ADDING VALUE TO A STUDY WITH A SAFETY MONITORING GROUP: DATA SAFETY MONITORING BOARDS AND CLINICAL WE’LL EARN YOUR APPROVAL. EVENTS COMMITTEES Safety Oversight Data Safety Management Board In 2006, the FDA released the “Guidance for Clinical Trial Sponsors- Establishment and Operation of Clinical Trial Data Monitoring Committees.” It provides guidelines that specify the relationship between DSMBs and IRBs, defines the circumstances under which they should be required, membership criteria, how they should operate, their responsibilities, and their obligations to maintain patient confidentiality. While the establishment of DSMBs was an important step in the evolution of safety oversight, as of yet, there are no formal regulations set forth that govern their structure and operation and that are legally enforceable. As a remedial effort, it has been a proactive action on the part of sponsors and investigators to include safety management boards in their study plans. In the guidance document, the FDA defines a DSMB as “a group of individuals with pertinent experience that reviews on a regular basis accumulating data from one or more ongoing trials. The DSMB advises the sponsor regarding the continuing safety of trial subjects and those yet to be recruited to the trial, as well as the continuing validity and scientific merit of the trial.” Furthermore, it is a group of experts external to the trial and independent of the sponsor whose principal mandate is to protect patient safety. The primary responsibilities of the DSMB are to periodically review and evaluate the accumulated study data for subject safety, study conduct and progress, and if appropriate, efficacy. 1 www.imarcresearch.com WE’LL EARN YOUR APPROVAL. In addition, the DSMB should: • Define safety and related parameters to be monitored, frequency of committee monitoring reviews, methods for review • Establish criteria for making recommendations to the sponsor • Review adverse event reports • Be a resource for the investigator for consultation regarding adverse study events • Research newly published findings and consider the impact on the safety of the study • Preserve confidentiality of the data • Make recommendations to the sponsor and investigators regarding the continuation, modification, or termination of the trial • Provide written reports to the IRB that summarize oversight activities, recommendations and subject safety concerns Other names for a DSMB can include Data Monitoring Committee (DMC), Independent Data-monitoring Committee, Data Monitoring Board, Treatment Effects Monitoring Committee (TEMC) and Data and Safety Monitoring Committee (DSMC). 2 www.imarcresearch.com WE’LL EARN YOUR APPROVAL. Clinical Events Committee An endpoint assessment/adjudication committee or clinical events committee (CEC) may also be established by a sponsor. CECs are used to adjudicate research endpoints by providing a standard, systematic, independent and unbiased assessment of endpoint. Although the value of eliminating variability in interpretation is clear, regulatory requirements are still lacking. With the need for endpoint adjudication continually evolving with increasing needs stemming from complex clinical events, it’s important to consider the processes and benefits of using a CEC: • Allows for reporting of endpoint events using standard criteria across multiple centers • Establishes data requirements that allow determination of endpoint events • Limits variability and bias and brings consistency - Adjudication completed by blinded, independent experts And consider the importance of the CEC process in regard to the complete reporting of events: • Endpoints are frequently misreported or underreported by site investigators • CEC adjudication corrects for misreporting and can query for missing data elements as needed • Specific uniform criteria for endpoint definitions allow capture of data elements upfront and for the detection of unreported events Although these committees do not conduct interim data analyses, their adjudications can help to ensure that the data reviewed are as accurate and free of bias as possible 3 www.imarcresearch.com Institutional Review Board Another group that shares in the responsibility of oversight for a clinical trial is an Institutional Review Board (IRB). Their primary directive is to protect the rights and safeguard the welfare of human research subjects as spelled out in 21 CFR Part 56. The IRB is responsible for, but not limited to, evaluating a study to determine whether “risks to subjects are minimized” and “risks to subjects are reasonable in relation to anticipated benefits” (21 CFR 56.111(a)(1) and (3)). Also, the Code of Federal Regulations stipulates that “when appropriate, the research plan makes adequate provision for monitoring the data collected to ensure the safety of subjects” (45 CFR 46.111(a)(6)). However, the IRB differs in their role from the DSMB and CEC in that the IRB is responsible for the prospective and continuing review and approval of research activities involving human subjects at a research site. Most functions and the basic composition of the IRB are federally regulated by 21 CFR 56 and 45 CFR 46. While safety monitoring groups have access to study data, the IRB generally has no access to interim or blinded data. In addition, the DSMB provides “recommendations” with regard to the entire trial to the sponsor (and in turn may be shared with the IRB), while the IRB sets “stipulations” that must be followed. 4 www.imarcresearch.com WE’LL EARN YOUR APPROVAL. History of the DSMB The concept of a DSMB started in the 1950s, but the first formal description did not show up until the 1967 Greenberg Report. This document was based on a project commissioned by the National Heart Institute in which a coordinating center was proposed to collect and frequently analyze accumulating data in a trial in order to permit “intelligent direction of the project as it progresses.” Additionally, the report outlined the formation of a policy board comprised of experts not otherwise participating in the study who would review and recommend changes to the protocol, settle disagreements during the study, and advise the sponsor about adding or discontinuing research groups. The report also insisted that the policy board only serve in a consulting capacity (offering advice only). Since then, use of DSMBs have gradually become the standard in large scale randomized clinical trials, multicenter clinical trials, and single center trials (especially in blinded studies) or those with higher levels of potential risk. Important Events for Safety Monitoring Groups: 1960s 1992 2004-2006 Greenberg Report suggests NIH held an international World Health Organization and safety monitoring concept workshop to discuss European Medicines Agency approaches to data monitoring publishes guidelines for 1970s DSMBs DSMB use began in trials 1994 sponsored by federal agencies, NIH began considering use 2006 such as the Department of of DSMBs FDA issues guidance Veterans Affairs in the U.S. and document for establishing by similar bodies abroad safety monitoring committees 1995-1998 ICH includes information on 1988 data monitoring in E3, E6, 2007 The FDA issued guidelines and E9 guidelines Office for Human Research for requiring proper safety Protections create guidance monitoring documents that reference 1998-2000 DSMBs Policies issued by NIH for 1980-1990 data and safety monitoring The use of DSMBs by the pharmaceutical industry was seen more frequently 5 www.imarcresearch.com WE’LL EARN YOUR APPROVAL. Requirements vs. Best Practice All studies require monitoring of study data and investigator compliance, but not all require safety monitoring committees. Currently, the only mention as part of an FDA regulatory requirement is found in 21 CFR 50.24(a)(7)(iv), the section on “Exception from informed consent requirements for emergency research.” This regulation states the need for “Establishment of an independent data monitoring committee to exercise oversight of the clinical investigation” for studies where human subjects are in a life-threatening situation and the investigation meets the criteria in 21 CFR 50.24. In addition, the Code of Federal Regulations indirectly references data safety monitoring in 45 CFR 46.111(a)(6) which states: “When appropriate, the research plan makes adequate provision for monitoring the data collected to ensure the safety of subjects.” In practice, the FDA often expects the use of DSMBs for large, randomized, multisite studies that evaluate treatments intended to prolong life or reduce risk of major adverse health outcome, typically being phase III- IV, pivotal and/or significant risk studies. DSMBs are also recommended for controlled trials of any size that will compare rates of mortality or major morbidity. Some best practice questions designed to help make a determination as to whether or not a DSMB should be put in place include: • Is there a large study population, or are there multiple study sites? • Is the trial intended to provide definitive information about effectiveness and /or safety of a medical intervention? • Do prior data suggest that the intervention being studied has the potential to induce unacceptable toxicity? • Does the trial evaluate mortality or another major endpoint, such that inferiority of one treatment arm has safety and effectiveness implications? • Would it be ethically important for the trial to stop early if the primary question addressed has been definitely answered, even if secondary questions