Data and Safety Monitoring Committees in Clinical Trials

Jay Herson

• Publisher: Chapman and Hall/CRC
• Year: 2016
• ISBN:
  9781351722377
• Edition: 2
• Topic: Matemáticas
• Subtopic: Probabilidad y estadística

Praise for the first edition:

"Given the author's years of experience as a statistician and as a founder of the first DMC in pharmaceutical industry trials, I highly recommend this book—not only for experts because of its cogent and organized presentation, but more importantly for young investigators who are seeking information about the logistical and philosophical aspects of a DMC."

-S. T. Ounpraseuth, The American Statistician

In the first edition of this well-regarded book, the author provided a groundbreaking and definitive guide to best practices in pharmaceutical industry data monitoring committees (DMCs). Maintaining all the material from the first edition and adding substantial new material, Data and Safety Monitoring Committees in Clinical Trials, Second Edition is ideal for training professionals to serve on their first DMC as well as for experienced clinical and biostatistical DMC members, sponsor and regulatory agency staff.

The second edition guides the reader through newly emerging DMC responsibilities brought about by regulations emphasizing risk vs benefit and the emergence of risk-based monitoring. It also provides the reader with many new statistical methods, clinical trial designs and clinical terminology that have emerged since the first edition. The references have been updated and the very popular end-of-chapter Q&A section has been supplemented with many new experiences since the first edition.

New to the Second Edition:

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• Presents statistical methods, tables, listings and graphs appropriate for safety review, efficacy analysis and risk vs benefit analysis, SPERT and PRISMA initiatives.

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• Newly added interim analysis for efficacy and futility section.

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• DMC responsibilities in SUSARs (Serious Unexpected Serious Adverse Reactions), basket trials, umbrella trials, dynamic treatment strategies /SMART trials, pragmatic trials, biosimilar trials, companion diagnostics, etc.

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• DMC responsibilities for data quality and fraud detection (Fraud Recovery Plan)

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• Use of patient reported outcomes of safety

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• Use of meta analysis and data outside the trial

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• New ideas for training and compensation of DMC members

Jay Herson is Senior Associate, Biostatistics, Johns Hopkins Bloomberg School of Public Health where he teaches courses on clinical trials and drug development based on his many years experience in clinical trials in academia and the pharmaceutical industry.

1

Introduction

PREVIEW The data monitoring committee is the keystone of the stewardship and the scientific/ethical integrity of a clinical trial. The independent review of safety in clinical trials began in the public-funded clinical trials and has become the mainstream in pharmaceutical industry clinical trials today. After acknowledging the limitations of a single clinical trial to find rare adverse events, a rule of thumb for measuring the sensitivity of a clinical program that observes adverse events of various frequencies is presented. Issues involved in safety monitoring may differ between the size of industry sponsor and public versus private company.

KEY WORDS: adverse event, Big Pharma, confirmatory clinical trial, data monitoring committee, Infant Pharma, masked, Middle Pharma, serious adverse event, sponsor

1.1 What Is a Data Monitoring Committee (DMC)?

Professor Jerome Cornfield once defined a clinical trial as cogent description (Cornfield 1973). It has become clear that objectivity in reviewing accumulating data in clinical trials is extremely important in maintaining cogency. One factor that can operate against cogency is bias. We will discuss the concept of bias in Chapter 6, but for now, let’s define it as a conscious or unconscious lack of objectivity due to a sponsor staff’s interest in getting the experimental treatment approved by regulatory agencies. Clinical trial sponsor staff can introduce bias into trial conduct if they review efficacy data during the trial and may have a tendency to underplay the importance of adverse events that present during the trial. This is especially true in oncology trials which are usually conducted with sponsor staff, investigators, and patients all aware of treatment assignment. Although sponsors tended to claim that their trial management did not introduce bias, the current feeling is that if clinical trial results are to be persuasive to regulatory agencies, practicing physicians, and the general public, even the appearance of bias must be avoided. The problem is complicated by the fact that investigators and others associated with the trial can also introduce bias. While bias reduction is important for scientific and regulatory reasons, it has also become evident that objective review of accumulating data is necessary to protect patient safety.

In the late 1980s, following the example of clinical trials run by the U.S. federal government through agencies such as the National Institutes of Health (NIH), the Veterans Administration (VA) and the Centers for Disease Control and Prevention (CDC), the British Medical Research Council, and the French INSERM, the pharmaceutical industry began to form DMCs. These committees took on various names and were of various forms. Initially some of these committees included members who were sponsor staff but regulatory agencies took a dim view of this practice. Eventually, membership evolved to individuals who were not members of the sponsor staff but were physicians of appropriate specialties and experienced clinical trial biostatisticians who could be trusted to review efficacy and safety data in such a way that bias is minimized. In subsequent chapters, we will review “best practices” for minimizing bias and for DMC operations in general. This book will concentrate on the safety role of the DMC in industry-sponsored trials. Safety data constitute 85% of data collected in clinical trials submitted to the U.S. Food and Drug Administration (Rochester 2008), are evaluated more subjectively than efficacy data, and, experience shows, constitute about 90% of DMC operations.

A recent draft guidance by the FDA on safety assessment practices introduces the term “Safety Assessment Committee (SAC).” The role of this committee is broader than that of the DMC. While the DMC will consist entirely outside consultants, the SAC will consist of sponsor internal as well as outside experts and will integrate safety information from a development program with information from other clinical trials of the same or similar drugs, preclinical studies, epidemiologic studies, and so on, in order to form a complete impression on emerging adverse events. There is also considerable overlap between DMC and SAC responsibilities and there may be some common members to both committees. There is no reason that a DMC cannot be a subcommittee of an SAC. Until there is some experience with the SAC concept, there is likely to be confusion as to who has the last word on the experimental drug’s safety profile. For now, it is important to note that the DMC is smaller and more focused than the SAC. We will continue to refer to the key safety committee as the DMC but, going forward, the reader should expect to see the term safety assessment committee appear in the literature (U.S. Food and Drug Administration 2015a).

1.2 Some Definitions

It will be useful to provide some brief definitions of important terms. We will return to these terms to provide more rigorous definitions later in the book.

The sponsor of a trial is the organization that has the ultimate responsibility for reporting the results to the regulatory authorities. For our purposes, it will most often be a pharmaceutical or biotechnology company but it could be a university, government agency, or, in the case of orphan drugs, a patient–parent support group.

An adverse event (AE) is any unfavorable and unintended sign (e.g., including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not considered related to the drug. An adverse event is deemed treatment-emergent if the adverse event is not a manifestation of a condition that existed prior to the clinical trial. It is not always easy to make this distinction. A serious adverse event (SAE) is any untoward medical occurrence that, at any dose, results in death, is life-threatening, requires inpatient hospitalization, or prolongation of existing hospitalization. This is the regulatory definition. We will see in Chapter 4, that this definition may generate different types of adverse events as serious in different countries due to differences in hospitalization policy.

The reader will be familiar with patients and possibly investigators being blinded to treatment assignment. In deference to our ophthalmology colleagues, we will use the term masked as a synonym for blinded. When treatment assignment is not masked to anyone we usually use the term open label.

The term monitoring is used in several different contexts in the pharmaceutical industry. Statistical monitoring refers to making calculations on accumulating efficacy data to justify early termination of a clinical trial (Proschan, Lan, and Wittes 2006) and/or sample size reestimation (Chuang-Stein, Anderson, Gallo et al. 2006). Safety monitoring by sponsor staff and DMC members refers to continual review of accumulating safety data during the trial. Site monitoring is a quality control procedure applied periodically during the trial by sponsor or contract clinical research associates (CRAs) (Woodin and Schneider 2003). In Chapter 8, we will review the newly emerging science of centralized statistical monitoring.

1.3 DMC in Federal Government–Sponsored Clinical Trials versus Pharmaceutical Industry Clinical Trials

DMCs had long been included in federal ...