NIDCR Clinical Terms of Award

1. Introduction

The National Institute of Dental and Craniofacial Research (NIDCR) Clinical Terms of Award (CToA) applies to all grant and cooperative agreement awards conducting human subjects research that have been determined by NIDCR to need additional oversight (as defined in Section 2) and/or accrual and retention monitoring. NIH defines clinical research as research with human subjects that is:

• Patient-oriented research: Research conducted with human subjects (or on material of human origin such as tissues, specimens, and cognitive phenomena) for which an investigator (or colleague) directly interacts with human subjects.
• Epidemiological and behavioral studies
• Outcomes research and health services research ¹

NIDCR’s human subjects research portfolio includes interventional clinical trials, observational studies, and studies involving analysis of existing data or specimens. For each study, NIDCR determines the level of oversight, which varies depending on the risk to human subjects and the complexity of the study. The NIDCR CToA  is intended to ensure that studies supported by NIDCR are well designed, conducted with rigor, monitored at a level commensurate with risk and complexity, and that the Institute is kept informed of study progress through reporting.

NIDCR award recipients (recipients) must comply with the CToA, which will be incorporated into the Notice of Award (NoA). These terms apply throughout the course of the research and are in addition to the terms within the NIH Grants Policy Statement (GPS) and any other award-specific terms and conditions. For studies subject to the NIDCR CToA, NIDCR will request submission of specified study documentation and/or plans that are not included or fully developed in the application, and compliance with certain study start-up activities prior to starting human subjects research. In addition, while the study is ongoing, NIDCR may request study documentation, reporting, and/or activities to ensure compliance with NIDCR oversight. Please note the  accrual and retention monitoring methods detailed in these terms of award do not apply to existing awards prior to the release of the revision detailed in NOT-DE-25-043, unless the recipient is notified by NIDCR.

The CToA  outlined here is in addition to and not in lieu of other federal regulations regarding human subjects research, see the Department of Health and Human Services regulations (45 CFR 46).

See also other applicable NIH and NIDCR policies, guidance, and federal regulations regarding grant administration:

• NIDCR Notices of Funding Opportunities (NOFOs) may include additional NOFO-specific instructions and/or guidance
• NIH Grants Policy Statement
• NIH Forms and Applications for Research Grants
• Uniform Administrative Requirements, Cost Principles, and Audit Requirements for Federal Awards (2 CFR 200)

Potential applicants are encouraged to contact NIDCR with questions concerning CToA.

2. NIDCR CToA Applies

A. Accrual and Retention Monitoring

As part of NIDCR’s responsibility to ensure the ethical conduct of human subjects research and proper stewardship of public funds, all studies subject to the NIDCR CToA must comply with NIDCR expectations for accrual and retention monitoring. For some studies, NIDCR may determine that only accrual and retention reporting is required to fulfill expectations as part of NIDCR CToA, without requiring additional NIDCR oversight (as described in 2.B).

Prior to the initiation of human subjects research, the recipient must complete a Study Accrual and Retention Plan (SARP) that outlines planned study dates and goals for accrual and retention. The SARP must be submitted to and approved by NIDCR. Following the initiation of human subjects research, the recipient will submit accrual and retention reports at specified time frames to NIDCR for review throughout the course of the study. If actual accrual and/or retention numbers fall behind planned goals or timelines, the recipient should be prepared to address any identified challenges, provide new strategies for improvement to study accrual and/or retention, and/or revise the SARP. NIDCR may take official actions based on continued deficiencies.

B. Additional NIDCR Oversight

In addition to accrual and retention monitoring, NIDCR may determine that certain studies require additional oversight throughout the stages of human subjects research to monitor data integrity and the safety of human subjects. NIDCR considers many factors in the context of risk to human subjects and complexity of the study when making oversight determinations for human subject research.

1. Types of Additional Oversight

   Additional NIDCR oversight may involve any of the following:

   1. NIDCR-Appointed Data and Safety Monitoring Board (DSMB) — NIDCR may appoint a DSMB for studies involving an intervention. The DSMB is an independent group of experts who have the primary responsibilities to 1) periodically evaluate the accumulating study data for participant safety, study conduct and progress, and, when appropriate, efficacy and/or futility; and 2) make recommendations to NIDCR concerning the continuation, modification, or termination of the study.
   2. NIDCR-Appointed Clinical Study Oversight Committee (CSOC) — NIDCR may appoint a CSOC for observational studies involving increased risk and/or level of complexity. The CSOC is an independent group of experts who have the primary responsibilities to 1) periodically evaluate the accumulating study data for participant safety, study conduct and progress; and 2) make recommendations to NIDCR concerning the continuation, modification, or termination of the study.
   3. NIDCR-Appointed Independent Safety Monitor (ISM) — NIDCR may appoint a qualified clinician with relevant expertise whose primary responsibility is to provide independent safety monitoring. This is accomplished by evaluation of safety data with follow-up through resolution or stabilization. The ISM evaluates individual participant and cumulative safety data when making recommendations to NIDCR regarding continuation of the study.
   4. NIDCR Medical Monitor — The NIDCR Medical Monitor oversight process is appropriate for clinical studies deemed as needing additional oversight but not requiring a Safety Committee. Generally, the recipient will submit a report to the NIDCR Medical Monitor every 6 months. This report will include enrollment and retention data; cumulative listings of adverse events, serious adverse events, unanticipated problems and protocol deviations; data on disposition of biospecimens, outcome measures, and other relevant parameters. The NIDCR Medical Monitor may make recommendations regarding the continuation, modification, or termination of the study.
   5. Recipient Institution-Appointed Oversight Body — In some instances, NIDCR may accept an independent oversight body appointed and managed by the recipient institution. NIDCR will require reports, minutes, and recommendations generated from this type of oversight and may request additional reporting using NIDCR-specified templates.

2. Additional Oversight Documentation and Activities

   For studies subject to additional oversight as part of the NIDCR CToA, NIDCR will request specified study documentation and compliance with certain start-up activities prior to starting human subjects research. In addition, reports and oversight activities will be required as the study progresses.

   1. Documents Requested and Activities to be Completed Prior to Enrolling Human Subjects
      NIDCR will request that the recipient provide the following documents for NIDCR’s information and assessment, and participate in certain oversight activities, prior to enrolling any human subjects:

      • Institutional Review Board (IRB)-approved clinical research protocol, identified by protocol title, version number, and date, utilizing the appropriate NIDCR protocol template for an interventional or observational study
      • IRB-approved consent form, identified by version number, date, or both
      • For studies with devices, official documentation of the significant or non-significant risk determination by either the IRB or the U.S. Food and Drug Administration (FDA)
      • Plans for data and safety monitoring, which may include preparation of a quality management plan, specification of independent data and safety oversight, plans for external clinical site monitoring, etc. NIDCR will advise recipients regarding the appropriate oversight plan (see Section 2.B.1)
      • Study Accrual and Retention Plan
      • Meetings with NIDCR staff to determine readiness (as appropriate)
      • DSMB/CSOC meeting participation (as appropriate)

      NIDCR staff comments on documents will be forwarded to the recipient. The recipient must address all concerns raised by NIDCR staff. No funds may be drawn down from the payment system and no obligations may be made against federal funds for enrolling human subjects into a study until NIDCR notifies the recipient that any identified issues have been resolved and associated restrictions have been lifted.

   2. Quality Management and Clinical Site Monitoring
      For studies requiring additional oversight, NIDCR or its designee may perform clinical site monitoring to ensure compliance with the protocol, study standard operating procedures, and human subject protections. NIDCR reserves the right to perform site monitoring for any study. When appropriate, NIDCR may determine that submission of quality management reports in lieu of clinical site monitoring is sufficient. Any monitoring conducted by NIDCR does not replace the recipient institution and Principal Investigator’s (PI’s) responsibilities for monitoring and quality assurance.

   3. Information/Documents Requested for Ongoing Studies
      The recipient must notify NIDCR of all changes to the study protocol and/or major changes in the status of ongoing studies. Information provided to NIDCR must include an explanation of any changes, plans to address any issues, details of IRB notifications, and any responses from the IRB. NIDCR may provide input regarding the changes to the protocol or changes in study status. Information/documentation requested for ongoing studies may include, but are not limited to:

      • All amendments or changes to the protocol, identified by protocol title, version number, and date
      • All changes in informed consent documents, identified by version number, version date, or both, and dates for which informed consent documents are valid
      • Termination or temporary suspension of subject enrollment
      • Termination or temporary suspension of the study
      • Any change in IRB approval
      • Any other delays or issues that could affect the safety of enrolled subjects, the integrity of data for the study, and/or study feasibility. These delays or issues may be operational in nature.

      To remain up to date and apprised of NIDCR-supported clinical study activities and progress and to ensure that the International Council for Harmonisation (ICH) Guidelines for Good Clinical Practice (GCP) standards are followed while the study is ongoing, NIDCR may request recipients to provide reports and documentation of study status, safety, and quality at intervals determined by NIDCR. Examples of information that may be requested include:

      • Accrual and retention plans and ongoing reports
      • Disposition of clinical samples
      • Disposition of study product
      • Protocol deviations
      • Routine or ad-hoc data and safety monitoring reports and responses to oversight recommendations
      • DSMB/CSOC reports, Medical Monitor or ISM Oversight Reports, and responses to recommendations, as applicable
      • Responses to clinical site monitoring or quality management report findings

   4. Required Time-Sensitive Safety Reporting for Clinical Research Studies
      NIDCR reserves the right to require time-sensitive reporting (such as Serious Adverse Events, Unanticipated Problems, and other clinically significant events not classified as Unanticipated Problems). As described above, a data and safety monitoring plan should be developed prior to starting human subjects research activities that will describe expectations for prompt reporting to NIDCR.
      
      Clinical trials and other clinical studies funded by NIDCR must also follow current applicable regulations and guidance for safety reporting and reporting of unanticipated problems set forth by the Office for Human Research Protections (OHRP), the U.S. Food and Drug Administration, and the ICH Guidelines for GCP. Information on the required formats, notification time frames, and the agencies, organizations, and offices to be notified can be found using the following links:

      • Unanticipated Problem Reporting
      • Investigational New Drug Safety Reporting
      • Reporting Unanticipated Adverse Device Effects
      • NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules

      When safety-related events and unanticipated problems are reported according to these requirements, the recipient must also notify NIDCR, using the procedures specified in the clinical protocol.

   5. Requirements for Research Involving Investigational New Drug or Investigational Device Exemption

      Consistent with federal regulations, clinical research in humans involving the use of investigational therapeutics or other medical interventions (including licensed products for a purpose other than that for which they were licensed) must be performed under an FDA Investigational New Drug application (IND) or Investigational Device Exemption (IDE), unless an exception has been granted. The recipient must provide NIDCR with any written documentation concerning an IND or IDE application or risk status (e.g., final application status, IND-exempt status, significant or non-significant risk standing received from the IRB or FDA concerning devices, and other inquiries or comments related to the status, such as necessary preliminary testing or amendments).

      If a clinical study funded by NIDCR will be performed under an IND or IDE, the recipient must provide NIDCR with the name and institution/organization of the IND or IDE sponsor, the date the IND or IDE was filed with the FDA, the FDA IND or IDE number, copies of transmittal memos pertaining to the IND or IDE, all comments from the FDA, and the written responses to those comments.

      The FDA requires that the investigator wait at least 30 days from the FDA receipt of an initial IND or IDE application for the IND/IDE to be in effect before initiating a clinical study.

      The recipient must notify NIDCR if the FDA places the study on clinical hold and provide NIDCR any written comments from the FDA, written responses to the comments, and documentation in writing that the hold has been lifted. A recipient must follow all applicable regulations and FDA guidance regarding human subjects engagement and other aspects of the study when the study has been placed on a clinical hold by the FDA. Depending on the circumstances, NIDCR may place a human subjects restriction on the NOA.

3. NIDCR CToA Does Not Apply

When NIDCR determines that a study is not subject to the NIDCR CToA, the PI, in conjunction with the NIDCR Program Official, provides the safety and data quality oversight. This should be accomplished by implementing an internal quality assurance plan to assess the conduct of the study and integrity of the data. The recipient is responsible for ensuring compliance with all policies under the NIH GPS, any other award-specific terms and conditions, and all other applicable human subjects requirements. Per the NIH GPS, as the funding agency, NIDCR must be informed of any unanticipated problems (as set forth by the OHRP), serious or continuing noncompliance with human subjects regulations or IRB requirements or determinations, and any suspension or termination of IRB approval.

• Unanticipated Problem Reporting

Revised July 2025

Reference

1. NIH Office of Extramural Research website. Glossary: Clinical Research definition.