The November 2001 GCRC Guidelines state that clinical trials conducted on the GCRC must have a data and safety monitoring plan. Effective November 2002, the guidelines were modified to state that all protocols conducted on the GCRC must have a GAC-approved data and safety monitoring plan. Please refer to the decision tree below.
The plan is to be submitted with the GCRC protocol application for review and approval by the GCRC Advisory Committee (GAC). The specifics of the plan will depend on the nature, size, complexity, and risk of the research study. The DSMP needs to address the nature of the safety monitoring and who will be conducting that monitoring. It may be reasonable for a single individual to perform the monitoring in a small trial with low (Level I) risk while a local independent or an external data and safety monitoring board (DSMB) may be required for more complex trials.
In an effort to streamline the application process, a data and safety monitoring plan template has been prepared by the UCI GCRC Research Subject Advocate program office for use by our investigators (GCRCApplication.AppendixA.07.15.04.doc). It is not a requirement of the UCI GCRC to use this form; it simply has been provided a tool.
The minimum required elements of a data and safety monitoring plan are as follows:
- Monitoring the progress of trials and the safety of participant.
Description of these monitoring processes should include:
- Name(s) and role(s) of those responsible for monitoring the trial.
- Describe how often the data are examined in the course of trial conduct.
- Identify the parameters at which the monitors are looking.
- Ensure that procedures are in place to insure adequate feedback of information to researchers and medical decision-makers, so that trials involving excessive risk in relation to anticipated benefits are terminated appropriately.
- Describe the oversight or supervisory role of institutional committees, if appropriate.
- Address procedures that the institution has for coordinating multi-center trials, if applicable
In relation to who actually has responsibility for monitoring a trial, the DSMP should explain how the institution averts or manages any conflict of interest implicit in having a principal investigator (or a direct report of the PI) as the only monitor of trials that pose significant risk to study subjects.
- Plan(s) for assuring compliance with requirements regarding the reporting of adverse events (AEs).
The plan should describe the processes and oversight in place for assuring that AE reporting requirements (including unanticipated and annual AE reporting) are actually met. For multi-center trials, the plan should outline procedures by which a central reporting entity is established that collects and reports AEs to all necessary destinations, including co-investigators at participating institutions.
The requirements for proper reporting of AEs on clinical trials are complex. Possible destinations for AE reports include the institutional IRB, the sponsor (if an IND is involved), the FDA (for AEs from commercially available agents), and, if gene transfer is involved, the NIH Office of Biotechnology Activities (OBA). Note that current federal regulations almost always require reporting of AEs in all categories of clinical trials to the institutional IRB, in addition to other relevant parties.
- Quantitative system(s) used to grade (severity) of each adverse event as well as its attribution (relatedness) to the investigational agent/treatment.
Standardized AE reporting facilitates the accumulation of new and important safety information. The use of a standard table for interpreting and grading abnormal signs, symptoms, and laboratory parameters is recommended. If the protocol has no defined grading system, or if the AE is not described in the existing grading system, the following guidelines should be used to qualify severity.
0 No adverse event or within normal limits or not clinically significant
1 Mild AE, did not require treatment
2 Moderate AE, resolved with treatment
3 Severe AE, resulted in inability to carry on normal activities and required professional medical attention
4 Life threatening or disabling AE
5 Fatal AE
- Plan(s) for assuring data accuracy and protocol compliance.
Investigators should describe what quality-control procedures are in place for assuring data accuracy and completeness in studies.
If an IND is in place, quality-control procedures are generally stipulated by the IND sponsor and may be simply referenced or summarized in the DSMP. For studies not done under an IND, the investigator should describe whatever procedures are in place to assure data integrity and protocol adherence. Appropriate procedures may range, for example, from regular data verification and protocol compliance checks performed by a data manager and a principal investigator, to a formal external data-audit process by an agent external to the institution.
- Plan(s) for safety review.
Investigators should describe what quality-control procedures are in place for assuring data accuracy and completeness in studies.
- Plan for safety review (by whom and at what frequency)
The content will include additional information as determined by the GAC as appropriate for the protocol. Examples may include:
Safety review questions:
- What was the reason for dropouts?
- Are AEs too frequent or severe for protocol to continue?
Enrollment numbers and protocol violations:
- Did all enrolled patients meet entry criteria?
Plan for ongoing review of results (if appropriate):
- No risk is justified if the hypothesis has been disproved.
Decision Tree for Data and Safety Monitoring
The National Advisory Research Resources Council (NARRC) recommends that “research subject safety issues need to be clearly thought out and defined,” and that “investigators may enhance safety by periodically reviewing the protocol.”
Aside from being recommended by the NARRC, periodic safety reviews are a required element of each and every Data and Safety Monitoring Plan. The frequency of said safety reviews is determined by the risk level of the research protocol taking into account both the study procedures and the subject population in which the study procedures are to be performed.
In an effort to streamline the application process, a data and safety monitoring report template has been prepared by the UCI GCRC Research Subject Advocate program office for use by our investigators (insert link). It is not a requirement of the UCI GCRC to use this form; it simply has been provided a tool.
The minimum required elements of an interim or final data and safety monitoring report are as follows:
- Changes to protocol
- Amendments to the protocol
- Investigator/key personnel changes
- Changes to the consent document and communications to participants regarding changes
- Cumulative adverse event summary
- Review and analysis of adverse events
- A summary of any other safety issues
- Monitoring the progress of trials
- Narrative summary of interim or final data analyses
The summary of interim or final data analyses shall address study hypotheses and specific aims.
- Protocol adherence
- Protocol violations
- Protocol deviations
- Recruitment and retention summaries
- Enrollment numbers
- Screening failures
- Withdrawals (provide summary of reason(s) for withdrawal)
- Dropouts (provide summary of reason(s) for dropouts)
- Deaths (provide summary of circumstances of each subject death)
- Summary report or minutes of DSMB meetings (when applicable)
http://grants.nih.gov/grants/guide/notice-files/not98-084.html
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html
http://www.ncrr.nih.gov/clinical/gcrcpatientsafety20010622.asp
http://www.ncrr.nih.gov/clinical/crguide2001/guidenov2001.pdf
http://www.ncrr.nih.gov/clinical/crguide2001/datasafemonplan112002.pdf
http://www.ncrr.nih.gov/clinical/gcrcpatientsafety20010622.asp#VII
http://www.ncrr.nih.gov/clinical/crguide2001/guidenov2001.pdf
http://www.ncrr.nih.gov/clinical/crguide2001/datasafemonplan112002.pdf
http://www.ncrr.nih.gov/clinical/gcrcpatientsafety20010622.asp
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