Clinical research is one of the most pressing and promising programmatic areas at the National Institute of Dental and Craniofacial Research (NIDCR). The institute recognizes that the nation’s progress against dental, oral and craniofacial diseases and disorders will be accelerated by rigorous clinical research studies whose outcomes contribute to knowledge and potentially to changing practice and improving care. To assure that the NIDCR is supporting high quality clinical research, the institute provides appropriate oversight and monitoring of the conduct of its clinical research portfolio, which includes observational studies that vary in size and complexity and interventional clinical trials. The NIDCR Clinical Terms of Award policy helps to ensure that all clinical research and clinical trials conducted under grants and cooperative agreements 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 NIDCR Clinical Terms of Award, which will be incorporated into the Notice of Grant Award (NGA) for grants and cooperative agreements that involve human subjects and meet the NIH definition of “clinical research.” Potential applicants are encouraged to contact appropriate NIDCR Program Officials or Office of Clinical Trial Operations and Management staff concerning this policy.
The Clinical Terms of Award outlined here are in addition to and not in lieu of other NIH policies. NIH policy requires certain information regarding research involving human subjects. These include instructions in the PHS 398 Grant Application for paper applications, the Supplemental Instructions for Preparing the Human Subjects Section of the Research Plan in the SF 424 R&R Grant Application Guide for electronic applications, and the PHS 2590 Non-Competing Grant Progress Report as well as NIDCR’s funding opportunity announcements (requests for proposals, requests for applications, and program announcements), the Department of Health and Human Services (DHHS) regulations (45 CFR 46), Public Health Service guidelines, DHHS grant administration regulations (45 CFR parts 74 and 92), and Office of Management and Budget administrative guidelines.
2. NIDCR Process Prior to Subject Enrollment for Any Clinical Research
One of the major responsibilities of an Institutional Review Board (IRB) is to assess the risks and benefits of proposed research. The IRB’s risk assessment and the size and complexity of the study are used by the NIDCR to determine the resources that will be needed to meet the Institute’s study oversight responsibilities. To assist the NIDCR in establishing a monitoring plan that is tailored to the risk and complexity of the study, the NIDCR Program Official will request that the awardee provide the following documents for Program information and assessment prior to any subject accrual or enrollment:
IRB-approved clinical research protocol identified by protocol title, version number and date, and including details of study design, proposed interventions, subject eligibility criteria and plans for assessing, managing and reporting adverse events and unanticipated problems [see Unanticipated Problems
Documentation of IRB approval
IRB approved consent form, identified by version number, date or both
Plans for data and safety monitoring (see Section 3 below).
NIDCR staff comments will be forwarded to the awardee within three weeks of receipt of the above package of information. 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 any research involving human subjects until the Program Official notifies the awardee that the identified issues have been resolved.
3. Safety and Monitoring
a. Institutional Review Board (IRB) Approval
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 clinical research 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 Program Official will request submission of the approval letters and consent forms from each reviewing IRB. For studies involving more than minimal risk to subjects or for complex studies, the Program Official will request documentation of approvals from IRB continuing reviews. These requests for documents 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.
The Clinical Terms of Award apply to grants and cooperative agreements throughout the course of the research, and the awardee may be asked to provide further study documentation to the NIDCR Program Official while the study is ongoing. To help ensure subject safety and data integrity, the awardee must provide the NIDCR Program Official with copies of documents related to all major changes in the status of ongoing protocols, including the following:
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 accrual
Termination or temporary suspension of the protocol
Any change in IRB approval and continuing reviews
Any changes in key clinical personnel conducting the study
Any other problems or issues that could affect the safety of enrolled subjects or the integrity of the primary endpoint of the clinical research or clinical trial.
Information provided to the Program Official must include an explanation of any changes, plans to address any issues, details of notification of the IRB and any responses from the IRB. If necessary, the Program Official will provide input regarding the changes to the protocol or changes in study status.
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 DNA Molecules.
b. Data and Safety Monitoring Requirements
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.”
NIDCR clinical research studies must be monitored for subject safety, protocol compliance and data integrity. The method and degree of monitoring required varies, depending on the potential risk for subjects and the complexity of the clinical study. Monitoring activities may range from data and safety monitoring implemented by the principal investigator to independent data and safety monitoring boards established by the NIDCR.
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)). For a clinical study 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 for Program assessment a plan for investigator-managed data and safety oversight.
For clinical research deemed to be more than minimal risk or for clinical research where the nature, size, complexity or importance of the study merits additional oversight, independent data and safety monitoring will usually be required. Such clinical 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. Independent monitoring can take a variety of forms. 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 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 committee charged with reviewing study data for subject safety and study conduct and progress, and providing recommendations to NIDCR with respect to study continuation, modification, and termination. For the majority of studies that require a DSMB, the NIDCR will select and appoint the board members. All phase III clinical trials must be reviewed by a DSMB; other trials may require DSMB oversight as well.
Safety Monitoring Committee (SMC) – a small group of independent experts who review study data primarily to monitor subject safety in Phase I or smaller Phase II trials.
Clinical Study Oversight Committee (CSOC) – an independent group of experts that assists NIDCR with oversight and monitoring of clinical studies, including behavioral interventions where nature, size, complexity, or programmatic importance of the study justifies additional oversight. The CSOC considers unanticipated problems, study conduct and progress, and provides recommendations to NIDCR with respect to study continuation, modification, and termination.
Independent Safety Monitor (ISM) – a physician or other appropriate expert who is independent of the study and available in real time to review and recommend appropriate action regarding adverse events and other safety issues.
Principal Investigator (PI) – the PI may provide the safety and data quality oversight of a minimal risk clinical study. This should be accomplished by implementing an internal quality assurance plan to assess the conduct of the study and integrity of data.
For each study, roles and responsibilities for oversight and monitoring will be defined and documented prior to subject enrollment. If a monitoring board or committee is organized, its charter or operating procedures (including a proposed meeting schedule and plan for review of adverse events), roster and curriculum vitae from all members will be approved by NIDCR before enrollment starts. When data and safety oversight and reporting responsibilities reside with the awardee, written summaries of all data and safety monitoring reviews will be provided to the NIDCR Program Official within 30 days of the review.
The awardee must develop and implement a quality management plan appropriate for the type of study being conducted to ensure human subject safety, quality and integrity of the data, and compliance with the protocol. The awardee must have standard operating procedures (SOPs) for quality management which describe this process. Upon the request of the NIDCR Program Official, the awardee must make the quality management plan and SOPs available for Program assessment.
For studies involving more than minimal risk to subjects or for complex studies, NIDCR or its designee will perform external clinical site monitoring to ensure compliance with the protocol, study SOPs and human subject protections. For minimal risk studies, NIDCR reserves the right to conduct site monitoring by NIDCR or its designee at any time, in cooperation with the awardee.
4. Investigational New Drug or Investigational Device Exemption Requirements
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 ever 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.
5. Required Time-Sensitive Notifications for Clinical Trials and Clinical Studies
Clinical trials and clinical studies funded by NIDCR must follow current applicable regulations and guidelines for safety reporting and reporting of unanticipated problems. Information on the required formats, notification time frames and the agencies, organizations and offices to be notified can be found using the following links:
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.
6. Study Status/Progress Reports and Documentation
In order 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:
Screening and accrual reports for each clinical site
IRB continuing review documentation annually or more frequently as required by IRB
Disposition of clinical samples
Disposition of study product
Protocol deviations and violations.
Revised 17 October 2011