Data Monitoring in Clinical Trials A Case Studies Approach

Randomized clinical trials are the gold standard for establishing many clinical practice guidelines and are central to evidence based medicine. Obtaining the best evidence through clinical trials must be done within the boundaries of rigorous science and ethical principles. One fundamental principle is that trials should not continue longer than necessary to reach their objectives. Therefore, trials must be monitored for recruitment progress, quality of data, adherence to patient care or prevention standards, and early evidence of benefit or harm. Frequently, a group of external experts, independent from the investigators and trial sponsor, is charged with this monitoring responsibility, especially for safety and early benefit. This group is referred to by various names, such as a data monitoring committee or a data and safety monitoring board. This book, through a series of case studies presented by many distinguished clinical trial experts, illustrates the complexity of this monitoring process. The editors provide an overview of the process and a summary of a multitude of the lessons learned from the cases presented.

This book should be useful to anyone serving on a data and safety monitoring board, or planning to do so, for colleagues in academia, industry and governmental agencies, and for teaching students in biostatistics, epidemiology, clinical trials and medical ethics. No other text has as extensive a collection of cases which provide insight into the many issues, often conflicting, that must be examined before recommendations to continue or discontinue a trial can be made. While depth in statistical methods is not required, some familiarity with statistical design and analysis issues in clinical trials is helpful. The cases cover trials which were terminated early for convincing evidence of benefit, or for harmful effects. Cases with complex issues are also included. This series of cases should provide broad background information for potential monitoring committee members and better prepare them for the challenges that may exist in the trials for which they are responsible.

The three editors have contributed two overview chapters as well as several case studies to go along with cases contributed by a distinguished group of colleagues experienced in the design, monitoring and analysis of clinical trials. Dr. David DeMets is currently Professor and Chair, Department of Biostatistics and Medical Informatics at the University of Wisconsin-Madison. He is past president of the Eastern North American Region (ENAR) of the International Biometric Society, a past member of the Board of Directors of the American Statistical Association and an elected Fellow. He recently received the Robert Gordon Lectureship Award, given by the National Institutes of Health, for significant contributions to the field of clinical trials. Dr. Curt Furberg, is currently Professor (and former Chair) of the Department of Public Health Sciences at Wake Forest University. Previously, he was Head of the Clinical Trials Branch and Associate Director of the Clinical Applications and Prevention Program at the National Heart, Lung, and Blood Institute. Dr. Lawrence Friedman is a former Director of the Division of Epidemiology and Clinical Applications and a former Assistant Director for Ethics and Clinical Research at the National Heart, Lung, and Blood Institute. All three are past presidents of the Society of Clinical Trials. The editors have collaborated previously as coauthors of a text: the Fundamentals of Clinical Trials.

Monitoring Committees: Why and How–David L. DeMets, Curt D. Furberg, Lawrence M. Friedman .-Lessons Learned–David L. DeMets .- FDA Perspective–Susan S. Ellenberg and Jay P. Siegel.- Introduction–Lawrence M. Friedman .- Assessing Possible Late Treatment Effects Early- The Diabetic Retinopathy Study Experience–Fred Ederer .- Data and Safety Monitoring in the Beta-Blocker Heart Attack Trial- Early Experiences in Formal Monitoring Methods–Lawrence M. Friedman, David L. DeMets and Robert Hardy .- Data Monitoring for the Aspirin Component of the Physicians Health Study- Importance of Secondary Outcomes–David L. DeMets and Charles H. Hennekens .- Early Termination of the Stroke Prevention in Atrial Fibrillation I Trial- Protecting Participant Interests in the Face of Scientific Uncertainties and the Cruel Play of Chance–Robert G. Hart, Lesly A. Pearce, Ruth McBride and Richard A. Kronmal .- Early Termination of the Diabetes Control and Complications Trial – Methodologic Issues–John M Lachin, Patricia Cleary, Oscar Crofford, Saul Genuth, David Nathan, Charles Clark, Frederick Ferris, and Carolyn Sieberg for the DCCT Research Group .- Data Monitoring in the AIDS Clinical Trials Group Study #981- Conflicting Interim Results–Dianne Finkelstein .- Challenges in Monitoring the Breast Cancer Prevention Trial–Carol K. Redmond,Joseph P. Costantino andTheodore Colton .- Metoprolol CR/XL Randomized Intervention Trial in Chronic Heart Failure- Potentially High Risk Treatment in High Risk Patients–Jan Feyzi, Desmond Julian, John Wikstrand and Hans Wedel .- Stopping the Randomized Aldactone Evaluation Study Early for Efficacy–Janet Wittes, Jean-Pierre Boissel, Curt Furberg, Desmond Julian, Henri Kulbertus and Stuart Pocock .- Data Monitoring in the Heart Outcomes Prevention Evaluation and the Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events Trials- Avoiding Important Information Loss–Janice Pogue, David Sackett, George Wyse and SalimYusuf .- Data Monitoring in the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity Program–Stuart Pocock, Duolao Wang,Lars Wilhelmsen andCharles Hennekens .- Intro–Curt D. Furberg .- Breaking New Ground - Data Monitoring in the Coronary Drug Project–Paul L. Canner .- Data Monitoring in the Cardiac Arrhythmia Suppression Trial – The Need to Be Prepared Early–David L. DeMets and Lawrence M. Friedman .- Data Monitoring in the Prospective Randomized Milrinone Survival Evaluation Trial- Dealing with an Agonizing Trend–Susan Anderson, Robert Cody, Milton Packer andRichard Schwarz .- Stopping the Carotene and Retinol Efficacy Trial - The Viewpoint of the Safety and Endpoint Monitoring Committee–Anthony B. Miller, Julie Buring and O. Dale Williams .- Monitoring a Clinical Trial with Waiver of Informed Consent: Diaspirin Cross-Linked Hemoglobin for Emergency Treatment of Post - Traumatic Shock–Roger L. Lewis and Norman Fost .- Challenges in Monitoring the Heart and Estrogen/progestin Replacement Study–Stephen B. Hulley,Deborah Grady, Eric Vittinghoff and O. Dale Williams .- Data Monitoring in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial- Early Termination of the Doxazosin Arm–Barry R. Davis and Jeffrey A. Cutler .- Data Monitoring in the Moxonidone Congestive Heart Failure Trial–Stuart Pocock, Lars Wilhelmsen, Kenneth Dickstein, Gary Francis and Janet Wittes .- Data Monitoring of a Placebo-controlled Trial of Daclizumab in Acute Graft-versus-Host Disease–David Zahrich, Stephanie J. Lee and David Harrington .- Introduction–David L. DeMets .- Clinical Trials of Herpes Simplex Encephalitis: The Role of the Data Monitoring Committee–Richard J. Whitley .- The Nocturnal Oxygen Therapy Trial Data Monitoring Experience – Problem with Reporting Lags–David L. DeMets, George W. Williams andByron W. Brown, Jr. .- The Cooperative North Scandinavian Enalapril Survival Study II Trial–Steven