDA regulations for studies involving investigational products.
• Making all study materials, procedure manuals, and final datasets available in the public domain, managed by the recipient institution. Recipients are expected to publish and publicly disseminate results, data, and other products of the study, concordant with NIH governance policies and protocols. Publications and oral presentations of work performed under this agreement will require appropriate acknowledgment of support by the NIH/NIDCR;
• Obtaining prior written approval of the NIDCR Grants Management Specialist, in consultation with the NIDCR Program Officer, for changes in any of the key personnel identified in the Notice of Grant Award.

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

An NIDCR Project Scientist will be assigned. The NIDCR Project Scientist will:

• Consult with the PD(s)/PI(s) regarding annual milestones for the UH3 implementation phase;
• Serve as a resource to provide scientific/programmatic support during research study implementation by providing input on experimental and clinical approaches and study protocols, and advising in the management and operational aspects of study implementation;
• Participate on teleconferences with PDs/PIs to monitor study implementation progress, adherence to the study protocol, conduct of the study, and recruitment and retention of study participants;
• Review the progress of the study through consideration of routine reporting, site visits, oversight committee recommendations, etc. This review may include, but would not be limited to, compliance with the study protocol, meeting participant enrollment targets, adherence to uniform data collection procedures, and the timeliness and quality of data reporting.

An NIDCR Program Official will be assigned. The NIDCR Program Official will:

• Carry out continuous review of all activities to ensure that the objectives are being met and that all regulatory, fiscal, and administrative matters are handled according to NIH guidelines;
• Periodically review reports of study progress. NIDCR staff may use information obtained from the data for the preparation of internal reports on the activities of the study. However, recipients will retain custody of and have primary rights to all data developed under these awards, subject to Government right of access consistent with HHS, PHS and NIH policies;
• Have the option to withhold support to a participating institution if technical performance requirements are not met;
• Perform other duties required for normal program stewardship of grants.
• Additionally, 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 notice of award.

An NIDCR Medical Officer will monitor the studies and serve as the Medical Monitor.

The NIDCR reserves the right to terminate or curtail a study or any portion of a study in the event of (a) failure to implement the study protocol, (b) a substantial shortfall in participant recruitment and/or retention, data reporting and dissemination, quality control or other major breach of the protocol, (c) substantive changes in the agreed-upon protocol with which the NIDCR does not concur, (d) reaching a major study objective substantially before schedule with persuasive statistical evidence, or human subject ethical issues that may dictate a premature termination.

Areas of Joint Responsibility include:

None, all responsibilities are divided between recipients and NIH staff as described above.

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel comprising three members will be convened. Members will be: a designee chosen by the PD/PI, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual recipient. This special dispute resolution procedure does not alter the recipient's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

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

4. Reporting

When multiple years are involved, recipients will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement Section 8.4.1 Reporting. To learn more about post-award monitoring and reporting, see the NIH Grants & Funding website, see Post-Award Monitoring and Reporting.

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 Section 8.6 Closeout. NIH NOFOs outline intended research goals and objectives. Post award, NIH will review and measure performance based on the details and outcomes that are shared within the RPPR, as described at 2 CFR Part 200.301.

Section VII. Agency Contacts

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

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

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

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-480-7075

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: support@grants.gov

For interventions testing a drug, biologic, device, or procedure, contact:

Dena Fischer, DDS, MSD, MS
National Institute of Dental and Craniofacial Research (NIDCR)
Telephone: 301-594-4876
Email: dena.fischer@nih.gov

For behavioral and social interventions, contact:

William Elwood, PhD
Chief, Behavioral and Social Sciences Research Branch
National Institute of Dental and Craniofacial Research (NIDCR)
Telephone: 301-402-0116
Email: william.elwood@nih.gov

Yasaman Shirazi, PhD
National Institute of Dental and Craniofacial Research (NIDCR)
Telephone: 301-594-5593
Email: yasaman.shirazi@nih.gov

Gabriel Hidalgo, MBA
National Institute of Dental and Craniofacial Research (NIDCR)
Telephone: 301-827-4630
Email: gabriel.hidalgo@nih.gov

Section VIII. Other Information

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

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