MARCH 18, 2008
__________________________________________________________________________
Policy
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 conduct of the study, and the availability of data in a timely manner . These guidelines replace the NIDCR Guide for Data and Safety Monitoring Boards released in November 2002.
Introduction
NIH policy stipulates that a system be in place for appropriate oversight and monitoring to ensure the safety of participants and the validity of the data in all NIH-sponsored or NIH-conducted clinical trials (http://grants.nih.gov/grants/guide/notice-files/not98-084.html). Data and safety monitoring is required for all types of clinical trials, including physiologic, toxicity, and dose-finding studies (Phase I); dose ranging studies (Phase II); efficacy, effectiveness and comparative trials (Phase III); and post-marketing studies (Phase IV). It includes all types of medical and non-medical intervention studies (e.g., behavioral, prevention, therapeutic diagnostic) trials. Monitoring should be commensurate with the study risks. This policy provides each 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 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html), released in June of 2000, stated that investigators must submit a monitoring plan for Phase I and Phase II clinical trials to the IC before the trial begins. Investigators are required to submit a description of a monitoring and implementation plan for all clinical trials to the funding Institute or Center (IC) as part of the research application prior to an award being made. The monitoring plan must include a general description of the mechanisms for reporting adverse events to the Institutional Review Board(s) (IRB), the Food and Drug Administration (FDA), and the National Institutes of Health (NIH). Oversight of the monitoring activity is the joint responsibility of the investigator(s) and the NIDCR.
Scope
This policy applies to all safety monitoring for any NIDCR-supported grant, cooperative agreement or contract that includes clinical research.
Background
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's clinical studies
Definitions
Clinical Research
Human subject research includes specimen collection, epidemiologic and behavioral studies, outcomes research, and health services research. Clinical research is research conducted with human subjects (or on material of human origin such as tissues, specimens, and cognitive phenomena) in which a researcher directly interacts with human subjects. It includes research on
- mechanisms of human disease,
- therapeutic interventions,
- clinical trials, and
- development of new technologies
It does not include in vitro studies using human tissues not linked to a living individual.
Clinical Trial
A prospective biomedical or behavioral research study of human subjects designed to answer specific questions about biomedical or behavioral interventions (drugs, treatments, devices, or new ways of using known drugs, treatments, or devices). Clinical trials are used to determine whether new biomedical or behavioral interventions are safe, efficacious, and effective.
http://grants.nih.gov/grants/glossary.htm#S
Formats for Monitoring
Data and Safety Monitoring Board
A Data and Safety Monitoring Board (DSMB) is an independent group of experts that advises NIDCR and 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 trial. DSMBs meet regularly and whenever any special need arises to review 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 trial may be based on any aspect of the trial it considers. A DSMB member's recommendation to terminate a trial 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 trials 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 trials with associated safety risk, including Phase I and Phase II trials.
Safety Monitoring Committee
A Safety Monitoring Committee (SMC) is an independent group of experts that advises NIDCR and the study investigators generally for Phase I and smaller Phase II trials. The primary responsibility of the SMC is to monitor participant safety. Roles and responsibilities are similar to those of a DSMB except interim evaluations of efficacy are not performed. Investigators and the NIDCR Program Official should consider having at least one member of the SMC serve as an Independent Safety Monitor (see below). The SMC must be able to convene on an ad hoc basis when immediate safety concerns arise. Its members may be from the investigator's institution or other participating sites but should not be directly involved with the trial or under the investigator's supervision. It may be sufficient for a SMC to rely on an ad hoc or study statistician to assist in interpreting the results, thereby obviating the need to have a statistician as a member.
Clinical Study Oversight Committee
A Clinical Study Oversight Committee (CSOC) is an independent group of experts that advises NIDCR and 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 reviewing and evaluating the accumulated study data, 2) review 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 physician with relevant expertise whose primary responsibility is to provide independent safety monitoring in a timely fashion. This is accomplished by review of adverse events, immediately after they occur, with follow-up through resolution or stabilization. The ISM evaluates individual and cumulative participant data when making recommendations regarding safety continuation of the study. An ISM could be the sole monitor for the study or may perform this role as a member of a DSMB or SMC. An ISM is appropriate as the sole independent safety monitor for small, early phase studies of short duration. DSMBs and SMCs 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.
Developing a Data and Safety Monitoring Plan
The NIDCR Medical Monitor will provide guidance on which format of monitoring oversight (DSMB, SMC,CSOC, ISM) will be implemented for the 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.
- SMC will oversee 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 for a DSMB or SMC for clinical trials.
The NIDCR Medical Monitor is a blinded, non-voting member of any safety oversight group. The NIDCR Medical Monitor will approve membership of the monitoring committees and the 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:
- composition of members;
- objectives;
- mechanism of reporting adverse events to members and IRBs, FDA and NIDCR;
- 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 makes the final decision with regard to the outcome of the monitoring committee's discussions and recommendations for the study/trial.
Implementation procedures for reporting adverse events to IRBs are provided in the NIH policy on "Guidance On Reporting Adverse Events To Institutional Review Boards For NIH-Supported Multicenter Clinical Trials" dated June11, 1999 (http://grants.nih.gov/grants/guide/notice-files/not99-107.html). While this policy applies specifically to DSMBs, applicability should be considered for 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 Medical Monitor. 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.