Data Monitoring Committees in adaptive clinical trials

Abstract

Data Monitoring Committees (DMCs) have been widely utilized in clinical trials for study monitoring. The DMC, independent of any activities related to clinical operation of the study, is a group of individuals with pertinent expertise who review on a regular basis accumulating data from one or more ongoing clinical trials [1]. Depending on the study objectives, the primary responsibility of the DMC is to ensure the validity and integrity of the intended clinical trial by performing ongoing safety monitoring, as well as interim analysis for efficacy [2–3,101–102]. The use of DMCs in clinical trials can be traced back to the early 1960s [1]. However, the DMC did not appear in pharmaceutical trials until the early 1990s [3]. In 2006, the US FDA published a guidance on the ‘Establishment and Operation of Clinical Trial Data Monitoring Committees’ [1] to assist the sponsor in: determining the need for a DMC; establishing a DMC; and, setting up standard operation procedures for DMC’s function and activity. Adaptive design clinical trials have received a great deal of attention in recent years due to their potential features of flexibility and efficiency. Practically, adaptive designs allow researchers to modify the trial procedures and/or statistical methods of ongoing clinical trials based on accrued data. In the FDA draft guidance, entitled ‘Adaptive Design Clinical Trials for Drugs and Biologics’, an adaptive design clinical study is defined as a study that includes a prospectively planned opportunity for modification of one or more specified aspects of the study design and hypotheses, based on analysis of data (usually interim data) from subjects in the study (fully blinded or unblinded manner) [4]. According to the FDA draft guidance [4], adaptive designs are classified into two categories: well-understood and less-wellunderstood designs. Well-understood design mainly refers to the study designs with planned modifications based on an interim analysis that either need no statistical correction or properly account for the analysis-related multiplicity issues, such as traditional group sequential designs. In general, regulatory agencies have extensive experiences in well-understood designs in terms of study conduct and statistical properties. Conversely, less-well-understood designs refer to the study designs with statistical properties that are not fully understood. There is relatively little regulatory experience in evaluating the validity and integrity of less-well-understood design approaches. The main concerns with any less-well-understood adaptive designs noted in the draft guidance are control of the study-wide type I error rate, minimization of the impact of any adaptation-associated statistical or operational bias on the estimates of treatment effects and the interpretability of the results. Although a DMC is not required in clinical studies [1], the use of a DMC in pharmaceutical industry trials, especially in confirmatory studies, has become popular over the past two decades [3]. In practice, the DMC has been widely used in clinical trials with group sequential designs to reduce potential operational “...while the Data Monitoring Committee plays an important role in maintaining the validity and integrity of the clinical trial, adaptive design clinical trials may trigger a greater role and increased responsibility for the Data Monitoring Committee.”