The NIDCR Clinical Terms of Award (CToA) policy applies to all grants and cooperative agreements conducting human subjects research. This includes studies that will enroll human subjects to collect new data and studies that use previously collected data or specimens that can still be linked to living individuals. 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 National Institute of Dental and Craniofacial Research (NIDCR) clinical research portfolio includes interventional clinical trials, observational studies, and studies involving secondary analysis of existing data or specimens. These trials and studies vary in the risk to human subjects and in the complexity of the study. NIDCR has oversight responsibilities for all human subjects research supported by the Institute. The NIDCR Clinical Terms of Award (CToA) policy helps to ensure that all human subjects studies supported by NIDCR are well designed, conducted with rigor, and monitored commensurate with risk and complexity, and that the Institute is kept informed of study progress through reporting.
Awardees must comply with the CToA policy, which will be incorporated into the Notice of Grant Award (NGA). The policy applies throughout the course of the research. Prior to starting human subjects research, the awardee will submit study documentation requested by the NIDCR Program Official under the CToA. To ensure that standards of Good Clinical Practice (GCP) are followed while the study is ongoing, the NIDCR Program Official may request further study documentation. Potential applicants are encouraged to contact appropriate NIDCR Program Officials with questions concerning this policy.
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 (requests for proposals, requests for applications, and program announcements)
- 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.
2. CToA Documentation
a. Documents Requested for Studies Enrolling Human Subjects
To assist the NIDCR in determining a study oversight plan tailored to the risk and complexity of a study, the NIDCR Program Official will request that the awardee provide the following documents for Program information and assessment prior to any subject enrollment:
- Institutional Review Board (IRB)-approved clinical research protocol identified by protocol title, version number and date, with all the required elements included in the NIDCR’s protocol template for an interventional or observational study
- Documentation of IRB approval (see Section 3a below)
- 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 3b below).
NIDCR staff comments will be forwarded to the awardee within three weeks of receipt of documents. The awardee must address all study design, operational and logistical issues, and safety, regulatory, ethical, and conflict of interest 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 the Program Official notifies the awardee that the identified issues have been resolved.
b. Documents Requested for Studies Using Previously Collected Data/Specimens
To assist NIDCR with its oversight responsibilities, the NIDCR Program Official will request that the awardee provide the following documents for Program information and assessment:
- IRB-approved protocol or IRB application with a complete description of the study plan
- Documentation of IRB approval (For secondary analysis of existing data/specimens, the investigator/IRB will assess whether the currently proposed research is compatible with what subjects agreed to in the original study’s consent document.)
- Plans for protection of human subjects and study quality management.
c. Documents Requested for Ongoing Studies
The awardee must notify the NIDCR Program Official of all major changes in the status of ongoing studies. Information provided to the Program Official must include an explanation of any changes, plans to address any issues, details of IRB notifications and any responses from the IRB. The Program Official 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, the Program Official may request that the awardee provide reports and documentation of study status, at intervals agreed upon by the Program Official and the awardee. Examples of information that may be requested include:
- IRB continuing review documentation, annually or more frequently as required by IRB
- Screening, enrollment, and retention reports for each clinical site
- Disposition of clinical samples
- Disposition of study product
- Protocol deviations.
d. 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 Conference on 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 (See Appendix M-I-C-4).
When safety-related events and unanticipated problems are reported according to these requirements, the awardee should also notify NIDCR, using the procedures specified in the clinical protocol.
e. 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, vaccines, or other medical interventions (including licensed products and devices for a purpose other than that for which they were licensed) under a research protocol must be performed under a Food and Drug Administration (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 awardee 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 awardee 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 awardee may not use grant or cooperative agreement funds to enroll new subjects in a clinical study during a clinical hold.
f. Requirements for Research Involving Recombinant or Synthetic Nucleic Acid Molecules
If a clinical protocol has been reviewed by an institutional biosafety committee (IBC) or the NIH Recombinant DNA Advisory Committee (RAC), the awardee must provide information about the initial and ongoing review and approval, if any. See the NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules.
3. Oversight of NIDCR Human Subjects Studies
NIDCR considers the Institutional Review Board (IRB) risk assessment and the complexity of a study when determining the resources that will be needed to meet the Institute’s study oversight responsibilities.
a. Institutional Review Board (IRB) Approval
One of the major responsibilities of an IRB is to assess the risks and benefits of proposed research. A risk to subjects is minimal when the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests (45 CFR Part 46.102(i)).
Documentation of IRB approval provides assurance to NIDCR that a study has been reviewed according to the criteria set forth in 45CFR46.111. At the request of the NIDCR Program Official, the awardee must submit a copy of the current IRB approval and current IRB-approved consent form for each discrete human subjects study contained within a grant. If more than one institution is involved in the research (e.g., a multicenter clinical trial or study, or a clinical site with more than one IRB), the PI will provide approval letters and consent forms from each reviewing IRB. The IRB documents provided to the Program Official are in addition to the Office of Human Research Protections (OHRP) federal-wide assurance (FWA) number for the institution or site and the IRB approval date that are provided to the NIDCR Grants Management Official as a requirement for grant award.
b. Data and Safety Monitoring Requirements
At NIDCR, study oversight may range from data and safety monitoring implemented by the principal investigator to independent data and safety monitoring boards established by the NIDCR.
For human subjects research that poses minimal risk to subjects and does not demand independent monitoring based on study complexity, the NIDCR Program Official will request that the awardee submit a plan for investigator-managed data and safety oversight.
For human subjects research deemed to be more than minimal risk or for research where the complexity of the study merits additional oversight, independent data and safety monitoring may be required. Such research may include clinical trials of investigational drugs, devices, or biologics; clinical trials of licensed products; clinical trials of surgical interventions including dental restorative and periodontal procedures; clinical trials of behavioral interventions; and certain non-interventional clinical research studies such as observational clinical studies, complex specimen collection studies or epidemiologic studies. NIH Policy for Data and Safety Monitoring [NOT-98-084] states, “each institute should have a system for oversight and monitoring of the conduct and integrity of clinical trials to ensure the safety of subjects and the validity and integrity of the data for all NIH-supported or conducted clinical trials.” Independent monitoring can take a variety of forms. Most Phase III clinical trials must be reviewed by an independent Data and Safety Monitoring Board (DSMB); other studies may require DSMB oversight as well. [See the NIDCR Policy for Data and Safety Monitoring of Clinical Research.]
Based on both study risk and complexity, the NIDCR Medical Monitor will provide guidance on the appropriate level of data and safety monitoring, which may include any of the following:
- Data and Safety Monitoring Board (DSMB)—an independent group of experts that makes recommendations to NIDCR, and through NIDCR to the study investigators. The primary responsibilities of the DSMB are to 1) periodically review and evaluate the accumulated study data for participant safety, study conduct and progress, and, when appropriate, efficacy, and 2) make recommendations to the NIDCR concerning the continuation, modification, or termination of the study.
- Clinical Study Oversight Committee (CSOC)—an independent group of experts that makes recommendations to NIDCR, and through NIDCR to the study investigators on clinical studies not involving an intervention. Such clinical research studies may be complex, involve risk or vulnerable populations, and may be observational, specimen collection, epidemiology, or surveillance studies. The responsibilities of the CSOC are to 1) monitor human subject safety by evaluating the accumulated study data, 2) evaluate study conduct and progress, and 3) make recommendations to NIDCR concerning the continuation, modification, or termination of the study.
- Independent Safety Monitor (ISM)—a qualified clinician with relevant expertise whose primary responsibility is to provide independent safety monitoring in a timely fashion. This is accomplished by evaluation of adverse events, immediately after they occur, with follow-up through resolution or stabilization. The ISM evaluates individual and cumulative participant safety data when making recommendations regarding continuation of the study.
- NIDCR Medical Monitor—The NIDCR Medical Monitor oversight process is appropriate for studies that are deemed as needing additional oversight by the NIDCR Medical Monitor but not requiring the intensity of the other monitoring models listed previously. These may be complex studies or those that include procedures that may be considered greater than minimal risk (punch biopsy, research x-rays, etc.). Generally the PI will submit a report to the NIDCR Medical Monitor every 6 months. This report will include data regarding enrollment and retention, unanticipated problems and protocol deviations, disposition of biospecimens, outcome measures and other relevant parameters.
- Principal Investigator (PI)—For those minimal risk studies not deemed as needing additional oversight, the PI may provide 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.
c. Clinical Site Monitoring
For studies involving more than minimal risk to subjects or for complex studies, NIDCR or its designee may perform clinical site monitoring to ensure compliance with the protocol, study SOPs and human subject protections. NIDCR reserves the right to perform site monitoring for any study.
Revised 01 October 2015