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NIDA - Data and Safety Monitoring Board Standard Operating Procedures
V7, May 26, 2000
The Data and Safety Monitoring Board (DSMB) is charged with monitoring the accumulating data from a pharmacotherapeutic clinical trial sponsored and/or administered by NIDA to detect and report early evidence of prespecified or unanticipated benefit or harm to trial participants that may be attributable to one of the treatments under evaluation. The DSMB will conduct an independent, objective review of all accumulated data from both blinded and unblinded clinical trials in such a manner as to maximize benefit to the trial participants and to the research effort. Based on this review the DSMB shall advise NIDA on the appropriateness of continuing clinical trials as designed. To effect its responsibilities, the DSMB will:
- Monitor and evaluate safety of the subjects as prespecified in the interim monitoring plan of a protocol and adhere to all appropriate human subject requirements;
- Monitor and evaluate the efficacy of the treatments being tested as specified in the interim monitoring plan of a protocol;
- Monitor for early-unanticipated therapeutic results;
- Monitor the performance of the clinical trial; and
- Make recommendations to NIDA to: continue, amend, improve, terminate, plan additional and future clinical trials, recommend administrative adjustments, assess the appropriateness of the statistical assumptions, provide advice on an ad hoc basis to NIDA for monitoring ongoing protocols, and ensure and preserve clinical trial integrity based on the interim analysis for safety and efficacy.
Meeting Schedule
The Board will meet on a quarterly basis each year. The annual meeting will be held in person in April. The remaining quarterly meetings (i.e., July, October and January) may be assembled as an in person meeting or conducted via teleconference or mail correspondence. The annual meeting will be convened in the Washington, D.C. area.
Information
Clinical trials must adhere to the following guidelines and information can be found at the following addresses:
Human subject protection, informed consent, and IRB review:
http://grants.nih.gov/grants/oprr/library_human.htm
Information Sheets guidance for institutional Review Boards and Clinical Investigators:
http://www.fda.gov/oc/oha/IRB/toc.html
Universally accepted principles of Good Clinical Practices:
http://www.access.gpo.gov/nara/cfr/waisidx_99/21cfr312_99.html
NIH initiative to reduce regulatory burden:
http://grants.nih.gov/grants/policy/regulatoryburden/index.htm
Clinical safety data management: definitions and standards for expedited reporting (adverse events):
http://www.fda.gov/cder/guidance/iche3.pdf
Inquires
General inquiries related to this notice may be directed to:
J. Mojsiak
Clinical Medical Branch
Division of Treatment Research and Development, NIDA
301-443-9804
FAX 301-443-2599
E-mail: jm200p@nih.gov
Reporting Responsibilities
After each DSMB meeting, the Chairperson will issue a written report describing all recommendations including additional safety steps. This report will be submitted directly to the Director, DTR&D. The FDA adverse drug experience reporting timelines will be utilized as timelines to disseminate feedback from the DSMB to the principal investigator and sub investigators. That is, three days for acute circumstances and ten days for nonacute circumstances. The DSMB's Chairperson through the Director, DTR&D will issue these directives in writing.
Scope of the Data
The DSMB will monitor all cocaine infusion clinical trials, all clinical trials longer than six months in duration, all clinical trials stipulating, a priori, an interim analysis and all data from clinical trials co-sponsored with a pharmaceutical company where efficacy analyses are conducted. In general, the data to be reviewed will include screening data, baseline data, efficacy data, safety data, quality assurance data, accrual status including projections, total number of case report forms that are in-house, total number of case report forms that have been quality assured, times to milestones, FDA reports including annual IND reports, safety data from other sources for each clinical trial reviewed, and any other data that will help in the assessment of the effectiveness of the clinical trial. For multi-center studies, all the data will be stratified by centers. Cross-study analysis of variables of interest prespecified by the DSMB or on an ad hoc basis will be prepared when requested by the DSMB.
All the adverse drug experiences regardless of severity will be reported by the principal investigator(s) to the DSMB.
In addition, each principal investigator will present an overall progress statement for each quarterly meeting. This written statement will be very brief. This statement should contain an assurance that each principal investigator considered the clinical trial's progress and that there is no evidence of toxicity or safety issues, which should be addressed by the DSMB.
Data Reporting for Ongoing Studies
DSMB members will receive the statistical report to be reviewed by overnight mail three weeks in advance of scheduled meetings. The data in the report will include all data reported to the data analysis center up to and including 30 days in advance of scheduled meetings. Any deaths and serious and unexpected adverse drug experiences that occur in this 30 day interval will be reported by the principal investigator and sub-investigators directly to the DSMB during the open session. For ad hoc meetings, due to the time constraint the board may be naive to the data under review.
Individuals involved in the conduct of the clinical trial (i.e., clinical and medical monitors, statisticians, programmers, data coordinators, clinical investigators and their study staff, patients) will be excluded from the closed session of the annual and ad hoc meetings and will not be apprised of the interim analysis.
Stopping Rules
Initially, the DSMB will adopt the stopping rules based on safety evaluation, dosage modification, and toxicity outlined in the protocol(s) of the clinical trial(s) under review. As the data matures, for specific variables of interest, the DSMB can institute its own monitoring boundaries and stopping rules. For specific variables of interest, the DSMB will prespecify confidence intervals or statistical differences to be detected at the end of each closed session for the next review. The DSMB may define stopping rules that are more rigorous than those in the protocol should safety considerations and data so warrant. The Board Chairperson will make the final decision. The sequence of events that will determine if a clinical trial is to be terminated are: a) evaluation of individual stopping rules; b) evaluations of several individuals as aggregate data; c) determination of the likelihood that the adverse events are drug related; d) if the severity of study related adverse experience(s) is judged extreme, then the study will be terminated and e) emergence of unexpected serious adverse experience(s) not specified in the stopping rules. (The medical monitor, NIDA and IRB will be informed by telephone within 24 hours of a death and serious or unexpected adverse drug reaction and written follow-up will be sent within 7 days).
Release of Interim Data
Release of results of interim analyses and deliberations of the DSMB should be carefully controlled in order to avoid the possible introduction of bias. Release of interim results could lead to premature termination of a trial, to impaired accrual, to individual unblinding, or to variations in toxicity or endpoint identification or reporting.
All requests for results of the interim analyses must be in writing and submitted to the Director, DTR&D for consideration and consultation with the DSMB.
The recommendation will include consideration of the impact on volunteers in the trial and to the scientific integrity of the ongoing trial; the reason for the request; the extent of critical endpoint data and/or blinding requested; the constraints on disseminations beyond the original requestor; the amount of work involved on part of the data management center in responding to the request and the priority of this work within the current workload.
The written response from the DSMB to the requestor will a) list the summary tables or analyses results or b) state the rationale for denying the request.
Operations
- A formal self-review will be conducted on an annual basis to make changes to the operating procedures of the DSMB. The self-review will be on the agenda of the closed session during the annual meeting.
- In order to assure and maintain scientific integrity of the DSMB, the issues of avoidance of conflict of interest, confidentiality and independence are primary.
- Conflict of Interest
In order to maintain a legitimate "state of equipoise" regarding the pharmacotherapies being studied, it is necessary to recuse those members with vested interest in a specific treatment or in a sponsor (i.e., drug firm) from participating in any discussions or decision making (i.e., voting).
- Confidentiality
Upon accepting the appointment to the DSMB, each member will be required to sign a NIDA confidentiality form.
- Independence
Membership to the DSMB will be independent of both investigators and drug firms (i.e., it is ethically imperative to dissociate the treating physician and the sponsor from the accruing data).
- Each DSMB member is entitled to one vote per issue. At each DSMB meeting five members are required to constitute a quorum. If no decision can be reached, the DSMB's Chairperson will resolve the issue.
Reporting Adverse Events to IRBs for Multicenter Trials
Investigators submitting a protocol for IRB review shall identify the DSMB that will be reviewing interim results and include a brief description of the monitoring plan as well as procedures for transmitting the DSMB's summary reports to the IRB. The DSMB will prepare clinical summary reports at regular and defined intervals. Investigators must submit a written summary of DSMB periodic reviews to their IRB. For multicenter clinical trials, each investigator should submit to the local IRB the DSMB's written summary report of adverse events at other trial sites.
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