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

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

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

Purpose

The NIDCR recognizes that behavioral and social factors play a role in many dental, oral and craniofacial (DOC) disorders and conditions, and that behavioral and social interventions have the potential to improve these conditions by targeting key behavioral and social factors. The NIDCR is committed to supporting the development and testing of behavioral and social interventions to improve DOC health, and to supporting careful planning for these intervention studies. The purpose of this FOA is to provide support for planning and implementing well-designed, rigorously-conducted behavioral or social intervention studies relevant to DOC health. This FOA will support a broad range of DOC intervention research projects, for participants of any age or developmental stage; for any DOC condition with public health significance (e.g., dental caries, periodontal disease, craniofacial anomalies, oral cancers, salivary gland dysfunctions, oral mucosal diseases, orofacial pain); for a range of outcomes (e.g., direct intervention with patients to improve DOC outcomes, intervention with practitioners to improve DOC care, intervention on health systems to improve continuity of care); for stakeholders from different sectors (e.g., patients, families, social networks and communities, practitioners, care-delivery systems, professional organizations, policy-makers); and for DOC intervention research at all stages, from early intervention development (e.g., Stage I) through implementation and health services research (Stages IV/V).

This FOA is also meant to support basic behavioral and social sciences studies (e.g., Stage 0) that are considered clinical trials based on the NIH's revised definition (please see Clinical Trial Requirements for Grants and Contracts, for guidance). Examples of such studies include experimental manipulation or laboratory-based studies in which behavioral or social probes are used to evoke participants' responses (e.g., emotional regulation, dental fear, social norms, pain intensity) under varied conditions, and for which proximal health-related behavioral or social outcomes but not disease outcomes--are assessed. Such studies are sometimes referred to as Stage 0 studies, or Type 1 translation studies, or basic mechanistic studies. These studies now meet the NIH definition of a clinical trial, and so are appropriate for this FOA. All studies that involve prospective assignment of one or more participants to an intervention or experimental manipulation to study processes proximally or distally related to DOC health are appropriate for this FOA.

This FOA will not be used to support the testing of drugs, devices or biologics regulated by the FDA. Applicants interested in conducting such trials are encouraged to contact an NIDCR Program Official and to visit the NIDCR Clinical Trials Program website.

The NIDCR behavioral and social sciences research program supports research consistent with two trans-NIH frameworks for approaching behavior change: the NIH Stage Model of intervention development, and the NIH Common Fund's Science of Behavior Change experimental medicine approach. Both frameworks emphasize the importance of understanding mechanisms of behavior change, as the building blocks of a cumulative science of behavior change, and as the essential elements of developing interventions and programs that can be adapted for sustainable delivery in their target settings.

The NIH Stage Model of Intervention Development

The Stage Model provides a framework for describing where an intervention is in the developmental pipeline, and specifies research activities appropriate for different stages of intervention development. For instance, the Stage Model describes different research activities that are typical in early intervention-development studies than are typical in effectiveness or implementation studies. The Stage Model also describes activities expected in all stages of intervention development, including the specification of hypothesized mechanisms of action of the intervention, and the inclusion of fidelity monitoring activities, although use of fidelity data may change with the stage of intervention development. The NIH Stage Model provides a common language that facilitates discussion of intervention development research by applicants, reviewers, and funders. Applications for NIDCR support of clinical trials research are expected to identify research proposals using the NIH Stage Model framework, described in detail at: https://www.nia.nih.gov/research/dbsr/stage-model-behavioral-intervention-development.

The NIH Common Fund's Science of Behavior Change Program

The NIDCR behavioral and social sciences clinical research and clinical trials program also draws on the mechanisms-focused, experimental medicine approach encouraged by the NIH Common Fund's Science of Behavior Change (SOBC) program. The experimental medicine approach to behavior change research encourages clear a priori specification of the intended behavioral and social target(s) of an intervention, and methods that test the degree to which an experimental manipulation or intervention engaged those targets. The SOBC program describes 4 steps involved in the experimental medicine approach: 1) identifying one or more hypothesized intervention targets; 2) attempting to engage the target(s) through experimentation or intervention; 3) measuring the degree to which the experimental manipulation or intervention actually engaged the hypothesized target(s); and 4) testing the degree to which target engagement produces the desired change in health behaviors or clinical outcomes. For more information about the SOBC program, please see: https://commonfund.nih.gov/behaviorchange. The purposes of this approach are to increase the contributions of each intervention study to a cumulative science of behavior change, to allow for mechanisms-based design of DOC behavior change interventions, and to facilitate testing of whether mechanisms-based interventions improve DOC health. Applications for NIDCR support of clinical trials research are expected to incorporate an experimental medicine approach. Applications that do not include an experimental medicine approach to behavior change must provide a strong justification for not doing so.

The experimental medicine approach is meant to be compatible with the NIH Stage Model of intervention development, and can be incorporated into any stage of intervention development. Examples of the experimental medicine approach in each stage include, but are not limited to:

Stage 0 - (bBSSR) research is a natural fit for a mechanisms-focused, experimental medicine approach, already asking questions about the mechanisms of behavior and behavior change which could be the targets of subsequent interventions. Stage 0 research could identify and test hypothesized targets for future interventions, e.g., from epidemiologic, observational, or experimental manipulation studies. Stage 0 research could also develop measures of hypothesized mechanisms of change/subsequent intervention targets, and demonstrate that those measures assess change in the intended target. Note that descriptive studies demonstrating correlations among widely-studied risk and protective factors, that do not advance understanding of causal mechanisms, are of lower priority to the NIDCR.

Stage I - (intervention generation and refinement) research incorporates the experimental medicine approach by specifying the intended intervention targets in an intervention manual, and by building into interventionist training materials and fidelity monitoring procedures a check on whether essential elements of the intervention were delivered as intended.

Stages II (efficacy) and III (efficacy in the "real world") research offer an opportunity to implement the experimental medicine approach in fully-powered clinical trials. A typical example is an intervention study that specifies the intended intervention targets, delivers the intervention, measures the degree to which the intervention actually engaged the intended targets, and finally, measures the degree to which target engagement produced changes in the intended health behaviors or clinical condition(s). Note that measuring target engagement is highly dependent on the timing of measurement. For example, measuring whether an intervention engaged a behavioral target (e.g., self-efficacy, motivation) 6 months after intervention delivery is unlikely to capture target engagement. Also, direct measures of target engagement are likely to be more useful than proxy measures, e.g., if an intervention is meant to teach tooth brushing skills, a direct measure of target engagement would be the participants' tooth brushing skills, while an indirect measure would be a clinical indicator of dental or oral disease.

Stages IV (effectiveness) and V (implementation) research apply the experimental medicine approach to hypothesized mechanisms of change in the service delivery system. Stage IV and V studies specify a priori hypotheses about the best strategies to implement evidence-based interventions in specific service delivery systems, implement those strategies, and use fidelity monitoring methods to understand the degree to which the hypothesized strategies led to successful implementation.

Scope of this UG3/UH3 FOA

• Clinical Trial Planning Phase (UG3)

The UG3 award will provide up to 2 years of support for scientific and operational planning activities necessary to conduct the clinical trial. The UG3 planning phase should incorporate all activities required and not yet completed--to prepare for conduct of a subsequent clinical trial (i.e., intervention or experimental manipulation study).

When not yet already completed, at a minimum, UG3 planning activities should include the following activities, included as UG3 milestones:

Development of NIDCR-required study documentation to ensure adherence to the principles of Good Clinical Practice (International Conference on Harmonisation (ICH) E6 http://www.fda.gov/downloads/Drugs/.../Guidances/ucm073122.pdf). At a minimum, required documentation includes a clinical protocol, clinical quality management plan, data quality management plan, and participant consent/assent forms and procedures. For some studies, additional documentation may be required, for instance a Manual of Operations is typically required for multi-site studies where site-level procedures may vary. Applications should describe plans for developing relevant study documentation that will be required before progressing to the UH3 phase.

Intervention target development: Applications should include plans for pilot testing to demonstrate that the hypothesized intervention targets can be engaged, and that target-engagement can be measured (i.e., Stage 0 activities, and first steps in the experimental medicine approach). For instance, if a study intends to test an intervention meant to increase self-efficacy for oral hygiene, the UG3 phase should demonstrate that the study intervention actually targets self-efficacy, and that changes in self-efficacy can be accurately measured.

Acceptability and feasibility of the study intervention(s): If acceptability and/or feasibility of the intervention has not yet been established in the study population, the UG3 phase should propose activities necessary to ensure acceptability and feasibility. Relevant Stage I activities may include consultation with stakeholders, delivery of the intervention to gather feedback from participants and providers, and/or other activities.

Acceptability and feasibility of study procedures: In addition to the acceptability and feasibility of the study intervention(s), planning activities should establish the acceptability and feasibility of proposed study procedures. If not already established, the UG3 planning phase should include pilot-testing of study procedures, such as participant recruitment, methods of data collection, interventionist training procedures, and other key aspects of study conduct.

Fidelity monitoring procedures: Monitoring the degree to which a study intervention is delivered as it was intended to be delivered (i.e., with fidelity) is expected at every stage of intervention development; although the way fidelity data is used differs depending on the stage of intervention development and the associated research question(s). For instance, in stages of intervention development where efficacy is being established, fidelity monitoring is used to ensure intervention fidelity, and to identify interventionists who may need re-training. For studies in later stages of intervention development where efficacy has already been established, and research questions concern effectiveness or implementation, fidelity data is used to identify challenges to intervention delivery. If methods for monitoring the fidelity of intervention delivery are not already established, UG3 planning activities should include the development of these methods.

• Clinical Trial Implementation Phase (UH3)

The objective of the Year 3 to Year 7 UH3 implementation phase is to conduct the clinical trial in accordance with activities planned in the UG3 phase. The NIDCR expects clinical trials supported during the UH3 phase to be hypothesis driven, milestone-defined, and have the potential for high impact within the research mission of the NIDCR. The clinical trial must meet all applicable NIH, and Office of Human Research Protections (OHRP) policy requirements.

At a minimum, UH3 activities should include the following operational activities, expressed as UH3 milestones:

• Site activation
• Enrollment of the first subject
• If applicable, enrollment and randomization, of 25%, 50%, 75% and 100% of the projected study population
• Completion of data collection
• Completion of primary study analyses
• Completion of final study report

UG3/UH3 Transition

At the completion of the UG3 planning phase, the applicant will be required to submit a detailed transition request to progress to the UH3 clinical trial implementation phase. UH3 transition requests will undergo administrative review by NIH staff to determine whether the study will be awarded the implementation phase (UH3). Transition decisions will be based on success in meeting study milestones, readiness to conduct the UH3 clinical trial, feasibility of completing the UH3 clinical trial, availability of funds, and program priorities.

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 funding is dependent on NIDCR program priorities and availability of funds. In addition, applicants should understand that transition to the UH3 phase of the project will occur only if the administrative review process determines that the UG3 planning milestones have been successfully met, and that the UH3 phase can proceed with confidence of success.

Additional Information

Awardees are required to comply with the NIDCR Clinical Terms of Award for any planning phase activities that involve human subjects and all subsequent UH3 implementation phase studies. It is recommended that applicants use the NIDCR tools and templates for development of the clinical trial documents. The details can be found at the following websites: NIDCR Clinical Terms of Award and NIDCR Toolkit for Clinical Researchers. Implementation of the Clinical Terms of Award ensures that the conduct of the clinical trial meets widely-accepted standards for ethical and rigorous research.

Each NIDCR UG3/UH3 Clinical Trial Cooperative Agreement application may only be used to propose the planning and implementation of a single clinical trial.

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

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

Higher Education Institutions

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

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

o Hispanic-serving Institutions

o Historically Black Colleges and Universities (HBCUs)

o Tribally Controlled Colleges and Universities (TCCUs)

o Alaska Native and Native Hawaiian Serving Institutions

o Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)
• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations
• Non-domestic (non-U.S.) Entities (Foreign Institutions)

Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are not allowed.

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• System for Award Management (SAM) (formerly CCR) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
• NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
• eRA Commons - Applicants must have an active DUNS number and SAM registration in order to complete the eRA Commons registration. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

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

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

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.

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

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

The NIH will not accept duplicate or highly overlapping applications under review at the same time. This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101).

Buttons to access the online ASSIST system or to download application forms are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

It is critical that applicants follow the Research (R) Instructions in the SF424 (R&R) Application Guide, except where instructed in this funding opportunity announcement 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.

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

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

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

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

The letter of intent should be sent to:

Yasaman Shirazi, PhD
Telephone: 301-594-5593
Fax: 301-480-8303
Email: yasaman.shirazi@nih.gov

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

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.

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

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

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

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

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

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

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

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

The research plan should provide the background and scientific justification for the trial, and should address the following.

Significance: The significance, biological and clinical relevance of the proposed trial must be stated clearly. It should be supported by the following:

• Innovation: A compelling argument of how the proposed trial study will shift clinical practice or inform health care policy should be presented. The application should describe any novel theoretical concepts, approaches or methodologies, instrumentation or interventions that will be used in the proposed clinical trial.
• Information about the generalizability of potential findings to US populations if this is a Stage III-V trial.
• Information adequate to determine the significance and timeliness of, as well as the need to perform, the trial. This may include preliminary data, clinical and/or preclinical studies, information in the literature, or knowledge of behavioral, social or biological mechanisms.

Research Strategy: The Research Strategy should provide justification for the selected trial elements provided in the Protocol Synopsis, and should include:

• A summary of the clinical trial's objectives describing the scientific rationale and clinical need for the trial, and an assessment of the previous preclinical and clinical studies and their quality.
• The translation of the clinical question into a statistical hypothesis.
• A compelling rationale for the selected study population, including justification for exclusions of children or other age groups such as those 65 years and older. Applications should describe the degree to which the eligible population is available; and plans for recruitment outreach, enrollment, retention, handling dropouts, missed visits, and losses to follow-up appropriate to ensure robust data collection.
• A discussion of potential ethical issues, including processes for obtaining informed consent or assent, and plans for assessing differences in the intervention effect due to sex/gender and race/ethnicity.
• Applications should describe plans for data management and quality control of data; planned analyses and statistical methods; and other relevant aspects of data management and analyses to ensure rigorous and successful completion of the study aims.
• An overview of the proposed study design that should justify the following:
• Primary Purpose (e.g., Treatment, Prevention, Implementation, etc.)
• Stage of Intervention Research (e.g., Stage 0 Basic behavioral or social science to Stage V Implementation science).
• The justification for the selected Stage. For example, there should be adequate evidence from previous studies to support specific Stage-I adaptations to an existing intervention for a new population or setting. Or there should be sufficient evidence from previous trials that an intervention is efficacious before conducting a Stage V Implementation study.
• The scientific rationale and justification for the selection of an intervention's "dose" or number of sessions, frequency and modality of administration.
• Rationale for the intervention and the behavioral or social targets it is hypothesized to engage (e.g., tantrums during night-time toothbrushing sessions make toothbrushing less likely and/or effective, so the intervention trains parents to manage tantrums and tests the effect on toothbrushing frequency and effectiveness).
• Plans for testing and/or ensuring intervention target engagement.
• Where applicable, plans for testing and/or ensuring that the study procedures are feasible and acceptable to the target population and interventionists.
• Where applicable, plans for testing and/or ensuring that the intervention is feasible and acceptable to the target population.
• Plans for monitoring and/or ensuring fidelity of intervention delivery.
• Rationale for the intervention study design (e.g., single case study, multiple baseline, adaptive/SMART design, factorial) and allocation method.
• Methods to ensure masking or to minimize bias if complete masking is not possible.
• Justification for selecting the process and outcome variables, including a specific explanation of the hypothesized relevance of each to the clinical and statistical hypothesis being tested (i.e., the hypothesized role each variable plays in the causal chain; specification of variables as hypothesized moderators, mediators, or outcomes).
• A discussion of potential biases or challenges in the trial and how they will be addressed and minimized.

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

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

Appendix:

Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide. The NIH announced a policy on allowable appendix materials (NOT-OD-17-098); however this FOA allows specific materials to be included as appendices that are otherwise disallowed by the general policy. Applications may include as appendices the following materials: focus group guides, structured interview schedules, questionnaires or surveys with instructions, observational coding systems, fidelity monitoring checklists and rating tools, and draft or sample intervention manuals.

Use only for applications with due dates on or after January 25, 2018. When involving NIH-defined human subjects research, clinical research, and/or clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

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

Study Record: PHS Human Subjects and Clinical Trials Information

All instructions in the SF424 (R&R) Application Guide must be followed with the following additional instructions:

Add only one study record for the UH3 clinical trial. The research strategy section of the application should justify the specifics of the trial, such as the proposed intervention and its target(s), stage of intervention research, and characteristics of the study population.

Section 2 - Study Population Characteristics

2.7 Study Timeline

The filename "Study Timeline" should be used to name this attachment. Applicants are encouraged to use the template (Appendix A) in the NIDCR Clinical Trial (Interventional) Protocol Template. Provide the proposed trial's schedule of events capturing time points and planned activity at study visits. For example:

• Screening Visit: Assessment of Eligibility Criteria, complete Informed Consent process;
• Baseline Visit: Randomize to condition, administer baseline questionnaires, and/or laboratory task(s);
• Weeks 2, 3, 4, 5, and 6 Study Visit(s): Administer intervention(s), administer study questionnaires, lab tasks, and/or other assessments;
• Weeks 12 and 24 Follow-up Study Visit(s). Administer final study questionnaires, lab tasks, and/or other assessments.

The study Study Timeline should include acceptable time windows for each activity.

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

Milestone Plan. The filename "Milestone Plan" should be used to name this attachment. The Milestone Plan must describe separate milestones for the UG3 and UH3 phases.

Applicants are required to provide detailed project performance and timeline milestones. This attachment must include two sections: those milestones to be completed during the UG3 planning phase and those to be completed during the UH3 phase. The plan should present an overview of the project timeline for the following general milestones, as applicable:

Milestones to be completed during the UG3 phase:

• Demonstration that the intervention engages the behavioral or social target it is hypothesized to engage;
• Demonstration that intervention target engagement can be measured;
• Collection and analysis of any data to assess the acceptability of the study intervention(s) to the target population and target interventionists (if applicable);
• Collection and analysis of any data to assess the acceptability of study procedures to the target population, and the feasibility of study procedures in the target setting(s) and for the target interventionists (if applicable);
• Finalization of agreements for use of resources available within CTSAs, practice-based research networks, patient registries, etc.;
• Finalization of clinical protocol;
• Acceptance of the protocol by NIDCR;
• Regulatory approvals (IRB and applicable oversight committees);
• Completion of the data management system;
• Finalization of all documents necessary to implement the trial, such as case report forms;
• Registration of clinical trial in ClinicalTrials.gov.

Milestones to be completed during the UH3 phase:

• Site activation;
• Enrollment of the first subject;
• If applicable, enrollment and randomization, of 25%, 50%, 75% and 100% of the projected study population;
• Completion of data collection;
• Completion of primary study analyses;
• Completion of final study report.

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

The Data and Safety Monitoring Plan should include a description of data monitoring activities, such as:

• 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., Case Report Forms/CRFs), data entry, data verification and data validation. Describe the data query process and frequencies and any planned mitigation strategies in the event of noncompliance;
• The process for locking the final trial datasets for analysis.

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

Section 5 - Other Clinical Trial-related Attachments

5.1 Other Clinical Trial-related Attachments

In addition to Sections 1, 2, 3 and 4 of the Study Record: PHS Human Subjects and Clinical Trials Information, the application must contain the following Other Attachment (Clinical Monitoring Plan), prepared according to the instructions below, to provide evidence that the investigator(s) are ready to proceed with a clinical trial. The information provided here supports the Research Strategy and should not duplicate it. The following document must be uploaded as a separate pdf file with the name indicated below.

Clinical Monitoring Plan. The filename "Clinical Monitoring Plan" should be used to name this attachment. Applicants are encouraged to read "NIDCR Clinical Monitoring Guidelines" for an overview of the practice of clinical monitoring.

The Clinical Monitoring Plan (CMP) is in addition to the application's Data and Safety Monitoring Plan (DSMP) attachment in Section 3 of the Study Record: PHS Human Subjects and Clinical Trial Information that describes how patient safety will be monitored during the trial. The purpose of clinical monitoring is to verify that the clinical trial is being conducted and documented in accordance with the Protocol, Standard Operating Procedures (SOPs), Good Clinical Practice (GCP), and the applicable regulatory requirement(s). As such, the CMP tends to focus on study operations, whereas the DSMP tends to focus on participant safety. The CMP should describe elements such as:

• The persons/entity responsible for conducting the monitoring (e.g., contracted Clinical Research Associate, Data Coordinating Center, Independent study monitor from the Clinical Coordinating Center);
• The frequency of planned monitoring activities (e.g., Study Initiation, Interim Visits, Study Close Out), locations where the monitoring will occur (e.g., participating clinical sites, data center, clinical coordinating center) and what data will be reviewed;
• Plans to ensure adherence to the protocol, adequate documentation of the consenting process, and the quality and consistency of the study intervention(s), including fidelity monitoring for behavioral interventions. Include methods to monitor study intervention and system 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 study specimens;
• 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, DSMB if one is assigned, FDA if applicable, institutional officials and the NIH.

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

Delayed Onset Study

All instructions in the SF424 (R&R) Application Guide must be followed. The delayed onset designation does not apply to this FOA. While human subjects recruitment may not start immediately after successful transition from the UG3 to the UH3, this is considered a delayed start study, and not a delayed onset study.

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

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

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

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

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

Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.

This initiative is not subject to intergovernmental review.

All NIH awards are subject to the terms and conditions, cost 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.

Applications must be submitted electronically following the instructions described in the SF424 (R&R) 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 Applying Electronically. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Guidelines for Applicants Experiencing System Issues. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.

The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization's profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

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

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 SF424 (R&R) Application Guide.

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

Important Update: See NOT-OD-18-228 for updated review language for due dates on or after January 25, 2019.

1. Criteria

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

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 review criteria and additional review criteria (as applicable for the project proposed).

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

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

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

Will the results of this study contribute to a cumulative science of behavior, social, or organizational change, above and beyond demonstrating that an intervention produced an effect for a specific community or population?

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

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

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

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

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

Does the application adequately address the following, if applicable:

Study Design

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

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

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

Data Management and Statistical Analysis

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

Is there a compelling rationale for the selected study population, including justification for exclusions of children or other age groups such as those 65 years and older? Does the application describe the degree to which the eligible population is available; and plans for recruitment outreach, enrollment, retention, handling dropouts, missed visits, and losses to follow-up appropriate to ensure robust data collection?

For this particular announcement, does the application adequately address the following?

• Are the proposed research activities described in terms of Stage of intervention research, and are the activities appropriate and justified given the Stage of intervention research?
• Are the scientific rationale and justification compelling for the selection of an intervention's "dose" or number of sessions, frequency and modality of administration?
• Is there a strong rationale for the intervention and the behavioral or social targets it is hypothesized to engage? Are there sufficient plans for testing and/or ensuring intervention target engagement?
• Where applicable, are there rigorous plans for testing and/or ensuring that the study procedures are feasible and acceptable to the target population and interventionists?
• Where applicable, are there rigorous plans for testing and/or ensuring that the intervention is feasible and acceptable to the target population?
• Does the application propose acceptable plans for monitoring and/or ensuring fidelity of intervention delivery?
• Does the application adequately justify the selection of process and outcome variables, including a specific explanation of the hypothesized relevance of each to the clinical and statistical hypothesis being tested (i.e., the hypothesized role each variable plays in the causal chain; specification of variables as hypothesized moderators, mediators, or outcomes)?

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

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

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

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

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

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

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

Study Timeline

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

Does the Study Timeline specify acceptable time windows for study visits and assessments?

Clinical Monitoring Plan

Is the Clinical Monitoring Plan sufficient to verify that the clinical trial is being conducted and documented in accordance with the Protocol, Standard Operating Procedures (SOPs), Good Clinical Practice (GCP), and the applicable regulatory requirement(s)? Does the Clinical Monitoring Plan describe an acceptable approach for who is responsible for conducting clinical monitoring, the frequency of monitoring activities, ensuring adherence to the protocol, and for remediation of any deficiencies in study conduct?

Study Milestones

Are appropriate, evaluative milestones clearly defined for the UG3 and UH3 phases, and is it likely that the investigator team will meet these milestones within the proposed project period?

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

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

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

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

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

For Resubmissions, the committee will evaluate the application as now presented, taking into consideration the responses to comments from the previous scientific review group and changes made to the project.

For Renewals, the committee will consider the progress made in the last funding period.

Not applicable.

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

Not applicable.

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

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

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

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

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

As part of the scientific peer review, all applications:

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

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 to this FOA. Following initial peer review, recommended applications will receive a second level of review by the National Advisory Dental and 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.

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.

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

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

Institutional Review Board or Independent Ethics Committee Approval: Grantee institutions must ensure that the application as well as all protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the awardee must provide NIH copies of documents related to all major changes in the status of ongoing protocols. Data and Safety Monitoring Requirements: The NIH policy for data and safety monitoring requires oversight and monitoring of all NIH-conducted or -supported human biomedical and behavioral intervention studies (clinical trials) to ensure the safety of participants and the validity and integrity of the data. Further information concerning these requirements is found at http://grants.nih.gov/grants/policy/hs/data_safety.htm and in the application instructions (SF424 (R&R) and PHS 398).

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

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.

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

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

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

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

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).

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person's race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency. HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator's scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research.

For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/index.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html; and https://www.hhs.gov/civil-rights/for-providers/laws-regulations-guidance/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant's integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 "Federal awarding agency review of risk posed by applicants." This provision will apply to all NIH grants and cooperative agreements except fellowships.

Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Part 75, and other HHS, PHS, and NIH grant administration policies.

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

The PD(s)/PI(s) will have the following primary responsibilities:

* All aspects of the study, including 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 are the PD(s)/PI(s) responsibilities. The awardee 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.

• The PD(s)/PI(s) will meet NIDCR policy requiring that studies be monitored commensurate with the degree of potential risk to study subjects and the complexity of the study (NOT-DE-08-011, March 27, 2008).
• Upon implementation of the protocol, each study, whether a single entity or a consortium of entities, will follow the procedures required by the protocol regarding study conduct and monitoring, participant management, data collection, and quality control.

The PD(s)/PI(s) will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies.

• The PD(s)/PI(s) will manage 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.
• The PD(s)/PI(s) will make all study materials and procedure manuals available in the public domain. Awardees are expected to publish and publicly disseminate results, data, and other products of the study, concordant with governance policies and protocols. Publications and oral presentations of work performed under this agreement will require appropriate acknowledgment of support by the NIDCR/NIH.
• The PD(s)/PI(s) will obtain 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 will have the following primary responsibilities:

An NIDCR Program staff member(s) acting as a Project Scientist(s) will be assigned to have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below. Additional NIDCR staff members may be designated to have substantial involvement. The NIDCR Project Scientist(s) and any other substantially involved staff members will not attend peer review meetings of renewal (competing continuation) and/or supplemental applications. If such participation is deemed essential, these individuals will seek NIDCR waiver according to the NIDCR procedures for management of conflict of interest. Some Program Officials will also have substantial programmatic involvement. In that case, the individual involved will not attend peer review meetings of renewal (competing continuation) and/or supplemental applications or will seek an NIDCR waiver as stated above.

The main activities of the NIDCR substantially involved staff members include but are not limited to the following aspects:

• Providing input on experimental and clinical approaches, assisting in designing protocols, and consulting on updates to project milestones;
• Assisting and advising awardees with regard to various regulatory and compliance issues;
• Participating in monthly teleconferences with PDs/PIs to monitor progress and facilitate cooperation;
• Monitoring progress of the trial towards meeting its primary outcome;
• Tracking monthly accrual of participants; and
• Reviewing the progress of the study, and of each participating component, through consideration of the annual reports, site visits, logs, etc. This review may include, but not be limited to, compliance with the study protocol, meeting subject enrollment targets, adherence to uniform data collection procedures, and the timeliness and quality of data reporting.

An NIDCR Program Official will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice. An NIDCR Medical or Dental Officer will monitor the studies and serve as the Medical Monitor.

Areas of Joint Responsibility:

As appropriate to a funded clinical trial, the following collaborative responsibilities will be incorporated in the grant award:

The NIDCR reserves the right to terminate, temporarily suspend, or modify 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, follow-up, 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.

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

A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.

In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period. The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 Award Term and Conditions for Recipient Integrity and Performance Matters.

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

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

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

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

Melissa W. Riddle, PhD
National Institute of Dental and Craniofacial Research (NIDCR)
Telephone: 301-451-3888
Email: riddleme@mail.nih.gov

Darien Weatherspoon, DDS, MPH
National Institute of Dental and Craniofacial Research (NIDCR)
Telephone: 301-594-5394
Email: darien.weatherspoon@nih.gov

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

Diana Rutberg, MBA
National Institute or Dental and Craniofacial Research (NIDCR)
Telephone: 301-594-4798
Email: rutbergd@mail.nih.gov

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost 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 45 CFR Part 75.