Ebook: 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.

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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.

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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.

Content:
Front Matter....Pages i-xxvi
Monitoring Committees: Why and How....Pages 3-13
Lessons Learned....Pages 14-38
FDA and Clinical Trial Data Monitoring Committees....Pages 39-49
Introduction to Case Studies Showing Benefit from the Intervention....Pages 53-54
Assessing Possible Late Treatment Effects Early: The Diabetic Retinopathy Study Experience....Pages 55-63
Data and Safety Monitoring in the Beta-Blocker Heart Attack Trial: Early Experience in Formal Monitoring Methods....Pages 64-72
Data Monitoring for the Aspirin Component of the Physicians’ Health Study: Issues in Early Termination for a Major Secondary Endpoint....Pages 73-84
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....Pages 85-92
Early Termination of the Diabetes Control and Complications Trial....Pages 93-108
Data Monitoring in the AIDS Clinical Trials Group Study #981: Conflicting Interim Results....Pages 109-117
Challenges in Monitoring the Breast Cancer Prevention Trial....Pages 118-135
Data Monitoring Experience in the Metoprolol CR/XL Randomized Intervention Trial in Chronic Heart Failure: Potentially High-Risk Treatment in High-Risk Patients....Pages 136-147
Stopping the Randomized Aldactone Evaluation Study Early for Efficacy....Pages 148-157
Data Monitoring in the Heart Outcomes Prevention Evaluation and the Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events Trials: Avoiding Important Information Loss....Pages 158-165
The Data Monitoring Experience in the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity Program....Pages 166-175
Introduction to Case Studies Showing Harmful Effects of the Intervention....Pages 179-179
Breaking New Ground: Data Monitoring in the Coronary Drug Project....Pages 183-197
The Data Monitoring Experience in the Cardiac Arrhythmia Suppression Trial: The Need to Be Prepared Early....Pages 198-208
Data Monitoring in the Prospective Randomized Milrinone Survival Evaluation: Dealing With an Agonizing Trend....Pages 209-219
Stopping the Carotene and Retinol Efficacy Trial: The Viewpoint of the Safety and Endpoint Monitoring Committee....Pages 220-227
Monitoring a Clinical Trial With Waiver of Informed Consent: Diaspirin Cross-Linked Hemoglobin for Emergency Treatment of Post—Traumatic Shock....Pages 228-235
Consideration of Early Stopping and Other Challenges in Monitoring the Heart and Estrogen/Progestin Replacement Study....Pages 236-247
Data Monitoring in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial: Early Termination of the Doxazosin Treatment Arm....Pages 248-259
Case 19: Data Monitoring Experience in the Moxonidine Congestive Heart Failure Trial....Pages 260-268
Data Monitoring of a Placebo-Controlled Trial of Daclizumab in Acute Graft-Versus-Host Disease....Pages 269-277
Introduction to Case Studies With Special Issues....Pages 281-283
Clinical Trials of Herpes Simplex Encephalitis: The Role of the Data Monitoring Committee....Pages 285-291
The Nocturnal Oxygen Therapy Trial Data Monitoring Experience: Problem With Reporting Lags....Pages 292-301
Stopping a Trial for Futility: The Cooperative New Scandinavian Enalapril Survival Study II....Pages 302-311
Lessons From Warfarin Trials in Atrial Fibrillation: Missing the Window of Opportunity....Pages 312-319
Data Monitoring Experience in the AIDS Toxoplasmic Encephalitis Study....Pages 320-329
Data Monitoring in the Randomized Evaluation of Strategies for Left Ventricular Dysfunction Pilot Study: When Reasonable People Disagree....Pages 330-336
The Data Monitoring Experience in the Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction Study: Hazards of Changing Primary Outcomes....Pages 337-345
Controversies in the Early Reporting of a Clinical Trial in Early Breast Cancer....Pages 346-359
Making Independence Work: Monitoring the Bevacizumab Colorectal Cancer Clinical Trial....Pages 360-367
Back Matter....Pages 368-374

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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.

Content:
Front Matter....Pages i-xxvi
Monitoring Committees: Why and How....Pages 3-13
Lessons Learned....Pages 14-38
FDA and Clinical Trial Data Monitoring Committees....Pages 39-49
Introduction to Case Studies Showing Benefit from the Intervention....Pages 53-54
Assessing Possible Late Treatment Effects Early: The Diabetic Retinopathy Study Experience....Pages 55-63
Data and Safety Monitoring in the Beta-Blocker Heart Attack Trial: Early Experience in Formal Monitoring Methods....Pages 64-72
Data Monitoring for the Aspirin Component of the Physicians’ Health Study: Issues in Early Termination for a Major Secondary Endpoint....Pages 73-84
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....Pages 85-92
Early Termination of the Diabetes Control and Complications Trial....Pages 93-108
Data Monitoring in the AIDS Clinical Trials Group Study #981: Conflicting Interim Results....Pages 109-117
Challenges in Monitoring the Breast Cancer Prevention Trial....Pages 118-135
Data Monitoring Experience in the Metoprolol CR/XL Randomized Intervention Trial in Chronic Heart Failure: Potentially High-Risk Treatment in High-Risk Patients....Pages 136-147
Stopping the Randomized Aldactone Evaluation Study Early for Efficacy....Pages 148-157
Data Monitoring in the Heart Outcomes Prevention Evaluation and the Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events Trials: Avoiding Important Information Loss....Pages 158-165
The Data Monitoring Experience in the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity Program....Pages 166-175
Introduction to Case Studies Showing Harmful Effects of the Intervention....Pages 179-179
Breaking New Ground: Data Monitoring in the Coronary Drug Project....Pages 183-197
The Data Monitoring Experience in the Cardiac Arrhythmia Suppression Trial: The Need to Be Prepared Early....Pages 198-208
Data Monitoring in the Prospective Randomized Milrinone Survival Evaluation: Dealing With an Agonizing Trend....Pages 209-219
Stopping the Carotene and Retinol Efficacy Trial: The Viewpoint of the Safety and Endpoint Monitoring Committee....Pages 220-227
Monitoring a Clinical Trial With Waiver of Informed Consent: Diaspirin Cross-Linked Hemoglobin for Emergency Treatment of Post—Traumatic Shock....Pages 228-235
Consideration of Early Stopping and Other Challenges in Monitoring the Heart and Estrogen/Progestin Replacement Study....Pages 236-247
Data Monitoring in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial: Early Termination of the Doxazosin Treatment Arm....Pages 248-259
Case 19: Data Monitoring Experience in the Moxonidine Congestive Heart Failure Trial....Pages 260-268
Data Monitoring of a Placebo-Controlled Trial of Daclizumab in Acute Graft-Versus-Host Disease....Pages 269-277
Introduction to Case Studies With Special Issues....Pages 281-283
Clinical Trials of Herpes Simplex Encephalitis: The Role of the Data Monitoring Committee....Pages 285-291
The Nocturnal Oxygen Therapy Trial Data Monitoring Experience: Problem With Reporting Lags....Pages 292-301
Stopping a Trial for Futility: The Cooperative New Scandinavian Enalapril Survival Study II....Pages 302-311
Lessons From Warfarin Trials in Atrial Fibrillation: Missing the Window of Opportunity....Pages 312-319
Data Monitoring Experience in the AIDS Toxoplasmic Encephalitis Study....Pages 320-329
Data Monitoring in the Randomized Evaluation of Strategies for Left Ventricular Dysfunction Pilot Study: When Reasonable People Disagree....Pages 330-336
The Data Monitoring Experience in the Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction Study: Hazards of Changing Primary Outcomes....Pages 337-345
Controversies in the Early Reporting of a Clinical Trial in Early Breast Cancer....Pages 346-359
Making Independence Work: Monitoring the Bevacizumab Colorectal Cancer Clinical Trial....Pages 360-367
Back Matter....Pages 368-374
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