A “One-Size” Data Monitoring Committee Does Not Fit All Clinical Trial Monitoring Needs

three people around a conference table

By Raymond P. Bain, PhD

Clinical Trial Design

A clinical research design “toolbox” consists of both observational and interventional designs.  A clinical trial is a prospective study comparing the effect of one or more interventions against a control intervention on a pre-specified outcome in human subjects.  The gold standard clinical trial includes randomization to two or more interventions with the interventions unknown (i.e. double-blinded) to the patient and the investigator (Friedman, Furberg and DeMets, 1996).  The goal of randomization is to minimize confounding (i.e. distortion in the intervention and outcome relationship due to a third factor, known as a confounder, which is associated with both the intervention and the outcome).  The goal of double-blinding is to minimize information bias (i.e. distortion in the intervention and outcome relationship due to a biased assessment of the intervention and/or outcome).

Data Monitoring Committee Role

In a randomized and double-blinded clinical trial, a Data Monitoring Committee (DMC) has the principle responsibility to monitor the emerging results of the trial (Ellenberg, Fleming and DeMets, 2003).  The role of the DMC is to monitor trial outcomes (i.e. efficacy and/or safety data unblinded to intervention actually received) to detect early benefits of the intervention or potential harms, to evaluate the benefit-risk of trial participants, and based on these considerations make recommendations to the trial’s Sponsor that the trial’s protocol be modified or the trial be terminated.  Typically, the DMC is external to the trial’s Sponsor that provides funding for the clinical trial (e.g. National Institutes of Health, pharmaceutical industry, or foundation) and termed an external DMC or eDMC.  The eDMC members are independent of the Sponsor, have no involvement in the trial execution and no known or perceived conflicts of interest relative to the trial’s goals.

Data Monitoring Committee Composition

The eDMC is a multidisciplinary group providing scientific peer review of accumulating information during the execution of a clinical trial.  The typical make-up of an eDMC includes clinical researchers with knowledge of the biomedical field under investigation and a biostatistician with experience in the interim monitoring of clinical trial data.  The two key members of the eDMC are the eDMC Chair and the eDMC biostatistician.  Other eDMC members may include regulatory scientists, epidemiologists, clinical pharmacologist, ethicist and patient advocate, as needed.  Identifying trained and experienced eDMC members can be challenging.  The number of clinical trials in need of a well-qualified eDMC has increased steadily over recent years.


Need for a Fully Independent eDMC


Given the challenges in identification of experienced and qualified eDMC members, we must critically evaluate the need for fully independent eDMCs.  As indicated in the 2006 report from the Society for Clinical Trials (SCT) Working Group on Data Monitoring, policy guidelines from the US National Institutes of Health indicate that a “data monitoring plan should exist for all clinical trials be they exploratory (Phase I, II) or confirmatory (Phase III)”.  The SCT Working Group indicated that most Phase II exploratory trials will have partially independent DMCs.  Therefore, careful consideration should be given to the use of a fully independent eDMC for exploratory Phase II trials.

Example of a Partially Independent DMC

Sponsors of clinical trials should consider the establishment of a single standing internal DMC (or siDMC) with similar characteristics to an eDMC but with more flexibility typically required for exploratory trials.  The siDMC would be partially independent (i.e. Sponsor staff are members of the siDMC but “independent” of the Sponsor staff conducting the exploratory trial monitored by the siDMC).  The responsibilities and processes of the siDMC should be documented in two Charters: (1) a general charter detailing the standard operating procedures of the siDMC across all the Sponsor-funded exploratory trials and (2) a trial-specific charter detailing the standard operating procedures (e.g. frequency of interim reports, monitoring guidelines) for an individual exploratory trial.  The standardized charter template developed by the DAMOCLES Study Group (Lancet, 2005) can be used for both the general and trial-specific charters.

Potential Advantages of a siDMC for Exploratory Trials

  • Improved productivity by standardized structure/function of the siDMC and the format of the interim analysis report
  • Improved recommendations based on interim data monitoring by a siDMC with appropriate expertise, ongoing training and mentoring
  • siDMC participation provides an opportunity to impact Sponsor’s decision-making and develop of the next generation of DMC members
  • In the event of unexpected results/concerns for a blinded exploratory trial without interim data monitoring, quickly convene and inform an experienced group to evaluate unblinded interim data
Monday, March 28, 2016 by Jamie Nunnelly