ࡱ> y bjbj 7{{zL>&&&8^B&j"(F$C"i$i$i$i$i$i$i$=lnHiuuuHiiM!M!M!u"iM!u"iM!M!.jaHng c@ii0jc|o&ongongW|M!dWWWHiHi 6WWWjuuuuoWWWWWWWWW :  DATA AND SAFETY MONITORING BOARD (DSMB) GUIDANCE FOR UNIVERSITY OF ALBERTA SPONSORED PI-INITIATED STUDIES I. INTRODUCTION Data and safety monitoring is required for all clinical research studies. An independent Data and Safety Monitoring Board (DSMB) is required for sponsored PI-Initiated clinical trials determined to be "high-risk" by the independent review conducted through the QMCR office (see Appendix C). These trials involve interventions that pose moderate to high potential risk to study participants. Per ICH Good Clinical Practice Guidelines, a Data and Safety Monitoring Board (DSMB) is defined as An independent data monitoring committee that may be established by the sponsor to assess at intervals the progress of a clinical trial, the safety data, and the critical efficacy endpoints, and to recommend to the sponsor whether to continue, modify, or stop a trial. A DSMB structure will be established (see Appendix B) and agreed upon by QMCR and the Health Research Ethics Board (HREB) (Appendix B) to review applicable clinical research studies, ensuring patient safety both by evaluating adverse events and by performing interim analyses of safety and/or efficacy. DSMB findings and recommendations for these PI-Initiated trials are to be reported to the study PI, the HREB, Health Canada (if applicable) and QMCR. DSMB RESPONSIBILITIES Prior to study initiation, DSMB members will review study protocols, informed consents, Data and Safety Monitoring Plans and other relevant documents as needed (case report forms, manual of procedures, etc.). During the study, DSMB members will review all study protocol amendments. PI-Initiated clinical trials being monitored by the DSMB will undergo periodic review of accumulating safety, endpoint and other study data (participant recruitment, retention and compliance, data quality and timeliness, risk vs. benefit). IIA) Depending on the nature of the study, it is suggested that the responsibilities of the DSMB include on e or more of the following: To monitor and evaluate the safety of subjects as predetermined in the protocols monitoring plan, while adhering to all applicable human subject protection guidelines and legislation To monitor for early unanticipated treatment adverse events, and to assess any changes to the benefit-to-risk ratio To monitor and assess the efficacy of treatments being tested To monitor the progress of the study, including assessment of data quality, recruitment and retention To make recommendations to terminate, amend (i.e. terminate one study arm), continue or improve the trial ) (see section IIC below) IIB) There are other functions that the DSMB may serve depending on the nature of the study. Examples of these have been included below as detailed by the DAMOCLES Study Group: assess data quality, including completeness (and by so doing encourage collection of high quality data) monitor recruitment figures and losses to follow-up monitor compliance with the protocol by participants and investigators monitor organization and implementation of trial protocol (the DSMB should only perform this role in the absence of other trial oversight committees) monitor evidence for treatment differences in the main efficacy outcome measures monitor evidence for treatment harm (eg, toxicity data, SAEs, deaths) decide whether to recommend that the trial continues to recruit participants or whether recruitment should be terminated either for everyone or for some treatment groups and/or some participant subgroups suggest additional data analyses advise on protocol modifications suggested by investigators or sponsors (eg, to inclusion criteria, trial endpoints, or sample size) monitor planned sample size assumptions monitor continuing appropriateness of patient information monitor compliance with previous DMC recommendations consider the ethical implications of any recommendations made by the DSMB assess the impact and relevance of external evidence IIC) The following decisions and/or recommendations will be open to the DSMB: No action needed, trial continues as planned. Early stopping due, for example, to clear benefit or harm of a treatment, futility, or external evidence. Stopping recruitment within a subgroup. Extending recruitment (based on actual control arm response rates being different to predicted rather than on emerging differences) or extending follow-up. Stopping a single arm of a multi-arm trial. Sanctioning and/or proposing protocol changes Frequency of DSMB reviews may be annual, semi-annual, quarterly or after a pre-defined number of subjects have been enrolled and followed. III. STRUCTURE OF COMMITTEE The DSMB may be appointed independently by the Investigator, or the Investigator may contact QMCR for assistance in identifying members. Membership should be determined prior to the enrollment of the first study subject. The Board should include at least one member with expertise in the clinical area being studied. If an efficacy assessment is needed, a statistical monitoring plan will be required to ensure the validity of the study. In this case a statistician should also be a member of the DSMB. A bioethicist or expert in trial methodology are examples of additional members who may also be required in certain studies. Qualifications of DSMB members should include: Expertise in the clinical area being studied Experience in clinical trials Statistical knowledge Independence from study team No conflict of interest The Board should have 3-5 members in total (should always be an odd number); members may be appointed from other divisions, as well as other hospitals. DSMB members must be completely independent of the trials being monitored (no financial, scientific or other conflicts of interest). DSMB members will complete a Conflict of Interest Form (see Appendix A) that will be updated annually, unless a conflict of interest occurs during the year, in which case it will be updated at the next DSMB meeting. IV. MEETING FORMAT AND CONDUCT Open sessions may be conducted that would include, in addition to DSMB members, the study investigator, key study staff and the study statistician. These sessions would precede closed sessions, and would be used for purposes of discussing trial conduct and progress, subject accrual, compliance, retention, and challenges encountered. Closed sessions will include only DSMB members, who will review the cumulative trial data either completely unblinded) or partially unblinded (Study Group A vs. Study Group B). The DSMB will be furnished with relevant information by the study PI to make decisions. All data information and study related discussions will remain completely confidential. The frequency of meetings will depend upon the specific trial and its statistical plan; however meetings should occur at least yearly. Minutes from meetings will be prepared and circulated to the DSMB membership. INTERIM REPORTS FOR DSMB REVIEW Contents of interim reports from the PI to the DSMB will be determined by the DSMB membership, with suggested input from the PI and her/his study team. Interim reports, generally prepared by the study statistician and other study personnel, will be distributed to the DSMB at least 10 working days prior to the next scheduled DSMB meeting. VI. DSMB REPORTS Within 48 hours of a DSMB meeting, a written summary report should be provided by the DSMB to the Investigator, with a copy to the HREB and QMCR. The report should indicate whether the study should continue, be modified to protect subject safety or be terminated. The DSMB will refrain from releasing any information in its report that could potentially compromise the study unless such a release is required for subject safety. The following guidelines should be observed: Individual centre results will not be released Individual patient results or treatment assignments will not be released Study results will not be communicated The magnitude of treatment efficacy differences will not be released The DSMB will complete a brief report documenting its decisions, and the rationale behind its decisions. Appendix A: Conflict of Interest Form for DSMB Members DSMB for protocol # _____________________ entitled: ____________________________________________________________________________________________________________________________________________________ Principal Investigator: ________________________________ I hereby certify that: I have not been within the past 12 months a part-time, full-time, paid or unpaid employee of, and I am not presently negotiating for employment under any organizations that are: (a) involved in the study under review; (b) whose products or services will be used or tested in the study under review, or (c) whose products or services could reasonably be affected by any outcome of the study under review. I am not an officer, director, consultant, member, owner or trustee of such organizations. I, and my spouse and dependent children, do not have any financial interests or assets that exceed $10,000 in any such organizations I have not been involved in any litigation involving such organizations. I do not have any intellectual property or other proprietary interest in any of the products involved in the study under review, or in any products in direct competition with the products under review. PLEASE SELECT ONE: All of the above certifications are accurate I will disclose all exceptions to the DSMB at the beginning of the next DSMB meeting. Such exceptions will be documented in the minutes. The DSMB shall discuss how to handle such exceptions. I will promptly notify the DSMB chair if any of the above certifications are no longer accurate during the term of my membership on the DSMB. I am aware of my responsibilities for maintaining confidentiality of any non-public information I receive as a result of my membership on the DSMB. ________________________ _________________________ __________________ Member Name Member signature Date Appendix B: Sample DSMB Agreement Data Safety Monitoring Board (DSMB) for the study entitled: ____________________________________________________________________________________________________________________________________________________ Protocol #:_______________ Principal Investigator: ____________________________ This Data Safety Monitoring Board (DSMB) will consist of an independent group of three/five members, supported as required by a biostatistician, including at least one member who is recognized as an experts in the conduct of area of study clinical trials. All DSMB members are completely independent of the trials being monitored (no financial, scientific or other conflicts of interest). The chairman of the DSMB (name) will receive interim reports (including information on safety/adverse events) from the Principal Investigator (PI) of the study, and the DSMB will formally review such reports. The primary function of the DSMB is to monitor the safety of the study at annual/semi-annual/quarterly intervals. This will include an analysis of all serious adverse events with particular emphasis on ____________________________________________________________________________________________________________________________________________________ Depending on the nature of the study, it is suggested that the responsibilities of the DSMB include on e or more of the following: Monitor and evaluate the safety of subjects as predetermined in the protocols monitoring plan, while adhering to all applicable human subject protection guidelines Monitor for early unanticipated treatment adverse events, and to assess any changes to the benefit-to-risk ratio Monitor and assess the efficacy of treatments being tested Monitor the progress of the study, including assessment of data quality, recruitment and retention Make recommendations to terminate, amend (i.e. terminate one study arm), continue or improve the trial (see section IIC of policy manual) There are other functions that the DSMB may serve depending on the nature of the study. Examples of these have been included below as detailed by the DAMOCLES Study Group: Assess data quality, including completeness Monitor recruitment figures and losses to follow-up Monitor compliance with the protocol by participants and investigators Monitor organization and implementation of trial protocol (the DSMB should only perform this role in the absence of other trial oversight committees) Monitor evidence for treatment differences in the main efficacy outcome measures Suggest additional data analyses Advise on protocol modifications suggested by investigators or sponsors (eg, to inclusion criteria, trial endpoints, or sample size) Monitor planned sample size assumptions Monitor continuing appropriateness of patient information Monitor compliance with previous DSMB recommendations Consider the ethical implications of any recommendations made by the DSMB Assess the impact and relevance of external evidence The following decisions and/or recommendations will be open to the DSMB: No action needed, trial continues as planned. Early stopping due, for example, to clear benefit or harm of a treatment, futility, or external evidence. Stopping recruitment within a subgroup. Extending recruitment (based on actual control arm response rates being different to predicted rather than on emerging differences) or extending follow-up. Stopping a single arm of a multi-arm trial. Sanctioning and/or proposing protocol changes The chairman, at any time, may consult with members of the DSMB and bring to the attention of the Health Research Ethics Board (HREB) any concerns that arise. The DSMB may request the attendance of relevant parties at an open session meeting so as to provide a forum for general study update, an opportunity to respond questions, and to provide any other information required by the DSMB. Minutes of the DSMB meetings will be taken; and any concerns or recommendations communicated to the PI, HREB and QMCR within 10 working days of a scheduled meeting. DSMB Members: Appendix C: PI-Initiated Study Risk Assessment Worksheet Use this table to assess the risks of the studys procedures, experimental treatments, and population vulnerability to derive an estimate of the overall risk of the study. For each factor please enter the appropriate score and add up. Please note, this assessment will simultaneously undergo a binding independent review through QMCR. Once this form is completed please return it to Lori Anderson at QMCR. Study Title: PI:  ENTER SCORE I. Experimental Treatment Low Risk No experimental treatment in study 1 point FORMTEXT       Moderate Risk Treatment effects documented from studies with similar and/or different populations and/or settings. No serious adverse events expected. Specific plans to monitor AEs detailed in DSMP 2 points High Risk Experimental treatment. (e.g. investigational drug, device, or biologic) 4 points II. Procedures, Measurements, and Data Collection Methods Low Risk Minimally invasive with low degree of emotional and/or physical discomfort. Probability of adverse events is low. Severity (magnitude) of adverse events is low. (Procedure may be rated low risk if probability of AE is moderate to high so long as the severity is low, as in the case of a bruise from phlebotomy) (e.g. procedures that meet IRB criteria for expedited review) 1 point FORMTEXT       Moderate Risk Moderate degree of emotional and/or physical discomfort. Probability of adverse events is low. Severity of adverse events is moderate to high. (e.g. PET scan, lumbar puncture, arterial lines) 2 points High Risk Moderate to high degree of emotional and/or physical discomfort. Probability of adverse events is moderate to high. Severity of adverse events is high. (e.g. heart muscle biopsy, insulin infusion) 4 points III. Decision-making Capability Non-vulnerable Adult who 1) demonstrates decision-making capacity and 2) demonstrates no perception of undue influence or coercion to participate. 1 point  FORMTEXT       Vulnerable Any minor. Adult who 1) demonstrates limitations in decision-making capacity and/or 2) is prone to perception of undue influence or coercion to participate.  2 points Review completed by: ____________________ Signature: ________________________ Date: ________TOTAL:   FORMTEXT      The Level of Overall Risk of the Study is: Low: 3 or 4 points Moderate: 5 points High: 6 to 10 points Monitoring Requirements: 3-5 points: may be monitored by the PI who provides an annual review of data and safety information. 6 points: may be monitored by the PI who provides a quarterly review of data and safety information. 7-10 points: must have an independent monitor or DSMB, who conducts a regular review of data and safety information. Are there any concerns regarding scientific validity or the probability of obtaining reasonable results? Yes No REFERENCES Data and Safety Monitoring Board Guidelines  Division of Microbiology and Infectious Diseases, National Institutes of Health ( HYPERLINK http://www.niaid.nih.gov/dmid/clinresearch/dsm.htm http://www.niaid.nih.gov/dmid/clinresearch/dsm.htm) Data Safety Monitoring Board Charter University of North Carolina at Chapel Hill School of Medicine NINDS Guidelines for Data and Safety Monitoring in Clinical Trials National Institute of Neurological Disorders and Stroke ( HYPERLINK http://www.ninds.nih.gov/about_ninds/clusters/data_safety_Monitoring.htm http://www.ninds.nih.gov/about_ninds/clusters/data_safety_Monitoring.htm) Guidelines for establishing a Data Safety Monitoring Plan Massachusetts General Hospital, 02/20/2004 Institutional Safety and Safety Monitoring Plan St. Jude Childrens Research Hospital Cancer Centre, 08/17/01 National Eye Institute Guidelines for Data and Safety Monitoring of Clinical Trials. National Eye Institute ( HYPERLINK http://www.nei.nih.gov/funding/policy/policy6.htm http://www.nei.nih.gov/funding/policy/policy6.htm) Data and Safety Monitoring Board Standard Operating Procedures. 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?2?3?A?F?O?^?b????????????ɻɭɭɭɭɟɟɟɎɟɭn\n#hvMhvM>*CJOJQJ^JaJ#hvMh_Y>*CJOJQJ^JaJh;#CJOJQJ^JaJ hThvMCJOJQJ^JaJhvMCJOJQJ^JaJho CJOJQJ^JaJh4CJOJQJ^JaJ hTh_YCJOJQJ^JaJ)hZkh2Q;B*CJOJQJ^JaJph hZkh2Q;CJOJQJ^JaJ#???????/@0@@@ArA{AAAAɻlZK<.hTCJOJQJ^JaJh;#5CJOJQJ^JaJhtG5CJOJQJ^JaJ#h^QhT5CJOJQJ^JaJ&h^QhT5>*CJOJQJ^JaJ h^QhTCJOJQJ^JaJ&h::hT5>*CJOJQJ^JaJ#hThT5CJOJQJ^JaJh;#haCJOJQJ^JaJhcjCJOJQJ^JaJhK4CJOJQJ^JaJhe]CJOJQJ^JaJhjh_YOJQJ^J????????0@AAAAAAAANkd$$IfTx0$4 xaT d$Ifgd :$IfgdgdTgdTAAAAAAAAAAAAABBxBBBBBBϡ~~iQi/jh::hTCJOJQJU^JaJ)jh::hTCJOJQJU^JaJ h@hTCJOJQJ^JaJ#h::hT5CJOJQJ^JaJ h::hTCJOJQJ^JaJhTCJOJQJ^JaJhT5CJOJQJ^JaJ#h(hT5CJOJQJ^JaJh;#CJOJQJ^JaJ h}qhTCJOJQJ^JaJABBB0B2BxBzBBB d$Ifgd;kdj$$IfTx$$4 xaT :$Ifgd BBBB%D1DDDDDEEEEFFFFFFFFFNHZH3I?IaIbIIII J J J"J$Jпппvп^/j4h::hTCJOJQJU^JaJ#h@hT5CJOJQJ^JaJ/j}h::hTCJOJQJU^JaJhtGCJOJQJ^JaJ h@hTCJOJQJ^JaJ h::hTCJOJQJ^JaJ)jh::hTCJOJQJU^JaJ4jh::hTCJOJQJU^JaJmHnHu$BBBBB%D&D/D0D{m{b{bb :$Ifgd$:$Ifa$gd d$Ifgdwkd>$$IfTx4\6$r`4 xaf4T0D1D2DADBD[DDDDD{p{gp{pp $Ifgd :$Ifgd d$Ifgdwkd$$IfTx4\6$r 4 xaf4T DDDDDD{p4{;kd!$$IfTx$$4 xaT :$Ifgd d$Ifgdwkd$$IfTx4\6$r 4 xaf4TDDDFFFFFFGGNHpb$:$Ifa$gdwkd$$IfTx4\6$r`4 xaf4T d$Ifgd :$Ifgd NHOHXHYHZH[HjHkH3I4I=I>Ipwkd$$IfTx4\6$r 4 xaf4T :$Ifgd d$Ifgd >I?I@IaIbIcI{p4{;kd$$IfTx$$4 xaT :$Ifgd d$Ifgdwkd9$$IfTx4\6$r 4 xaf4TcIrIsIIIJJJJJ J2J :$Ifgd d$Ifgd$:$Ifa$gd $J.J0J4JJKKKKKLRLZLzLLLLLLLLLLL Mп{iXп@пi/j~h::hTCJOJQJU^JaJ h}qhTCJOJQJ^JaJ#h}qhT5CJOJQJ^JaJ#hqhT5CJOJQJ^JaJhT5CJOJQJ^JaJ#h@hT5CJOJQJ^JaJ h@hTCJOJQJ^JaJ h::hTCJOJQJ^JaJ)jh::hTCJOJQJU^JaJ4jh::hTCJOJQJU^JaJmHnHu2J4J6JTJVJKKKK{p{p{pp :$Ifgd d$Ifgdwkd$$IfTx4\6$r`4 xaf4TKKKKTLVLXL{pp{p :$Ifgd d$IfgdwkdK$$IfTx4\6$r 4 xaf4TXLZLzLLLLLL d$Ifgd$:$Ifa$gd :$IfgdNkd$$IfTx0$4 xaTLLMMNhNNDOPreT7$8$H$^`gdT n^`ngdT `@ ^@ `gdTgdTvkd$$IfTx!\6$r4 xaT MMM\MlMMMM NhNqNNNOODOzOOPP PPPPw`w`L&hT5B*CJOJQJ^JaJph,h@hT5B*CJOJQJ^JaJph)h@hTB*CJOJQJ^JaJph-htG5@B*CJOJQJ\^JaJph3h@hT5@B*CJOJQJ\^JaJphhtGCJOJQJ^JaJ#h}qhT5CJOJQJ^JaJ#h}qhT>*CJOJQJ^JaJ h}qhTCJOJQJ^JaJPPPP2P4PRRvRwRSSSTpTqTSUTU01>?mngdu'0$a$gdu'0PPP0P4P2Q4QQQQ R RRRJSKSLSSSSSTTUUUPUQUUUUqeO+j hu'0hu'0OJQJU^JaJhOJQJ^JaJ+j hu'0hu'0OJQJU^JaJ hu'0hu'00JOJQJ^JaJ+j hu'0hu'0OJQJU^JaJ%jhu'0hu'0OJQJU^JaJhu'0hu'0OJQJ^JaJhu'05>*ϴ"'0'05>*ϴ;#5>*ϴUUU-.4;<wxִ|k[Ek+jhChu'0OJQJU^JaJhChu'06OJQJ^JaJ hChu'00JOJQJ^JaJ+jhChu'0OJQJU^JaJ%jhChu'0OJQJU^JaJhChu'0OJQJ^JaJhu'0hu'0OJQJ^JaJ hu'0hu'00JOJQJ^JaJU%jhu'0hu'0OJQJU^JaJ+j hu'0hu'0OJQJU^JaJhttp://www.nida.nih.gov/funding/DSMB_SOP.html) Data Monitoring Committees in Practice. Applied Clinical Trials, 03/01/04. ( HYPERLINK http://www.actmagazine.com/appliedclinicaltrials/content/printContentPopup.jsp?id=87247 http://www.actmagazine.com/appliedclinicaltrials/content/printContentPopup.jsp?id=87247) The Role of Data Monitoring Committees and their impact on Clinical Research Associate Responsibilities. SoCRA SOURCE February 2003 Guidelines for NIH Intramural Investigators and Institutional Review Boards on Data and Safety Monitoring. The Office of Human Subjects Research, National Institutes of Health ( HYPERLINK http://ohsr.od.nih.gov/info/rinfo_18.php3 http://ohsr.od.nih.gov/info/rinfo_18.php3) DAMOCLES Study group. A proposed charter for clinical trial data monitoring committees: helping them do their job well: The Lancet; 365: 2005. Slutsky AS, Lavery JV. Data Safety and Monitoring Boards. 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