December 22, 2014
The National Institute of Dental and Craniofacial Research (NIDCR) has established the following system for the appropriate oversight and monitoring of the conduct of NIDCR-supported clinical research in order to ensure the safety of participants, the validity and integrity of the data, the appropriate conduct of the study, and the availability of data in a timely manner. These guidelines replace the NIDCR Policy for Data and Safety Monitoring of Clinical Research released September 26, 2014.
NIH policy stipulates that a system be in place for appropriate oversight and monitoring to ensure the safety of participants and the validity and integrity of the data in all NIH-supported or NIH-conducted clinical trials. Data and safety monitoring is required for all types of clinical trials, including physiologic, toxicity, and dose-finding studies (Phase I); studies seeking further safety data and preliminary evidence of efficacy (Phase II); efficacy, effectiveness and comparative trials (Phase III), etc. Monitoring should be commensurate with the study risks, size and complexity. This policy provides each Institute or Center (IC) with the flexibility to implement the requirement for data and safety monitoring as appropriate for its clinical research activities. Further guidance to this policy, released in June of 2000, stated that investigators must submit a general description of the data and safety monitoring plan for Phase I and Phase II clinical trials as part of the research application, prior to an award being made. Investigators are required to submit a detailed monitoring plan for Phase I and Phase II clinical trials to the IC before the trial begins. All monitoring plans must include a description of the mechanisms for reporting adverse events (AEs) and unanticipated problems (UPs) to the Institutional Review Board(s) (IRB), the National Institutes of Health (NIH), the Food and Drug Administration (FDA), and the Office of Human Research Protections (OHRP) as appropriate.
This policy applies to all data and safety monitoring for any NIDCR-supported grant, cooperative agreement or contract that includes clinical research.
NIDCR supports clinical research, interventional clinical trials and observational studies that vary in size and complexity. It is NIDCR's responsibility to ensure the appropriate oversight and monitoring of the conduct of all NIDCR clinical studies.
Defined in the PHS 398 Definitions
and the Grants Policy Statement Glossary
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. Excluded from this definition are in vitro studies that utilize human tissues that cannot be linked to a living individual. Patient-oriented research includes:
- mechanisms of human disease,
- therapeutic intervention,
- clinical trials, or
- development of new technologies.
- Epidemiological and behavioral studies.
- Outcomes research and health services research.
Studies falling under 45 CFR part 46.101(b) (4) (Exemption 4) are not considered clinical research by this definition.
A research study in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes.
Formats for Monitoring
According to the NIH policy, monitoring may be conducted in various ways or by various individuals or groups, depending on the size and scope of the research effort. NIDCR uses the following formats when studies require monitoring beyond that provided by the principal investigator:
Data and Safety Monitoring Board
A Data and Safety Monitoring Board (DSMB) is 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. DSMBs meet regularly and whenever any special need arises to evaluate study conduct and cumulative study data, and to recommend whether the study should continue without change, be modified, or be terminated. Recommendations to modify or terminate a study may be based on any aspect of the study it considers.
All DSMB members have the ability to review unmasked clinical trial data during the closed session of the DSMB meeting. During the introductory meeting of the DSMB, members will be made aware of their ability to request unmasked data at any time.
A DSMB's recommendation to terminate a study based on finding efficacy (i.e., early rejection of the null hypothesis concerning the primary endpoint) requires statistical adjustments for interim evaluations and thus requires a pre-specified plan for interim statistical analysis. Therefore, it is essential that the DSMB for such studies include a member with appropriate statistical expertise. All NIDCR-sponsored Phase III trials are subject to DSMB review. DSMB oversight should also be considered for other clinical studies with associated safety risk, including Phase I and Phase II trials. DSMBs are governed by a Charter that is reviewed at the organizational meeting and can be updated as the Board evolves.
Clinical Study Oversight Committee
A Clinical Study Oversight Committee (CSOC) is 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. The CSOC considers study-specific data as well as relevant background information about the disease, procedures and progress of the study.
Independent Safety Monitor
An Independent Safety Monitor (ISM) is 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. An ISM could be the sole independent monitor for the study or may perform this role as a member of a DSMB. An ISM is appropriate as the sole independent safety monitor for small, early phase studies of short duration. DSMBs should consider the need to designate one or more members as ISM(s). In the case of DSMBs, the ISM focus may be directed at serious adverse events rather than all adverse events.
NIDCR Medical Monitor
The NIDCR Medical Monitor (MM) 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 are studies that may include procedures that are considered greater than minimal risk (punch biopsy, additional x-rays, etc.), may be high profile for NIDCR, or involve a substantial investment on the part of the NIDCR. 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.
NIDCR Participation in Oversight Committee Meetings
The NIDCR Medical Monitor, the NIDCR Program Official (for Extramural studies) and Clinical Director (for Intramural studies) will be invited to attend the open sessions of the oversight committee meetings. They may give an introductory statement delineating their role at NIDCR and thanking the members of the oversight committee for their efforts on this committee. Other relevant NIDCR staff members may attend the open session (Office of Clinical Trials Operations and Management (OCTOM) representatives, health specialists, etc.). They will announce their presence and their role. No NIDCR staff members will attend the closed session of the oversight committee meeting. Program participants are not to be considered as members of the oversight committee.
Developing a Data and Safety Monitoring Plan
Based on study risk and complexity, the NIDCR Medical Monitor will make a determination of the appropriate format for data and safety monitoring (DSMB, CSOC, ISM, NIDCR MM) for a clinical study or trial. Generally, oversight will be designated as follows:
DSMB will oversee phase II/III, phase III and phase IV clinical trials where the primary outcome is safety and efficacy. DSMB may also be designated for certain complex clinical studies and phase I and II clinical trials where the primary outcome is safety.
- CSOC will oversee complex observational or clinical specimen studies not involving an intervention for human subject protections, study conduct, and unanticipated problems.
- ISM will oversee subject safety. This may be the only safety oversight for small clinical studies with invasive (non-drug/device) interventions. The ISM may also be a member of a DSMB for clinical trials.
- NIDCR MM will oversee studies that have been designated as needing additional oversight but not rising to the level of needing external oversight.
The NIDCR Medical Monitor is a non-voting member of every safety oversight group. The NIDCR Medical Monitor will approve membership of the monitoring committees and the appointment of an Independent Safety Monitor. This policy is flexible to allow for a data and safety monitoring plan to be developed with the level of monitoring commensurate with risk, primary outcome, and study objectives. The data and safety monitoring plan should include:
- identification of expertise needed for an oversight committee or an individual providing oversight;
- identification of study aspects to be evaluated including study conduct and subject accrual and retention;
- identification of specific interim and final data to be made available for evaluation;
- mechanism of reporting unanticipated problems, serious adverse events and adverse events to monitoring committee members and IRBs, FDA, NIDCR, and OHRP as appropriate;
- methods for reporting a safety committee meeting summary to the IRB and NIDCR; and
- frequency of meetings.
The data and safety monitoring plan may be documented in the form of a Charter or in the protocol, as appropriate.
The monitoring committees make recommendations to NIDCR and are independent from the study investigator(s). The NIDCR considers the monitoring committee’s discussions and recommendations and makes the final decision regarding continuation, modification, or termination of a study/trial. Implementation procedures for reporting adverse events to IRBs are provided in the NIH policy, "Guidance On Reporting Adverse Events To Institutional Review Boards For NIH-Supported Multicenter Clinical Trials" dated June 11, 1999 . While this policy applies specifically to DSMBs, it should be considered applicable to all monitoring formats.
Conflict of Interest
Individuals invited to serve on a safety oversight committee, as either a voting or non-voting member, will disclose any potential conflicts of interest, whether real or perceived, to the NIDCR. Conflict of interest can include financial interest, professional interest (in the sense of the study outcome benefiting the individual professionally), proprietary interest, and miscellaneous interest as described in the NIH Grants Policy and 45 CFR Part 94. Collaboratively NIDCR and the study leadership will make decisions regarding service by individuals with potential conflicts of interest or the appearance of conflicts of interest.