MONITORING OF CLINICAL-TRIALS - ISSUES AND RECOMMENDATIONS

Interim analyses of randomized trials enable investigators to make mor e efficient use of limited research resources and to satisfy ethical r equirements that a regimen be discontinued as soon as it has been esta blished to have an inferior efficacy/toxicity profile. Unfortunately, the integrity and credibility of these trials can be compromised if in appropriate procedures are used in monitoring interim data. In this pa per we discuss how group sequential designs provide useful guidelines that enable one to satisfy the valid objectives of interim monitoring while avoiding undesirable consequences, and we consider how flexible one can be in the way such designs are implemented. We also provide mo tivation for the role of data-monitoring committees in preserving stud y integrity and credibility in either government- or industry-sponsore d trials. In our view, these committees should have multidisciplinary representation and membership limited to individuals free of apparent significant conflict of interest, and ideally should be the only indiv iduals to whom the data analysis center provides interim results on re lative efficacy of treatment regimens. Finally, we discuss some import ant practical issues such as estimation following group sequential tes ting, analysis of secondary outcomes after using a group sequential de sign applied to a primary outcome, early stopping of negative trials, and the role of administrative analyses.