Monitoring Committee Structure and Function

The investigator’s ethical responsibility to the study participants demands that safety and clinical benefit be monitored during trials. If data partway through the trial indicate that the intervention is harmful to the participants, early termination of the trial should be considered. If these data demonstrate a clear definitive benefit from the intervention, the trial may also be stopped early because continuing would be unethical to the participants in the control group. In addition, if differences in primary and possibly secondary response variables are so unimpressive that the prospect of a clear result is extremely unlikely, it may not be justifiable in terms of time, money, and effort to continue the trial. Also, monitoring of response variables can identify the need to collect additional data to clarify questions of benefit or toxicity that may arise during the trial. Finally, monitoring may reveal logistical problems or issues involving data quality that need to be promptly addressed. Thus, there are ethical, scientific, and economic reasons for interim evaluation of a trial [1–3]. In order to fulfill the monitoring function, the data must be collected and processed in a timely fashion as the trial progresses. Data monitoring would be of limited value if conducted only at a time when all or most of the data had been collected. The specific issues related to monitoring of recruitment, adherence, and quality control are covered in other chapters and will not be discussed here. The monitoring committee process has been described in detail [4] as have case studies representing trials, which were terminated for benefit, harm, or futility [5]. One of the earliest discussions of the basic rationale for data monitoring was included in a report of a committee initiated at the request of the council advisory to the then National Heart Institute and chaired by Bernard Greenberg [3]. This report outlined a clinical trial model depicted in Fig. 16.1, variations of which have been implemented widely by institutes at the National Institutes of Health (NIH). The key components are the Steering Committee, the Statistical and Data Coordinating Center, the Clinics, and the Data Monitoring Committee. Later the pharmaceutical and device industries [6] adopted a modified version of this NIH model, depicted in Fig. 16.2. The main modification was to separate the Statistical Data Coordinating Center into a Statistical Data Analysis Center and a Data Coordinating Center. Many of the early experiences have been described and formed the basis of current practice [7–34], particularly in trials of cardiovascular disease [35–37]. Over the past decade especially, the number of DMCs has increased dramatically [38]. In 2013, of over 120,000 trials registered in Clintrials.gov, more than 13,000 were interventional trials and 40% of those included a DMC. This suggests over 5,000 DMCs are or have existed in this period of time. The highest DMC utilization was in cardiovascular and oncology trials. Of the 630 trials that were NIH sponsored, 74% had a DMC. For the 55% that were industry sponsored, about a third had a DMC. Some of this difference is reflected in the written policies or guidelines by the NIH and the FDA. The Office of Inspector General (OIG) issued a report in 1998 that reviewed the adequacy of IRB oversight in clinical trials and recommended that the NIH and the FDA provide guidance on when a more focused monitoring committee might be needed. In response, NIH issued a policy statement that was consistent with their longstanding practice in many of their institutes of having an independent DMC for all Phase III randomized trials that they funded [39]. Soon after, the FDA began to develop a guidance document that was issued as a draft in 2001 and finalized in 2006 [40]. The FDA guidance recommended DMCs for trials with high risk patients or high risk or novel interventions, not all Phase III or IV trials conducted by industry.