Session 3: Data Monitoring Committees
Organizer: Michael Pencina (Duke)
Chair: Michael Pencina (Duke)
Karim Anton Calis (FDA) “Challenges and Opportunities in Data Monitoring and Trial Oversight”
Clinical trial oversight requires coordination and review by a number of groups and committees whose diverse focus includes safety, quality, ethics, adjudication, operations, and logistics. Although some of these evolving roles and responsibilities invariably overlap, independent data monitoring committees (IDMCs) hold a unique place in trial oversight. IDMCs periodically review the accumulating safety and efficacy data by treatment group and advise the sponsor on whether to continue, modify, or terminate a trial based on risk-benefit assessment. They also play a critical role in assessing the validity and integrity of the trial to enhance its potential to generate reliable findings. IDMCs typically oversee a single trial but occasionally review multiple related trials. Emerging functions of IDMCs include the monitoring of pragmatic clinical trials and perhaps even the entire portfolio of research related to an investigational product throughout its clinical development life cycle. IDMCs should be composed of qualified individuals with knowledge of ethical principles and expertise in biostatistics, research methodology, and relevant areas of science and clinical medicine. IDMC members must be independent of the sponsor and afforded adequate resources and flexibility to perform their duties. Roles and responsibilities of the IDMC—including contingency and communication plans—should be clearly delineated in a succinct, well-organized charter that empowers IDMC members. Although IDMCs have been established for decades, the transformation of the clinical trial landscape has created new opportunities as well as scientific and regulatory challenges in the oversight of clinical trials.
Frank Rockhold (GSK) “Benefit to risk considerations and methods applied to the ongoing monitoring of clinical trials”
The overall goal of the clinical trial is to assess a primary objective and endpoint (usually a benefit) over the background of secondary endpoints including patient safety. The objective of the IDMC is to integrate the information efficacy and safety information in some fashion to make ongoing decisions about whether to continue the trial as is, have the design altered, or prematurely discontinue based on the benefits and harms they are observing in the trial. Thus in some fashion the IDMC is tasked with creating a “benefit to risk” picture for the trial patients and future patients. The science of Benefit to risk for quantitatively summarizing completed trials (one or many) has evolved over the past decade. The purpose of this talk to is to explore how one might apply these techniques in a more structured and systematic way in an ongoing IDMC setting. Some things to be discussed are a review basic IDMC and B-R practices and processes, examples of how to integrate data in an evolving manner as part of data monitoring, use graphical and other methods usually used to display BR data at the end of the trial adapted to interim looks, and an example reworked in a BR framework over the life of a trial using methods outlined. Some thought questions will also be proposed around what, if any, impact of type I error adjustment (if any) on the data review and presentation and the impact of regulatory guidelines, if any, on these recommendations. The intent of this talk is to start the discussion of combining classical IDMC process with the more recent advances in Benefit to Risk methodology.
Bob Bigelow (Duke) “Interim data analysis: Distinguishing signal from noise”
The goal of many clinical trials is to reach a decision on comparative treatment effects based entirely on information from the trial. Pre-specification of endpoints, sample size, acceptable type I and II errors, and statistical analyses increase the chances that hypothetical treatment differences (or similarities) can be demonstrated in the presence of background noise. However, patient safety information from an ongoing trial is often not sufficient for an IDMC to make conclusive recommendations, and reliance on expert clinical judgment and familiarity with external data are necessary. In this presentation we will discuss challenges of interim safety assessment and consider methods to improve statistical rigor in IDMC analyses.
Susan Halabi (Duke) “Group Sequential Design: Uses and Abuses”
Group sequential design (GSD) is considered part of standard statistical practice has been developed for interim monitoring (and potential termination) of clinical trials to minimize the role of subjective judgment. Most randomized clinical trials include strategies for terminating the trial early if a treatment arm is found to be either effective or harmful to the patients. Although GSDs serve as an aid in monitoring throughout the trial, the decision to stop a trial early is complex. In this talk, the consequences of terminating a trial early will be discussed with an emphasis on statistical issues related to the estimation of the treatment effect and the analysis and interpretation of the primary and secondary endpoints. Several examples of oncology trials that were stopped early for superiority will be considered.
