University of Pittsburgh Cancer Institute

Data Safety and Monitoring Committee

The Data Safety and Monitoring Committee (DSMC), which reports to the Clinical Research Oversight Committee (CROC), convened in January 2003. The DSMC meets monthly while the CROC meets quarterly. The DSMC is delegated the responsibility for continued review and monitoring of all clinical trials conducted by the UPCI. The committee provides oversight of study progress (previously handled by a subcommittee of the PRC) and safety. This is accomplished by reviewing accruals, performing internal audits for quality control, and monitoring the frequency of serious adverse events of all active protocols. This information includes the minutes of the monthly multidisciplinary disease-site program or group meetings, which summarize accruals to active trials, protocol violations, serious adverse events, and any deaths on study. The DSMC submits recommendations for corrective action to the CROC before submitting final recommendations to the principal investigator/study chair and the regulatory oversight committees (e.g. FDA, OBA, NIH, NCI, IRB, etc.).

DSMC Membership

The University of Pittsburgh IRB recently decided that for the UPCI DSMC to monitor high-risk studies, its membership should be broadened to includea lay member (possibly a cancer survivor), and its chair should be a physician independent of UPCI. The DSMC is in the process of altering the committee membership to comply with these mandates. The current composition of the committee is as follows:

UPCI DSMC monitoring requirements and examples of actions taken are as follows:

Phase I Trials

Investigators conduct continuous review of data and patient safety at their weekly Phase I Group meetings. The results of each patient's treatment are discussed, and the discussion is documented in a format that can be submitted to the DSMC. The discussion includes for each study dose level, the number of patients, significant toxicities as described in the protocol, dose adjustments, and responses observed. Monthly summaries of the information discussed at these meetings are submitted to the DSMC for review. The DSMC has the authority to suspend accrual or further investigative treatments for any trial based on information received that warrants this action.

Phase II Trials

Data related to these trials are discussed at regularly scheduled meetings involving the principal investigator, co-investigators, and the clinical research coordinator. The results of each patient's treatment are discussed, and the discussion is summarized in a format that can be submitted to the DSMC. The summary forwarded to the DSMC includes information pertaining to the treatment arm/dose level, the number of patients, significant toxicities as described in the protocol, dose adjustments, and responses observed. The DSMC has the authority to suspend accrual or further investigative treatments to any trial based on information received that warrants this action.

Phase III Trials and Trials Enrolling >300 Patients

All phase III trials and trials enrolling >300 patients must have an external Data and Safety Monitoring Board (DSMB) (e.g. ECOG, RTOG, NSABP, Industry-sponsored trials, etc.). These trials will be reviewed by the PRC, which provides the scientific review of the trial. The PRC reviews all data safety monitoring plans included in these new studies in order to ensure that they are appropriate for the study design and level of risk. In addition, the DSMC reviews NIH-supported phase III trials as required by NIH policy. The DSMC has the authority to suspend accrual or further investigative treatment for any trial, based on information received that warrants this action.

Multicenter Industry and Investigator-Initiated Trials

The PRC reviews all data safety monitoring plans included in these studies as part of its initial review in order to determine that the plans contained are appropriate according to the study design and level of risk. If the plan is not adequate, the PRC advises the principal investigator and requests that the plan be revised according to the UPCI's DSMP guidelines. These guidelines include: 1) who (e.g. principal investigator or internal/external committee) will review the data and the frequency of the review; 2) specifics of evaluation and progress of the research study, including assessments of data quality and timeliness of participant recruitment and accrual retention; 3) what information will be reported to the IRB and the frequency of reporting; 4) how serious-adverse events information will be reported and how the risk/benefit ratio will be reassessed; 5) how the review of external factors like literature or scientific reports will be reviewed in order to determine if the study should continue; and 6) how breeches in confidentiality of the data will be handled. The study will not be approved by the PRC until the plan has been acceptably revised. Until PRC approval is received, the study cannot be submitted to other committees or regulatory agencies.

Data related to these trials are discussed at regularly scheduled meetings involving the principal investigator, co-investigators, and the clinical research coordinator. The results of each patient's treatment are discussed and the discussion is summarized in a format that can be submitted to the DSMC. The summary forwarded to the DSMC includes information pertaining to significant toxicities as described in the protocol. The DSMC has the authority to suspend accrual or further investigative treatments to any trial based on information received that warrants this action.

Study Progress

Study progress assessments are performed semi-annually to determine whether accrual projections are being met and whether the trial should be continued, based upon the likelihood of timely completion. Principal investigators of slow-accruing protocols are advised to consider strategies to increase accrual, and the study is scheduled for reevaluation in 3 months.

Protocols defined as slowly accruing are those that achieve less than 30% of their projected yearly accrual. However, such studies are allowed to continue for the following reasons: 1) protocol not yet opened because of pending grant or contract support; 2) very recently opened protocols that were delayed in initiation because of drug availability issues, pending peer reviewed support, or contract delays; and 3) those protocols for which the principal investigator has recently taken substantive steps to enhance accrual. This system is based on objective and well-defined criteria for accrual, but does permit remedial action or recognition of unavoidable reasons for slow accrual.

Review of Adverse Event Rates

Once a month, adverse events are monitored utilizing the UPCI Clinical Trials Management Application (CTMA) database. If any study has a frequency of Serious Adverse Event (SAE) reports that appears to be excessive, the UPCI DSMC Chair reviews the summary of SAEs, discusses events with the committee, and conducts a more detailed review with the external DSMB, if warranted. The DSMC Chair will determine whether further action is required. The UPCI Clinical Research Coordinator ensures that participating sites are notified of all SAEs that occur on a multiple-institutional clinical trial coordinated by the UPCI.

Data Quality Control

Three types of procedures ensure that UPCI protocol/patient data are of the highest quality: auditing, response review, and quality assurance review. Reports of these quality control activities are submitted and discussed at the UPCI DSMC meeting and then submitted with recommendations for follow-up or corrective action to the CROC. The CROC reviews the reports, implements corrective action, and notifies the principal investigator/study chair of these actions.