BACKGROUND PURPOSE 9/24/2009 DATA AND SAFETY MONITORING

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1 DATA AND SAFETY MONITORING September 2009 Joey Casanova, BBA, CIP Human Subject Research Office SECTION 1 BACKGROUND PURPOSE Data and safety monitoring is the process for reviewing accumulated outcome data from an ongoing research study to protect the safety of research participants and the validity and scientific merit of the trial A written Data and Safety Monitoring i Plan (DSMP) formalizes the monitoring process and assigns responsibility for monitoring study-specific events on a pre-defined schedule All research proposals should include a DSMP, especially those that present greater than minimal risk to subjects 1

2 PRINCIPLES OF MONITORING DATA AND SAFETY All clinical trials require monitoring Monitoring should be commensurate with risks Determine safe and effective conduct Recommend conclusion of the trial when significant benefits or risks have developed Recommend conclusion of the trial when trial is unlikely to be concluded successfully Monitoring should be commensurate with size and complexity SAMPLE POLICY: NATIONAL INSTITUTES OF HEALTH Each Institute and Center should have a system for the appropriate oversight and monitoring of: 1. Safety of participants 2. Validity and integrity of the data Establishment of Data Safety Monitoring Boards (DSMBs) is required for multi-site clinical trials involving interventions that entail potential risk to the participants Data and safety monitoring functions and their oversight are distinct from the requirement for study review and approval by an IRB KEY ELEMENTS OF A DATA AND SAFETY MONITORING PLAN 1. Type of data or events to be captured 2. Who will be responsible for monitoring the data collected 3. Frequency of assessments/analysis of data or events captured by the monitoring plan 4. Time frame for reporting unanticipated problems, adverse events, protocol deviations and protocol violations 5. Definition of specific or stopping rules 6. Procedures and time frames for communicating outcomes of monitoring reviews to the IRB, study sponsor and/or indicated entities (e.g. NIH, FDA) 7. Plans to monitor adherence to the IRB-approved protocol and assure the validity and integrity of data. 2

3 DESCRIBE PROCEDURES FOR Frequency of reports and reporting of concerns to the IRB, monitoring body and, if appropriate, the FDA. Routine review and reporting of adverse events to the monitoring body Specific triggers for ad hoc review as well as the process for ad hoc review. Interim analysis, along with its schedule Stopping rules, especially with high risk interventions or populations SECTION 2 ESSENTIAL ELEMENTS OF DATA & SAFETY MONITORING MONITOR THE PROGRESS OF A TRIAL AND THE SAFETY OF PARTICIPANTS 1. Who actually monitors the trials? 2. How often are the data examined? 3. What do the monitors look for? 4. What are the procedures to appropriately terminate the study? 5. What is the oversight role of institutional committees? 6. What procedures are in place for coordinating multi-center trials? 3

4 ESTABLISH PLAN FOR REPORTING OF ADVERSE EVENTS Describe processes for assuring that AE reporting requirements are actually met Outline procedures by which a central reporting entity is established to collect and report AEs to all necessary destinations, including co-investigators at participating institutions ESTABLISH A PLAN FOR REPORTING SUSPENSIONS APPROPRIATELY IRB Decision FDA communications Warning letters Notice of Initiation of Disqualification Proceedings and Opportunity to Explain Notice of Opportunity for Hearing Notice of Disqualification Consent Agreements Clinical hold letters that pertain to breaches of either GMP, GCP or other major issues requiring significant changes in the protocol ASSURE DATA ACCURACY AND PROTOCOL COMPLIANCE Quality-control procedures for assuring data accuracy and completeness IND in place Generally stipulated by IND sponsor No IND in place Investigator should describe procedures in place to assure data integrity it and protocol adherence May range from regular data verification and protocol compliance checks performed by a data manager and PI to formal external data-audit process by an agent external to the institution 4

5 SECTION 3 APPROPRIATE MONITORING METHODS/ENTITIES Independent Investigator Independent Monitoring Review Expert Review Committee Data and Safety Monitoring Board INVESTIGATOR REVIEW Appropriate when: Study involves a small number of subjects Study is conducted only at one site Range of possible study events that could have an important impact on the risks and benefits to research participants i t is narrow Continuous monitoring of events by the investigator and prompt reporting of unanticipated problems to the IRB, FDA and/or others as appropriate The issue of possible conflicts of interest must be taken into account 5

6 INDEPENDENT EXPERT REVIEW Appropriate when IRB determines that objective monitoring is necessary or when someone outside of the study team should be unblinded A physician or other appropriate expert who is independent of the study and available in real time to review and recommend appropriate action regarding adverse events and other safety issues The name and qualifications of the expert should be stated to the IRB at the time of review INDEPENDENT MONITORING COMMITTEE Appropriate for centers or institutions that conduct a high volume of clinical trials Small group of independent investigators and biostatisticians who review data from a particular study Local example: Sylvester Comprehensive Cancer Center DATA AND SAFETY MONITORING BOARD (DSMB) Appropriate for studies involving: Large numbers of subjects Blinded study treatment groups Multiple clinical sites High risk interventions Controlled trials with mortality or major morbidity as a primary or secondary endpoint 6

7 DATA AND SAFETY MONITORING BOARD (DSMB) Responsibilities and Functions Collect and analyze data during a study Examine safety and efficacy data on an explicitly defined schedule Monitor for adverse events Interpret data and make findings that may warrant modification or termination of the trial or notification of subjects Review the general progress and conduct of the study SECTION 4 WHEN IS AN INDEPENDENT DSMB NEEDED? PRACTICAL REASONS FOR A DSMB Trial is intended to provide definitive information about effectiveness and/or safety of a medical or bio-behavioral intervention Prior data suggest the intervention has the potential ti to induce potentially ti unacceptable toxicity it Trial is evaluating mortality or another major endpoint Ethically important to stop trial early if the primary question addressed has been definitively answered 7

8 YOU MAY EXPECT A DSMB TO BE REQUIRED WHEN Phase III studies (with the exception of low-risk behavioral and nutritional studies) May still be requested for low-risk studies if the studies are exceptionally large, long term, and/or involve vulnerable subjects. Some Phase II clinical trials which are multicenter and randomized Some Phase II studies which are high risk WHEN IS A DSMB NOT NEEDED? Single-center open-label Phase I and II clinical trials A multicenter, high-risk Phase I clinical trial may not require a DSMB if there are very clear rules for stopping the trial For example: a classic open-label dose escalation trial with clear and objective criteria for halting the dose escalation when unacceptable side effects are observed Clinical trials that are expected to accrue too quickly to allow for a DSMB to be constituted and complete data and safety monitoring FACTORS TO CONSIDER Type of Trial Risk Level Size and Duration of the Trial Use of Blinded Interventions Vulnerable Populations Scientific Integrity 8

9 SECTION 5 UM-JMH POLICIES FACTORS CONSIDERED BY THE IRB Large study populations Multiple study sites Highly toxic therapies or dangerous procedures High expected rates of morbidity or mortality High chance of early termination of the study for reasons of safety, futility or efficacy DSMB MEMBERSHIP Experts in the scientific field of study Independent from the study May be either internal or external to the institution No professional or financial interest in the outcome of the study 9

10 DSMB DETERMINATIONS Monitoring of data throughout the duration of the study to determine if continuation of the study is appropriate scientifically and ethically DSMB determinations shall be considered as recommendations to the IRB DSMB determinations must be reported by the Principal Investigator to the IRB The Principal Investigator is responsible for oversight of all aspects of the trial, including safety. The inclusion of other reviewers or safety monitoring mechanisms does not relieve the investigator s responsibility. 10