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Data and Safety Monitoring

Data and Safety Monitoring. Laurie Shaker-Irwin, Ph.D., M.S. Research Subject Advocate Assistant Professor of Medicine Office of Research Participant Advocacy (ORPA) UCLA General Clinical Research Center. Goals.

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Data and Safety Monitoring

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  1. Data and Safety Monitoring Laurie Shaker-Irwin, Ph.D., M.S. Research Subject Advocate Assistant Professor of Medicine Office of Research Participant Advocacy (ORPA) UCLA General Clinical Research Center OHRPP October 2010

  2. Goals • Understand the importance of data and safety monitoring in all research studies involving humans • Be able to identify the contents of a data and safety monitoring plan and selection of monitors • Know that safety monitoring is contingent upon the type and complexity of the research study and enrollment rates OHRPP October 2010

  3. “Teen Dies Undergoing Gene Therapy” • Dose-finding gene transfer study of ornithine transcarbamylase deficiency • Attenuated adenovirus vector • Fever shortly after gene infusion • Liver failure after 1 day • Multisystem organ failure and brain death after 4 days, despite aggressive measures (Washington Post 1999) OHRPP October 2010

  4. Safety Quality Integrity Trust OHRPP October 2010

  5. Current Events in Clinical Research • Data call into question HIV study results (WSJ 10/09) • Doctor rebuked over research (LAT 01/10) ; Lancet retracts study tying vaccine to autism (WSJ 02/10) • Doctor is accused of faking painkiller studies (LAT 01/10) • Violations at brain lab may have wide fallout (LAT 07/10) • U.S. Apologizes for Syphilis Tests in Guatemala (NYT 10/10) OHRPP October 2010

  6. Definition of Data and Safety Monitoring (DSM) • Systematic review of the data and adverse events at regular intervals to assess the ongoing safety of the participants and the integrity of the overall study • Data and Safety Monitoring methods are usually detailed in a specific Data and Safety Monitoring Plan (DSMP) OHRPP October 2010

  7. Fundamental Principles of Data Monitoring • Safeguard the interest of study participants • Preserve the integrity and credibility of the study • Ensure that definitive and reliable results be available in a timely manner to the medical community and to the public Ellenber g S, Fleming T, DeMets D. Data Monitoring Committees in Clinical Trials John Wiley & Sons, Ltd. 2002 OHRPP October 2010

  8. Regulations • NIH Guidelines • Federal Regulations 45 CFR 46.111(a)(6) • FDA Guidelines • IRB Review OHRPP October 2010

  9. Important Common Elements of DSMPs • Description of the collection, review and reporting mechanisms for adverse events and safety information to the study monitors, IRB, FDA, sponsor (NIH, industry), and other applicable offices, agencies • Description of any setpoints/guidance for modifying or stopping the study • Description of the quality assurance efforts OHRPP October 2010

  10. Important Study Considerations for Development of a DSMP • Risk to Participants • Type and Complexity of Study • Other Factors OHRPP October 2010

  11. Types of Risk • Physical • Psychological • Social • Economic OHRPP October 2010

  12. Likelihood of Risk • Probable • Improbable • Theoretical OHRPP October 2010

  13. Type and Complexity of Study • Intensity of the intervention (e.g. type of agent, dose escalation, early phase studies) • Vulnerability of the population (e.g. age, cognitive function, disease condition, healthy volunteers, pregnant women) OHRPP October 2010

  14. Other Factors Related to DSMP Preparation • Blinded • Placebo-controlled • Multi-center • New science • Investigator IND • Investigator experience • DSM oversight by external entities OHRPP October 2010

  15. Nuts and Bolts of the DSMP • Deciding on the Monitoring Body • Selection of Monitor(s) • Content of Monitoring • Frequency of Monitoring • Decision-Making Criteria/Guidelines • Reporting Mechanisms OHRPP October 2010

  16. Sample DSMP • “An independent DSMB will be established to monitor the course of the clinical study. The responsibilities of the board will be to review, control, and assess the adverse events and other safety data and to give advice when considered necessary regarding the management of the trial and the trial protocol, always trying to ensure the safety and well-being of the study patients and the trial integrity” OHRPP October 2010

  17. Sample DSMP (continued) • The members of the DSMB will be experts who are independent of the sponsor and the CRO. The procedures and responsibilities for the collection, analysis, and review of the data by the DSMB as well as communication and documentation of their opinions and recommendations will be defined in the DSMB charter which will be agreed upon and written before the trial starts”. OHRPP October 2010

  18. DSMB Responsibilities • Evaluate research protocol and monitoring plans • Regularly review data • Make recommendations to sponsor, IRB, and investigators regarding the continuation, modification or conclusion of the trial. • Maintain confidentiality of the data OHRPP October 2010

  19. Biostatistical Considerations • WHAT: Primary vs. Secondary endpoint decisions • WHEN: Short-term vs. long-term treatment effects determines when to analyze the data • HOW: Subgroup analysis, where certain groups have different responses than others (e.g. by gender or a specific risk factor) • WHAT ELSE? Available external information from other research. OHRPP October 2010

  20. JUPITER Trial 2008 • Stopped after 1.9 years of follow-up; rosuvastatin significantly reduced the primary end point (disease and death from cardiovascular outcomes) by 44%, compared with placebo. There was a 55% reduction in nonfatal MI, a 48% reduction in the risk of nonfatal stroke and a 47% reduction in the risk of MI/stroke/CV death OHRPP October 2010

  21. JUPITER Trial (continued) “Nine of the 14 authors have financial ties to the sponsor and the principal investigator has personal conflict of interest as a co-holder of the patent for the CRP test. The chair of the DSMB, which made the recommendation to stop the trial for efficacy, also comes in for criticism on this front, with others saying he has been and still is involved in many other industry-sponsored lipid-lowering trials, raising issues of conflicts of interest.” OHRPP October 2010

  22. ACCORD - 2008 • ACCORD DSMB stated that a medical treatment strategy to intensively lower blood sugar below current guidelines increased the risk of death compared to standard blood sugar lowering treatment in type 2 diabetes patients at high risk for cardiovascular disease. Result: Transition everyone over to standard treatment OHRPP October 2010

  23. Testosterone 2010 • Clinical trial of testosterone found a higher rate of adverse cardiovascular events, such as heart attacks and elevated blood pressure, in a group of older men receiving testosterone gel compared to those receiving placebo. Due to these events, the treatment phase of the trial was stopped, however evaluation of participants continues OHRPP October 2010

  24. Communicating with Participants about DSMB Decisions • Maintain confidentiality until it is absolutely necessary to disclose to the public • Notify all participants as quickly as possible and document notification • Follow-up with hardcopy notice of changes to study, if applicable • Ensure that all methods used in communicating study information have been reviewed by the IRB. OHRPP October 2010

  25. Goals of Quality Assurance • Accrual Rates and Recruitment Sources • Eligibility Criteria • Informed Consents • Accuracy of Data • Completeness of Data • Confidentiality of Data OHRPP October 2010

  26. Clinical Research Problems and Events • Investigational drug research requires an effective system for collecting accurate and timely data on unanticipated problems and adverse events. OHRPP October 2010

  27. Events in Data and Safety Monitoring: Adverse Events, Incidents, Unanticipated Problems • Protection and safety of study subjects • Greater understanding of overall safety profile of the study • Recognition of dose-related toxicities • Appropriate modification of study protocols • Improvements in study design and/or procedures • Adherence to regulatory requirements OHRPP October 2010

  28. Event Follow-up and Reporting Requirements • Recognize events • Record all details of events • Evaluate in context of study as to relationship and context • Report per policy to: data and safety monitors, IRB, campus departments, FDA, and sponsors OHRPP October 2010

  29. Some Problems Observed with Event Reporting • Inaccurate/inadequate or missing source documents (medical records) • Delegation of event identification and review to unqualified personnel • Insufficient follow up of events to determine resolution • Events that are not reported to the IRB/other agencies in a timely fashion OHRPP October 2010

  30. Problems Observed with Event Reporting (continued) • Description is not sufficient • Less serious aspects are described and more serious aspects are omitted • Missing concomitant drugs • Data on reports do not match data on source documents or case report forms OHRPP October 2010

  31. Remember….. Knowing is not enough, we must apply. Willing is not enough, we must do J.W. Goethe (c) January 2009

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