BOOK REVIEW: Data and Safety Monitoring Committees in Clinical Trials

Journal of Biopharmaceutical Statistics, 19: 1168–1171, 2009 Copyright © Taylor & Francis Group, LLC ISSN: 1054-3406 print/1520-5711 online DOI: 10.1080/10543400903244288

BOOK REVIEW

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Data and Safety Monitoring Committees in Clinical Trials, by J. Herson, Boca Raton, FL: Chapman & Hall/CRC, 2009, ISBN 978-1-4200-7037-8, xviii + 173 pp., $89.95.

This book is the most recent addition to a group of texts addressing monitoring of interim data and Data Monitoring Committee (DMC) processes and practices. This set was basically empty at the start of this decade, but reflecting the increased importance of this aspect of current clinical trial practice, it now includes several members, starting with the landmark work by Ellenberg et al. (2002), as well as a number of other entries (e.g., DeMets et al., 2006; Moyé, 2006) and regulatory guidance documents (CHMP, 2006; FDA, 2006).

As mentioned at the start of the preface, the focus of this book is on best practices, i.e., on setting up and implementing appropriate processes for DMC activities, and on proper behavior and execution of those processes by the parties involved. The key parties are the DMC members themselves, sponsor trial operations personnel, and personnel from the Data Analysis Center (DAC) providing results to the DMC (other roles in the process addressed to a lesser extent include Steering Committees, Institutional Review Boards [IRBs], investigators, and regulatory agencies). The text specifically focuses on safety monitoring by the DMC, i.e., ensuring patient safety by periodic monitoring of safety data, particularly examining for trends in serious adverse events. Other familiar DMC roles, such as decision making associated with group sequential schemes allowing early stopping for efficacy, or for making futility judgments, are not directly addressed here, apart from some brief discussions of how a DMC might in some circumstances take riskbenefit considerations into account.

The target audience includes those who might serve in any of the key roles just mentioned, particularly those who may be undertaking such a role for the first time, or who at least are not highly experienced in the role in which they are serving.

This book is lively and readable and has somewhat of an informal tone, no doubt heavily advised by the author’s substantial experience as a biostatistical consultant and a member of many DMCs. It gives much emphasis to real-world complications, subtleties, and “glitches” where practical realities may deviate a bit from the ideal or the anticipated. These are somewhat inevitable in DMC work, as there is a “moving target” aspect to accruing interim data; the amount of information reviewed by a DMC at an interim time point generally was not planned to be definitive for the main research questions of the study, and can be subject to various types of biasing influences as the DMC attempts to separate signal from noise. The different parties 1168

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involved may tend to have different perspectives that must be reconciled, though always with the overriding objective of protecting patient safety. Some difficulties may be avoided or minimized through increased experience and better preparation or behavior. In that vein, a particularly useful and entertaining feature of this book is “DMCounselor,” a series of questions and answers at the end of each chapter dealing with scenarios reflecting those real-world complexities, all of which have been motivated by actual experiences of the author or others.

Throughout the book, there is a useful categorization of industry sponsors into three classes: “Big Pharma,” “Middle Pharma,” “Infant Pharma.” One might perhaps quibble over a specific annual revenues threshold that would lead to a company being classified as “Big” as opposed to “Middle,” but that would miss the point that there are undeniably different tendencies of different companies, and issues that are more likely to arise depending on the size, resources, and experience of the sponsor; thus, this is a useful device for this text.

Most of the statistical material in the book is presented in an overview mode aimed at clarifying statistical concepts for non-statisticians, so there is a limited amount of statistically technical terminology. Statisticians are nevertheless very much included in the target audience for the book, because they can serve in any of the key roles associated with DMC processes and activities, whether as a member of the DMC, the sponsor team, or the DAC. Chapter 1 is introductory, providing definitions and describing the basic roles of the participants in the DMC process. It gives some relevant history and presents distinctions for how processes may be expected to differ between governmentand industry-sponsored trials, and among the different types of industry sponsors alluded to earlier, and across different types of trials (e.g., exploratory, confirmatory, open-label extensions, etc.). Chapter 2 digs a bit deeper into the various roles in the DMC process, defining the appropriate interactions among the DMC, sponsor, DAC, IRBs, and regulators. Qualifications for the various roles and characteristics that should lead to successful interactions are described.

Chapter 3 addresses meetings involving the DMC. In addition to meetings at which the DMC will review data, this chapter correctly gives much emphasis to the orientation meeting, involving the DMC, DAC, and sponsor staff involved in the trial. An effective orientation meeting is critical to ensuring that all parties have a reasonably common understanding of roles, responsibilities, monitoring objectives, processes to be followed, and aspects of the monitoring such as data flow, planned report content, masking policy, etc. Indeed, many difficulties and misunderstandings that might arise as the study progresses could be prevented if common understanding was achieved at this initial planning meeting (this point comes through clearly in some of the DMCounselor questions and answers throughout the book). Tables in this chapter give sample agendas and points of discussion for the various meeting types, which will be useful for those involved in these activities for the first time.

Chapter 4, “Clinical Issues,” contains a brief refresher of conventions and practices regarding adverse events, i.e., their definitions, categories, coding procedures. I would expect that most personnel involved in clinical trials sufficiently to be the target audience of this book should already be largely familiar with these conventions and definitions. This chapter also describes some issues specific

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to multinational clinical trials that it will be helpful for participants in the DMC process to be aware of in such trials.

Chapter 5, “Statistical Issues,” is the longest in the book, and touches on different types of quantitative issues. As within-trial DMC data review is different in nature and purpose from the more comprehensive examinations performed for a final trial report or regulatory submission, data presentations and summaries for DMCs can be expected to differ also. Data displays, both tabular and graphical, are described that have been found to be useful in facilitating DMC review. Basic concepts of statistical inference are described in a nontechnical manner for the benefit of non-statisticians. A fairly lengthy and more statistically oriented subsection describing likelihood methods and their potential role for DMC interpretation is presented; this could serve as a good introduction to this topic for statisticians not highly familiar with this methodology.

Chapter 6, “Bias and Pitfalls,” gathers and describes several mechanisms by which bias can arise and result in some distortion of safety information. These include operational bias due to knowledge of treatment assignment outside of the DMC, and issues such as incomplete follow-up and competing risks. An important issue that arises several times in the book, but most notably in this chapter, is granularity of adverse event reporting: Presentation of terms that are too finely divided can mask meaningful signals, while defining broader, less granular groupings, particularly when those groupings are defined after unmasked results have been seen, could have some potential to introduce bias.

Chapter 7, “Data Monitoring Committee Decisions,” lays out a general framework for decision processes that a DMC might face. It describes the spectrum of actions available to a DMC when its members perceive there is a safety concern, along with implications of particular actions. It addresses how the DMC might consider information external to the trial that they feel might assist their interpretation, though this is not necessarily free of pitfalls. The relevance of metaanalyses in this context is also discussed.

The book’s concluding chapter is entitled “Emerging Issues.” It describes the potential ramifications for DMC practices of some current technology changes, such as the recent interest in adaptive trial designs, and also communication technologies such as real-time Internet reporting. It describes the need for training for DMC members and how this might be achieved, and discusses changes within the pharmaceutical industry with regard to issues such as mergers, out-licensing, and a modified cost environment, and how it can be assured that these do not compromise DMC responsibilities for patient safety.

In concluding, I return to a statement in the preface in which the author points out that it might be viewed that the art and science of current DMC safety monitoring practices have reached “adolescence.” Thus, we might be at a good time point for an objective evaluation of practices based on a few decades of actual experience and factoring in the current state of various relevant technologies. This book, lively and readable and reflecting real-world experiences and lessons from DMC safety monitoring, is a useful complement to other available texts on this subject.

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REFERENCES

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Committee for Medicinal Products for Human Use. (2006). Guideline on Data Monitoring Committees. London.

DeMets, D. L., Furberg, C. D., Friedman, L. M. (2006). Data Monitoring in Clinical Trials: A Case Studies Approach. New York: Springer.

Ellenberg, S. S., Fleming, T. R., DeMets, D. L. (2002). Data Monitoring Committees in Clinical Trials: A Practical Perspective. New York: Wiley.

Food and Drug Administration. (2006). Guidance for Clinical Trial Sponsors: Establishment and Operation of Clinical Trial Data Monitoring Committees. Rockville, MD. MoyĂŠ, L. A. (2006). Statistical Monitoring of Clinical Trials: Fundamentals for Investigators.

New York: Springer.

Paul P. Gallo Novartis Pharmaceuticals, East Hanover, New Jersey