Data Safety Monitoring Boards and Clinical Events

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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 or complete safety information were not yet fully addressed?

A DSMB should usually be implemented if the answer to two or more of the above questions is “yes.”

6 www.imarcresearch.com WE’LL EARN YOUR APPROVAL. Impact One of the most critical effects the DSMB may have as a result of their role in safety management is deciding to cease a trial due to excess harm or benefit in a treatment group before its planned conclusion.

These decisions play an important part in the contribution of safety to clinical research.

There are, however, other levels of impact that bring further purpose to data safety monitoring boards:

• Eliminates potential conflicts of interest during safety evaluations • Ensures the credibility of the study

• Ensures the validity of study results and strengthens scientific integrity • Identifies emerging issues, alerts the sponsor, and provides expertise to deal with problems that arise during the trial • Enhances the safety of trial participants

7 WE’LL EARN YOUR APPROVAL. Consideration of an Independent DSMB and CEC

When a DSMB and/or CEC are implemented for a study, it’s important to know they are not all created equal. The Data Safety Monitoring Boards (DSMB) review cumulative information from a study and monitor safety oversight with teams of independent physicians and medical professors. A Clinical Events Committee (CEC) adjudicates individual adverse events within a study to determine if those events are related to the study or not. While it is critical to understand the primary purposes of a DSMB/CEC, it’s equally important to go beyond meeting basic requirements in order to be the most confident in efforts for patient protection and study results.

Examine these qualities when assembling a safety management board and consider if the DSMB/CEC (and the Administrator) provides the quality listed in Figure #1 and described below.

Characteristics of a High-Quality Safety Monitoring Group

Independence

Consistency and Organization

Credibility and Experience of the Board Member

Time and Availability Required to Fulfill the Duties of Maintaining a Board

Attention to Detail

Meeting Flexibility

Timeliness

Figure #1

8 www.imarcresearch.com WE’LL EARN YOUR APPROVAL. Independence

The safety monitoring group members should be free of conflicts of interest that could bias their review of study data. Bias could be introduced in a number of ways or be inadvertent so it is important that potential members are thoroughly screened to assure the integrity of data reviews. Potential conflicts of interest could include receipt of grants or honoraria from a sponsor, consulting or speaking engagements, or other payments. Members should not be investigators on the study of interest or on competing studies; screening should include a discussion of participation on similar studies or those with overlapping patient populations. Other potential conflicts could include affiliation with the sponsor or collaborative relationships with other investigators working on the study, but each case should be assessed individually to determine if a true conflict exists.

In addition to the group members’ independence, consider the administration of the safety monitoring group. Some sponsors may choose to handle this function internally, while others prefer to outsource to a clinical research organization. The choice to outsource may come from resourcing and budget constraints, as well as a desire for overall independence of the safety monitoring group. A clinical or contract research organization can offer a distinct separation between the safety monitoring group and the core study team members involved in the daily details of running a study. This separation allows the board or committee to be fully objective about the study, without the potential influence of working directly for or with the sponsor. The FDA guidance emphasizes the importance of the independence of the safety monitoring group, while recognizing that absolute independence is not usually possible and that sponsor interaction with the group can be valuable, such as during open sessions of meetings to review study updates.

9 www.imarcresearch.com WE’LL EARN YOUR APPROVAL. Consistency and Organization A safety monitoring group should function ac- • General Procedure Topics cording to standard operating procedures that • Relevant Definitions and References guide their activities. These procedures should • Safety Monitoring Group Responsibilities define key requirements for all safety monitoring groups, and allow flexibility for study-spe- • Establishment of a Safety Monitoring Group cific requirements to be outlined in individual • Membership charters. That way member qualifications and • Meetings meeting formats can be determined per study • Responding to External Requests for Information based on risk, preference and study needs. • General Documentation Requirements Some key topics that should be • Confidentiality Requirements covered in standard operating • Membership Procedure Topics procedures are outlined in • Selection of Safety Monitoring Group Members Figure #2 on the right. • Removal of Safety Monitoring Group Members • Selection and Removal of the Safety Monitoring Chairperson • Temporary Membership • Terms of Safety Monitoring Group Membership • Training Requirements for Members • Evaluating Conflicts of Interest • Membership Documentation Requirements • Meeting Conduct Procedure Topics • Frequency and Types of Meetings • Notification and Stopping Thresholds (if needed) • Structure of Meetings • Voting at Meetings • Documentation of Meetings • Findings and Recommendations

Figure #2

10 www.imarcresearch.com WE’LL EARN YOUR APPROVAL. Credibility and Experience of the Board Members The FDA Guidance for Establishment and Operation of Clinical Trial Data Monitoring Committees emphasizes the importance of a thoughtfully composed safety monitoring group that should have members with relevant clinical expertise, without significant conflicts of interest, and ideally with previous experience in clinical research and/or safety committees.

“A poorly constituted data monitoring committee (DMC) may fail to note problems that should be addressed, or may make recommendations that are unwarranted or whose consequences are inadequately considered, thereby undermining the safety of participants as well as the value of the trial. The ability of DMCs to provide the anticipated additional assurance of patient safety and trial integrity therefore depends on appropriate selection of DMC members.”

– FDA Guidance, Establishment and Operation of Clinical Trial Data Safety Monitoring Committees, 2006

Safety monitoring group members may be clinicians, biostatisticians, or other specialists; a medical degree is not required by regulation. The composition and number of group members should be based on the study safety concerns and qualifications needed to adequately assess the significance of safety data for study subjects as well as future patients. Members should collectively be able to review safety information and determine whether the data indicates an unacceptable level of risk to patients or not, and may need the expertise of several people to accomplish this task. The FDA guidance points out that other specialists and scientists such as epidemiologists, medical ethicists, or clinical pharmacologists may be called on to participate. Additionally, other individuals who represent the patient population (that are not also study participants) may provide useful perspectives as members of a safety monitoring group.

When assembling a safety monitoring group, clinical or professional expertise is very important, but these are not the only characteristics needed for a well functioning group.

11 www.imarcresearch.com WE’LL EARN YOUR APPROVAL. Time and Availability Required to Fulfill the Duties of Maintaining a Board

Members of a safety monitoring group should be qualified, certainly, but this is not the only factor when considering who will have a positive impact on the board or committee. Many members are extremely busy clinicians with incredibly full schedules. However, members who are responsive to scheduling requests and urgent safety notifications take their roles in protecting patients seriously. Members should also be willing to review and approve documentation of their efforts, even if meeting minutes are drafted by an administrator. And of course, members must be willing to make room in their busy schedules to attend meetings (whether in-person or remotely) as well as review preparatory materials and complete follow-up action items. An independent CRO can help screen potential members for these other qualities and will have a network of trusted professionals available for future projects.

Attention to Detail Safety monitoring group members should of course pay close attention to the data presented to them in order to make accurate assessments of relevance and risk to subjects. In addition, the supporting staff responsible for administration of safety monitoring groups must have a high level of attention to detail. While the members are responsible for attending meetings, the administrators must keep a close watch on charters, timelines, schedules, meeting minutes, notifications, payments, agreements, conflicts of interest, follow-up recommendations, and other details involved in keeping safety monitoring groups running smoothly.

12 www.imarcresearch.com WE’LL EARN YOUR APPROVAL. Meeting Flexibility Each study and each sponsor will have different requirements, preferences, and considerations for determining the format of safety monitoring group meetings. Most often, the busy schedules of members makes in-person meetings difficult to arrange and remote meetings are used. This also offers the advantage of drawing from a much wider geographical pool of potential experts for the group, rather than limiting to a specific location. However, in-person meetings offer face-to-face interactions among the group and can make communication easier. Local safety monitoring groups may also be advantageous for certain situations where local insight is required. The study charter will specify the preferred format(s) for meetings of that particular study, and using a CRO that can coordinate both in- person and remote meetings will allow flexibility where needed.

Timeliness The safety monitoring group will have different goals and responsibilities depending on whether it is a DSMB, CEC or conducts medical monitoring. But regardless of the specific obligations, the group should be committed to timeliness as it relates to their objectives. Timeliness is important when the recommendations of a safety monitoring group could have a great impact on subject safety through potential modifications to the study or even discontinuation when risks become unacceptable. When adjudications are needed from a CEC, delays can also impact data analyses or the sponsor’s understanding of safety events.

For a DSMB, the board should be able to provide the sponsor with documentation of any recommendations to continue, modify, or terminate a study within the timeline specified in the Charter. This will depend on the sponsor and DSMB’s preferences and on the study-specific safety considerations. This timeline can range from two business days to four weeks but should be agreed upon by all participants what is an acceptable expectation for the sponsor to receive the board’s meeting results. For a CEC, the committee should be able to review and provide completed adjudications according to the timeline specified in the Charter and/or member agreements. Again, the time frame will depend on the study needs and participant

13 www.imarcresearch.com WE’LL EARN YOUR APPROVAL. preferences. For a CEC that reviews all adjudications together in real time, in person or remotely, completed adjudications could be reasonably expected by the sponsor within a few business days of the meeting. When CEC members review adjudications independently, a completion deadline might be used instead with a window ranging from a few days to a few weeks. Whatever the situation, expectations for timeliness should be clearly established and agreed upon by the safety group members, sponsor, and understood by the supporting administrators.

DSMB/CEC Set-up: Where to Start If a sponsor determines a safety monitoring group is needed based on an assessment of the study risks, there will be several steps needed to put together a well-functioning group. Consider establishing processes to allow selection of suitable members, developing a charter, and communicating confidentiality requirements.

With the qualities described above in mind, one consideration for managing a DSMB/CEC and comprehensively addressing this list is a Contract Research Organization (CRO). Utilizing an independent, third party outside of the sponsor organization can offer numerous benefits. Having a CRO can establish a “firewall” between the Sponsor and the safety management boards, therefore freeing the sponsor and study of any additional scrutiny for potential for bias. An independent CRO to administrate also promotes objectivity that benefits the safety of the subjects and the integrity of the trial. A CRO that offers administration of safety monitoring groups will have well-established processes and follow these for your study-specific requirements.

The CRO can also offer another layer of independence through assessing Conflicts of Interest (COI), managing member agreements, and managing member compensation. An independent administrator brings consistency and organization through standardized procedures and because managing safety boards are their primary concern.

Rather than having a DSMB/CEC that tries to run itself with physicians who are already busy, a CRO is available to deliver reliable results in a timely manner. Critical timelines, reports, notifications, and follow-ups don’t get behind and are maintained seamlessly. Study physicians can focus then on their areas of expertise without distraction. And if meeting location can be an issue, a CRO can organize remote or local sessions. This also offers the flexibility to work with individuals from not only across the country, but around the globe providing a greater network of respected therapeutic expertise to use for a study. Take a look at the graphic on the next page for some best practices in these areas.

14 www.imarcresearch.com WE’LL EARN YOUR APPROVAL. Selection of Suitable Members • Define ‘suitable’ for the project • Establish criteria for expertise needed • Collect and assess any disclosed conflicts of interest • Collect credentials (CVs, licenses) and verify employability • Complete onboarding and training of selected members

Confidentiality Requirements • Obtain agreement from members to maintain confidentiality of reviewed information • Select supporting tools to help ensure confidentiality, such as controlled access file sharing systems, and a secure physical or electronic system for retaining documents • Remind group members of confidential nature of their role at subsequent meetings

Charter Development • Add study details to template, including pre-determined requirements such as protocol-defined stopping rules or safety • Request input from members and sponsor for review schedule, data to be reviewed, and any notification of stopping criteria • Define responsibilities and timelines as needed

Conduct of Meetings • Plan the processes for and follow-up of meetings • Determine logistics for remote or in-person meetings • Develop relevant templates for meeting minutes, attendance, and recommendations and/or adjudications as needed

Ongoing Administration • Document group activities and meeting or adjudications • Plan for handling of requests for information from IRBs • Track and resolve follow-up actions • Distribute notifications from the sponsor to members and track responses • Update Charters as needed • Maintain members’ documentation and update as needed (CVs, licenses, COI forms)

15 www.imarcresearch.com WE’LL EARN YOUR APPROVAL. A safety monitoring group may be called many different things— a data monitoring committee, a data safety monitoring board, a clinical events committee, a medical monitoring group, among others. The sponsor will determine if and what type of safety monitoring group will be needed based on study risks. The objectives and procedures may vary depending on the role of the safety monitoring group or depending on the risks involved in the study. A DSMB will review cumulative safety data, and possibly effectiveness data as well, and make recommendations to the sponsor regarding whether it feels the study should continue, continue with modifications, or be terminated. The CEC instead reviews individual qualifying adverse events and provides adjudications to the sponsor, often to assess relatedness to the investigational product and/or study procedure. But the overall goal of a safety monitoring group is always the same: additional, independent oversight of a study involving human subjects. A safety monitoring group such as a DSMB or CEC is an investment in safety and data integrity that goes beyond checking a box. Seek qualities in an independent, high-quality safety management team that will be sure to add value to the study.

16 www.imarcresearch.com WE’LL EARN YOUR APPROVAL. References 1 U.S. Food and Drug Administration [FDA] (2006).Guidance for clinical trial sponsors: establishment and operation of clinical trial data monitoring committees. Retrieved from http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm127073.pdf.

2 Institutional Review Boards, 21 CFR § 56. (2015).

3 Heart Special Project Committee to the National Advisory Heart Council. Organization, review, and administration of cooperative studies (Greenberg Report). Controlled Clinical Trials 1988; 9:137-48.

4 Office for Human Research Protections- Department of Health and Human Services (2010). Guidance on IRB Continuing Review of Research. Retrieved from http://www.hhs.gov/ohrp/sites/default/files/ohrp/policy/continuingreview2010.pdf

5 Armstrong, P., Furberg, C. (1995). Clinical Trial Data and Safety Monitoring Boards: The Search for a Constitution. Circulation, 91(3): 901-4. DOI:10.1161/01.CIR.91.3.901

6 Drazen, J., and Wood, A. (2010). Don’t mess with the DSMB. The New England Journal of Medicine, 363:477-478. DOI: 10.1056/NEJMe1007445

7 Ellenberg SS, Fleming TR, DeMets DL. Data monitoring committees in clinical trials: a practical perpective. John Wiley & Sons, 2003.

8 National Institutes of Health [NIH] (2000). Further guidance on a data and safety monitoring for phase I and phase II trials. Retrieved from https://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html.

9 Levinson, D. (2013). Data and safety monitoring boards in NIH clinical trials: meeting guidance, but facing some issues. Department of Health and Human Services Office of Inspector General. Retrieved from https://oig.hhs.gov/oei/reports/oei-12-11-00070.pdf.

10 National Institutes of Health [NIH] (1998). NIH policy for data and safety monitoring. Retrieved from https://grants.nih.gov/grants/guide/notice-files/not98-084.html.

11 Shalala, D (2000). Protecting research subjects- what must be done. The New England Journal of Medicine, 343(11):808-10. DOI: 10.1056/NEJM200009143431112.

Rachel Silver-Kessler, BS, CCRA Director of Clinical Support Services

Utilizing her background as a biomedical engineer, Rachel brings a unique perspective and valuable tool set to clinical research. Her critical thinking skills allow her to apply the regulations across various roles including as a monitor, auditor, trainer, and manager for DSMBs, CECs, and medical monitors. These skills and experiences have influenced her advancement to her current position as Director of Clinical Support Services at IMARC.

In October 2015, Rachel helped IMARC launch its Safety Management services, and she oversees the administration of independent safety oversight for studies. Rachel was also part of the core team that launched IMARC University, a series of affordable online training and continuing education courses designed to prepare clinical research professionals for compliance. Rachel also assisted IMARC in achieving ISO 9001 certification with the implementation of a robust quality management system.

She has been a member of the Association of Clinical Research Professionals since 2011 and became a Certified Clinical Research Associate in 2013. She holds a Bachelor of Science degree in Biomedical Engineering from Case Western Reserve University and is a student in the Clinical Research Administration Master’s program through The George Washington University.

Toni Hegyi, BSAS Clinical Support Services Associate, DSMB/CEC Administrator

Toni joined IMARC in March of 2014 as a Research Assistant and quickly advanced in responsibility due to her keen attention to detail and passion for learning new skills. Her current position as Clinical Support Services Associate also includes the functional role as DSMB and CEC Administrator. Toni is actively involved with IMARC’s internal and external training and development programs and core quality management team as well.

Before her work at IMARC, Toni was in Global Training and Development with ConocoPhillips where she was a Project Facilitator supporting the development of multiple extensive, international, multi-cultural, multi-lingual, and multi-discipline global training programs for engineering and geoscience professionals. Additionally, she was a global training instructor on the topic of “Critical Thinking”, and Toni continues to share her knowledge on this topic with IMARC employees.

She earned her Bachelor of Science in Applied Science from Youngstown State University and also maintains a Registered Dental Hygienist (RDH) license.

For more information on how you can help prepare your sites for a better outcome, starting from Day One, please contact John Lehmann at 440.801.1540 or via e-mail at [email protected].

WE’LL EARN YOUR APPROVAL.

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