Data Monitoring Committees in Clinical Trials

A Practical Perspective

Susan S. Ellenberg, Thomas R. Fleming, David L. DeMets

• Publisher: Wiley
• Year: 2019
• Print ISBN: 9781119512653
• eBook ISBN: 9781119512677
• Edition: 2
• Topic: Medicine
• Subtopic: Pharmacology

­The authoritative guide for Data Monitoring Committees—fully revised and updated

The number of clinical trials sponsored by government agencies and pharmaceutical companies has grown in recent years, prompting an increased need for interim monitoring of data on safety and efficacy. Data Monitoring Committees (DMCs) are an essential component of many clinical trials, safeguarding trial participants and protecting the credibility and validity of the study. Data Monitoring Committees in Clinical Trials: A Practical Perspective, 2nd Edition offers practical advice for those managing and conducting clinical trials and serving on Data Monitoring Committees, providing a practical overview of the establishment, purpose, and responsibilities of these committees.

Examination of topics such as the composition and independence of DMCs, statistical, philosophical and ethical considerations, and determining when a DMC is needed, presents readers with a comprehensive foundational knowledge of clinical trial oversight.

Providing recent examples to illustrate DMC principles, this fully-updated guide reflects current developments and practices in clinical trial oversight and offers expanded coverage of emerging issues and challenges in the field. This new second edition covers the most current information on DMC policies, issues in monitoring trials using new designs, and recent trial publications relevant to DMC decision-making.

• Presents practical advice for those managing and conducting clinical trials and serving on Data Monitoring Committees

• Illustrates the types of challenging issues Data Monitoring Committees face in practical situations

• Provides updated and expanded coverage of topics including regulatory and funding agency guidelines and trial designs and their associated demands and limitations

• Includes a new chapter addressing legal issues that affect DMC members and discusses general litigation concerns relevant to clinical research

• Expands treatment of current journal publications addressing DMC issues

Data Monitoring Committees in Clinical Trials: A Practical Perspective, 2nd Edition is a must-have text for anyone engaged in DMC activities as well as trial sponsors, clinical trial researchers, regulatory and bioethics professionals, and those associated with clinical trials in academic, government and industry settings.

1
Introduction

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Key Points

• The purpose of data monitoring committees (DMCs) is to protect the safety of trial participants, the credibility of the study, and the validity of study results.
• DMCs have a long history in trials sponsored by government agencies in the USA and Europe.
• Pharmaceutical companies use DMCs in many trials of investigational drugs, biologics, and medical devices.
• Statistical methods have been developed for interim monitoring of clinical trials.
• While not all trials need DMCs, trials that address major health outcomes and are designed to definitively address efficacy and safety issues should incorporate DMC oversight.

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1.1 Motivation

In randomized clinical trials designed to assess the efficacy and safety of medical interventions, evolving data are typically reviewed on a periodic basis during the conduct of the study. These interim reviews are especially important in trials conducted in the setting of diseases that are life‐threatening or result in irreversible major morbidity. Such reviews have many purposes. They may identify unacceptably slow rates of accrual or high rates of ineligibility determined after randomization, protocol violations that suggest that clarification of or changes to the study protocol are needed, or unexpectedly high dropout rates that threaten the trial's ability to produce credible results. The most important purpose, however, is to ensure that the trial remains appropriate and safe for the individuals who have been or are still to be enrolled. Unacceptable levels of treatment toxicity may require an adjustment of dosage or schedule of administration, or even abandonment of the study. Efficacy results, too, must be monitored to enable benefit‐to‐risk assessments. Interim results may demonstrate that one intervention group has such unfavorable outcomes with regard to survival or a major morbidity endpoint that its benefit‐to‐risk profile is clearly inferior to that of the comparator treatment. In such cases, it may be appropriate to terminate the inferior intervention or the entire trial early so that current study participants, as well as future patients, will no longer be provided with inferior treatment.

Relatively early in the development of modern clinical trial methodology, some investigators recognized that, despite the compelling ethical need to monitor the accumulating results, repeated review of interim data raised some problems. Repeated statistical testing was seen to increase the chance of a “false positive” result unless nominal significance levels were somehow adjusted. In addition, it was recognized that awareness of the pattern of accumulating data on the part of investigators, sponsors or trial participants could affect the course of the trial and the validity of the results. For example, if investigators were aware that the interim trial results were favoring one of the treatment groups, they might be reluctant to continue to encourage adherence to all regimens in the trial, or to continue to enter patients on the trial, or they might limit the types of patients they would consider entering. Furthermore, influenced by financial or scientific conflicts of interest, investigators or the sponsor might take actions that could diminish the integrity or credibility of the trial. For example, a sponsor observing interim data showing that the new treatment had little if any effect on the pre‐specified primary endpoint but a much stronger effect on an important secondary endpoint might be tempted to switch the designation of these two endpoints.

A natural – and practical – approach to dealing with these problems is to assign sole responsibility for interim monitoring of data on safety and efficacy to a committee whose members have no involvement in the trial, no vested interest in the trial results, and sufficient understanding of trial design, conduct and data‐analytical issues to interpret interim analyses with appropriate caution. These “data monitoring committees” (DMCs) have become critical components of many clinical trials.

The interim monitoring experience of an early AIDS clinical trial illustrates some of the inherent difficulties and challenges that arise in the review of accumulating data from clinical trials.

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Example 1.1 Treatment for HIV infection

Trial 002 of the Community Programs for Clinical Research in AIDS (CPCRA) was designed to compare the efficacy of two antiretroviral agents, zalcitabine (ddC) and didanosine (ddI), in HIV‐infected patients who did not derive benefit from zidovudine (AZT), at that time the first‐line treatment for HIV infection (Abrams et al. 1994). When the trial was initiated, ddI was considered the first‐line treatment in this patient population; the goal of the trial was to determine whether ddC was approximately equivalent to ddI by seeing whether as much as a 25% advantage for ddI in the time to disease progression or death could be ruled out. A total of 467 patients were randomized to receive either ddI or ddC. To achieve the desired level of statistical power, it was calculated that patient follow‐up would be needed until 243 patients had been observed to reach the endpoint of disease progression or death.

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This trial was initiated in December 1990, at a time when little in the way of effective treatments for this population was available, when the numbers of new HIV infections and deaths were increasing, and when both the patient community and their physicians were increasingly desperate to identify treatments that could buy a little more time for those suffering from this disease. Patients entering such trials were generally young men who were facing a very premature death from a disease they may not have even known about at the time they contracted it. Further, more pharmaceutical companies were initiating drug development for treatment of HIV, but with a great deal of caution, as would be expected in a completely new disease area. While there are inherent tensions in all trials testing new agents for serious diseases, the atmosphere surrounding early trials of AIDS treatments, such as this one, was particularly “high pressure.” Trial 002 was monitored by the DMC that had been established by the National Institute of Allergy and Infectious Diseases (NIAID) to oversee all of its extramural trials of treatment for HIV infection (DeMets et al. 1995). The CPCRA was a clinical trials group funded by NIAID; therefore, access to interim data was limited to DMC members – none of whom were treating patients on this or any other NIAID‐funded AIDS trial, or had any financial stake in the trial outcome – and to a limited number of NIAID staff.

The interim results from this trial, shown in Figures 1.1 and 1.2, illustrate how substantially relative risk estimates can change over time. At the first interim analysis in August 1991, the early trial results strongly favored ddI. At that time, the ddI group had experienced many fewer disease progressions (19 versus 39) and fewer deaths (6 versus 12) than the ddC group. The effects on...

Table of contents

• Cover
• Table of Contents
• Preface to the Second Edition
• Preface to the First Edition
• 1 Introduction
• 2 Responsibilities of the Data Monitoring Committee and Motivating Illustrations
• 3 Composition of a Data Monitoring Committee
• 4 Independence of the Data Monitoring Committee: Avoiding Conflicts of Interest
• 5 Confidentiality Issues Relating to the Data Monitoring Committee
• 6 Data Monitoring Committee Meetings
• 7 Data Monitoring Committee Interactions with Other Trial Components or Related Groups
• 8 Statistical, Philosophical, and Ethical Issues in Data Monitoring
• 9 Determining When a Data Monitoring Committee is Needed
• 10 Regulatory Considerations for the Operation of Data Monitoring Committees
• 11 Legal Considerations for DMCs
• Appendix A: The Data Monitoring Committee Charter
• Appendix B: Performance Standards Document
• Statistics in Practice
• Index
• End User License Agreement