NIDCR Clinical Terms of Award

1. Introduction

The National Institute of Dental and Craniofacial Research (NIDCR) Clinical Terms of Award (CToA) policy applies to all grants and cooperative agreements conducting human subjects research that have been determined by NIDCR to need additional oversight (as defined in Section 2). The 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

The NIDCR clinical research portfolio includes interventional clinical trials, observational studies, and studies involving analysis of existing data or specimens. The level of oversight for each study varies depending on the risk to human subjects and the complexity of the study. The NIDCR CToA policy helps 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.

Recipients must comply with the CToA policy, which will be incorporated into the Notice of Award (NoA) and applies throughout the course of the research. For studies subject to the NIDCR CToA policy, NIDCR will request specified study documentation that is not included or fully developed in the application, and compliance with certain start-up activities prior to starting human subjects research. In addition, to ensure that standards of Good Clinical Practice (GCP) are followed while the study is ongoing, NIDCR may request further study documentation and compliance with oversight activities.

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

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

• NIDCR funding opportunity announcements (funding opportunity announcements (requests for proposals, requests for applications, and program announcements) may include additional FOA-specific instructions and/or guidelines)
• NIH Grants Policy Statement
• NIH Forms and Applications for Research Grants
• DHHS grant administration regulations (45 CFR parts 74 and 92)
• Office of Management and Budget Uniform Administrative Requirements for federal awards.

Potential applicants are encouraged to contact NIDCR with questions concerning this policy.

2. Human Subjects Research Subject to NIDCR CToA

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. All studies determined by NIDCR to need additional oversight are subject to the NIDCR CToA in addition to the terms within the NIH Grants Policy Statement.

A. Types of Additional Oversight

NIDCR additional 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 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 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.
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.

B. CToA Documentation and Activities

For studies subject to the NIDCR CToA policy, 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 information and assessment, and participate in certain oversight activities, prior to any subject enrollment:

   • 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
   • 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 investigators regarding the appropriate oversight plan (see Section 2A).
   • 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.

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 take the place of monitoring and quality assurance responsibilities of the recipient institution and Principal Investigator.

3. Information/Documents Requested for Ongoing Studies

   The recipient must notify NIDCR of all 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. Changes in the status of ongoing studies include:

   • 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 problems or issues that could affect the safety of enrolled subjects or the integrity of data for the study.

   To stay apprised of NIDCR-supported clinical study activities and progress, NIDCR may request that the recipient provide reports and documentation of study status, safety, and quality, at intervals agreed upon by NIDCR and the recipient. Examples of information that may be requested include:

   • Screening, enrollment, and retention reports for each clinical site
   • 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

   Clinical trials and other clinical studies funded by NIDCR must follow current applicable regulations and guidelines for safety reporting and reporting of unanticipated problems set forth by the Office for Human Research Protections (OHRP), the Food and Drug Administration, and the International Council for Harmonisation (ICH) Guidelines for Good Clinical Practice (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
   • IND 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 should also notify NIDCR, using the procedures specified in the clinical protocol.

   NIDCR reserves the right to require additional time-sensitive reporting (such as Serious Adverse Events and Clinically Significant events not classified as Unanticipated Problems).

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

   Consistent with Federal regulations, clinical research involving the use in humans of investigational therapeutics or other medical interventions (including licensed products for a purpose other than that for which they were licensed) under a research protocol must be performed under an FDA Investigational New Drug application (IND) or Investigational Device Exemption (IDE). Exceptions must be granted in writing by the FDA.

   If a clinical trial funded by NIDCR will be performed under an IND or IDE, the recipient must provide NIDCR the name and institution of the IND or IDE sponsor, the date the IND or IDE was filed with FDA, the FDA IND or IDE number, copies of transmittal memos 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 trial.

   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. The recipient may not use grant or cooperative agreement funds to enroll new subjects in a clinical study during a clinical hold.

6. NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules

   Refer to the NIH Guidelines for expectations regarding research involving Recombinant or Synthetic Nucleic Acid Molecules.

3. Human Subjects Research Not Subject to NIDCR CToA

When NIDCR determines that a study does not require additional oversight, the Principal Investigator (PI) 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 data. The recipient is responsible for ensuring compliance with all policies under the NIH Grants Policy Statement and Terms of Award and all other applicable human subjects requirements.

Revised [30 July 2019]

Effective [01 January 2020]

References

1. NIH Office of Extramural Research website Glossary & Acronym List Clinical Research definition