July 20, 2007

Background

• To assure participant safety and clinical research integrity, data from clinical studies must be routinely reviewed and monitored in the context of the disease being studied and the type and risk level of the clinical study. Such review is called Data and Safety Monitoring (DSM).
• DSM is required for all clinical research studies. It is highly recommended that grant funding be sought for DSM activities related to clinical research studies.
• A Data and Safety Monitoring Plan (DSMP) for a clinical study is an outline set out in advance for the routine review and evaluation of enrollment, data, outcomes, and adverse events.
• The data and safety monitoring program for the GCRC will be coordinated by the Office for Research Participant Advocacy (ORPA). ORPA will assist investigators in implementing all aspects of data and safety monitoring.
• The level of monitoring for clinical studies is commensurate with the type of study and level of risk. Monitors will recommend the continuation, modification, or termination of clinical studies based upon their evaluation and review of the data which is organized in the form of a Data and Safety Monitoring Report (DSMR).
• In the case of low/minimal risk studies, the Investigator or Co-Investigator may perform the data and safety monitoring (DSM) activities. A "minimal risk" study is defined by the IRB as one where "the magnitude of harm or discomfort is not greater than that encountered in daily life or the performance of routine physical or psychological examinations or tests."
• In the case of above minimal risk studies, internal or external monitors chosen by the investigator, but completely independent of the research group, will serve on a committee, usually known as a Data and Safety Monitoring Board (DSMB).
• A Data and Safety Monitoring Board (DSMB) is required for the following specific types of studies: 1) above minimal risk 2) vulnerable populations 3) blinded studies 4) new science (i.e. gene therapy, biologics) or 5) multi-center studies. The DSMB is charged with reviewing data and making recommendations following the DSMP specified in the protocol.
• Monitors are usually physicians, statisticians, and other voluntary members who, independent of the investigator, collect and analyze data and endpoints at specified intervals. Monitors should be fairly knowledgeable in the area under study, up-to-date with scientific and therapeutic developments, and be able to review the data and information in the context of the research field being studied. They should not have any conflicts of interest that would influence their objectivity in the review of the data. Biostatistical input and support is highly recommended.
• In order to assist investigators with the DSM requirement on multi-center studies, the GAC will accept DSMPs and DSMRs from external reporting bodies provided they satisfy the minimum requirements.
• For studies conducted at the General Clinical Research Center (GCRC), DSMPs require both the approval of the IRB and the GCRC Advisory Committee (GAC). The GAC is required to maintain a log of minutes relating to review of DSMPs, which may be requested or reviewed by the National Center for Research Resources (NCRR), the funding agency for the GCRC.

Data and Safety Monitoring Plans (DSMPs)

     The two required elements of Data and Safety Monitoring Plans (DSMPs) are the safety review plan and the plan for adverse event reporting. Questions regarding DSMPs will be asked in the GCRC application.

1) Safety Review Plan

• Selection criteria for monitors and a listing of their names and contact information
• Frequency of data review
• Type of data to be reviewed (e.g. clinical data, primary/secondary endpoints, adverse events, etc.)
• Preliminary criteria for decision-making regarding continuation, modification, or termination of the clinical study
• Method for documenting study discussions and meeting minutes, as well as follow-up communications
• Designation of study contact person for communications with ORPA

2) Adverse Events

     Adverse event recognition, evaluation, and reporting is an important component of safety monitoring. Sometimes adverse events are recognized by the study team and sometimes by the GCRC staff. When recognized by GCRC staff, the GCRC adverse event policy is implemented. See IRB reporting mechanisms here.

To assure the highest level of participant safety at the GCRC, immediate verbal contact (in person or by telephone) with the GCRC nurse management should be made for the following a) unexpected and/or serious adverse events that take place on or off the GCRC for a GCRC-supported protocol.

Data and Safety Monitoring Reports (DSMRs)

     Data and Safety Monitoring Reports (DSMRs) are organized and reviewed by the monitor(s) as per the DSMP. The monitors meet together to discuss the DSMR and document their discussions in the form of meeting minutes/logs. The DSMR and the minutes/logs are submitted directly to ORPA by the monitors for GAC review as per regulatory requirements. Ongoing review of DSM for all GCRC studies will be conducted by the GAC. Studies not in compliance may be subject to GAC actions.

    ORPA will assist in the planning of monitor meetings and the design and formatting of both reports and minutes/logs. ORPA will assist monitors and investigators in the resolution of questions/issues raised at meetings.

The required content of DSMRs is as follows:

• Date and type of report
• Enrollment numbers (i.e. number enrolled, refused, withdrawals, terminations, deaths)
• Screening failure information (including reasons)
• Reasons for withdrawals/dropouts/deaths
• Protocol violations/deviations at enrollment or during the study
• Changes/Amendments to protocol with IRB approval on file or in the process of being obtained
• Frequency of AEs (i.e. listing of patients with no AEs, with 1 or more AEs, and those with missing AE information); Severity and attribution of the AEs
• Overall aggregate analysis of AEs in the context of the monitoring plan
• Protocol recommendations for modification, closure, or termination based upon the above data and the reasons for any major decisions (include scientific, clinical, biostatistical, or other reviews)
• Investigator or key personnel changes Communications to participants regarding safety data and results of study determinations

ORPA's assistance to investigators and study personnel

ORPA is available to assist investigators and study personnel in satisfying the regulatory requirements per NCRR guidelines.

• Providing education and instruction in the formulation of a DSMP and the selection of monitors.
• Acceptance of DSMPs from the Johnson Comprehensive Cancer Center (JCCC), consortiums, or other institutions or bodies.
• Acceptance of DSM-related reporting from JCCC, consortiums, or other institutions or bodies provided that they satisfy the GCRC minimum requirements. If the minimum requirements are not met satisfactorily, the Research Subject Advocate (RSA) at ORPA will speak with study personnel and assist them in satisfying the remaining requirements.
• Available for DSM-related discussions and inquiries at any time.
• Assistance in documentation of DSM-related reports, meetings, and discussions if so requested.
• These guidelines are subject to revision at any time due to regulatory or institutional changes. ORPA will assist investigators and study personnel in staying abreast of changes to the DSM program at the GCRC.