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Handbook of Neuroemergency Clinical Trials
1st Edition - December 15, 2005
Editors: Wayne M. Alves, Brett E. Skolnick
Language: English
Hardback ISBN:9780126480825
9 7 8 - 0 - 1 2 - 6 4 8 0 8 2 - 5
eBook ISBN:9780080454351
9 7 8 - 0 - 0 8 - 0 4 5 4 3 5 - 1
During the 1990’s, scientific advances in understanding the mechanisms and pathophysiology of acute central nervous system injury were offset by a history of disappointing results…Read more
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During the 1990’s, scientific advances in understanding the mechanisms and pathophysiology of acute central nervous system injury were offset by a history of disappointing results from Phase III clinical trials of novel neuroprotective drugs. Numerous novel compounds were “tested,” and seemingly fell by the wayside. This book is intended to focus on novel therapies and the unique challenges their intended targets pose for the design and analysis of clinical trials. The authors explore the issues facing research in this area and the strategies that might lead to future success in this critical area of unmet medical need. It represents a compendium of information gained from over 20 years of clinical trial experience in areas of acute neurology and neurosurgery. From the knowledge of clinical assessment using standardized tools, to the intricate design of difficult hyper-acute neuroemergencies trials, the reader will benefit from the authors’ perspectives.
* Presents new perspectives on acute neuroemergency clinical trials * Includes insights from clinical pharmacology and industry perspectives * Discusses historical lessons learned from early and recent trials in acute neuroscience populations
Researchers involved with the design of neuroemergency clinical trials, at research labs in universities, hospitals, major pharmaceutical (e.g., Astra Zeneca, GSK), biotechnology companies involved in these clinical areas.
Foreword
Acknowledgments
Introduction
Chapter 1: Acute Ischemic Stroke
Publisher Summary
STROKE THROMBOLYSIS
ANTITHROMBOTIC DRUGS
NEUROPROTECTIVE DRUGS IN ACUTE ISCHEMIC STROKE
STUMBLING FROM THE BENCH TO BEDSIDE
FUTURE STROKE TRIALS: THE STROKE THERAPY ACADEMIC INDUSTRY ROUNDTABLE
CONCLUSIONS
Chapter 2: Subarachnoid Hemorrhage
Publisher Summary
ETIOLOGY, EPIDEMIOLOGY, AND NATURAL HISTORY
DIAGNOSIS, DEFINITION OF SUBPOPULATIONS, AND OUTCOMES ASSESSMENT
CURRENT MANAGEMENT OF ANEURYSMAL SAH
NOVEL, INVESTIGATIONAL, AND FAILED THERAPEUTICS
BIOLOGICAL MARKERS, SURROGATE ENDPOINTS, AND OUTCOMES
WHY DO SO MANY CLINICAL TRIALS FAIL?
EMERGENT CLINICAL TECHNOLOGIES AND METHODOLOGIES
CONCLUSION
Chapter 3: Spontaneous Intracerebral Hemorrhage
Publisher Summary
WHY ACUTE ICH CLINICAL TRIALS ARE DIFFICULT
ANIMAL MODELS: RELEVANT ISSUES FOR CLINICAL DEVELOPMENT PROGRAMS
EPIDEMIOLOGY AND NATURAL HISTORY
DIAGNOSIS AND SUBPOPULATIONS
CURRENT DISEASE MANAGEMENT
ISSUES IN CLINICAL PROTOCOL DEVELOPMENT
OUTCOMES
EFFICACY EVALUATION
GOLD STANDARD MEASURES
SURROGATE ENDPOINTS
SAFETY EVALUATION
Chapter 4: Traumatic Brain Injury
Publisher Summary
HISTORICAL CONTEXT OF TRAUMATIC BRAIN INJURY CLINICAL TRIALS
DRUG DEVELOPMENT PROGRAMS FOR TRAUMATIC BRAIN INJURY
TRAUMATIC BRAIN INJURY DRUGS AND TREATMENTS
EARLY CLINICAL TRIALS OF DRUGS AND BIOLOGICS FOR TRAUMATIC BRAIN INJURY
WHY HAVE TRAUMATIC BRAIN INJURY CLINICAL TRIALS PROVED DIFFICULT?
CURRENT ENVIRONMENT OF TRAUMATIC BRAIN INJURY DRUG DEVELOPMENT
KEY ISSUES IN TRAUMATIC BRAIN INJURY CLINICAL TRIALS DESIGN AND ANALYSIS
IMPROVED CLASSIFICATIONS OF TRAUMATIC BRAIN INJURY POPULATIONS
DAMAGE AND OUTCOME MEASURES
SHAPE OF OUTCOME DISTRIBUTION
PHARMACOKINETIC—PHARMACODYNAMIC CORRELATIONS
CENSORING TREATMENT POPULATIONS
CONCLUSION
Chapter 5: Acute Seizures and Status Epilepticus
Publisher Summary
DEFINITIONS
ANIMAL MODELS: RELEVANT ISSUES FOR CLINICAL DEVELOPMENT PROGRAMS
EPIDEMIOLOGY AND NATURAL HISTORY
MECHANISMS OF DISEASE AND PATHOLOGY
DIAGNOSIS AND SUBPOPULATIONS
CURRENT DISEASE MANAGEMENT AND CONTROVERSIES
ISSUES IN CLINICAL PROTOCOL DEVELOPMENT
OUTCOME MEASURES
SURROGATE ENDPOINTS
SAFETY EVALUATION
CONCLUSION
Chapter 6: Clinical Trials in Neuro-Ophthalmology
Publisher Summary
OPTIC NEURITIS TREATMENT TRIAL
ISCHEMIC OPTIC NEUROPATHY DECOMPRESSION TRIAL
Outcomes of IONDT
Results of Clinical Severity Measures
Chapter 7: Brain Resuscitation
Publisher Summary
EPIDEMIOLOGY AND NATURAL HISTORY
DIAGNOSIS AND SUBPOPULATIONS
CURRENT DISEASE MANAGEMENT
ISSUES OF CLINICAL THERAPEUTIC PROTOCOL DEVELOPMENT
OUTCOMES OF RESUSCITATION
GOLD AND SILVER STANDARDS
CONCLUSION
Chapter 8: Clinical Trials in Brain Injury After Cardiac Arrest
Publisher Summary
EPIDEMIOLOGY
RESEARCH AND PRACTICE INITIATIVES
PATHOPHYSIOLOGY
SECONDARY BRAIN INJURIES AFTER CARDIAC ARREST
FUTURE DIRECTIONS
CLINICAL EDUCATION AND TRIAL NETWORKS
Chapter 9: Efficient Dose-Response Finding Strategies for Acute Neuroemergency Treatments
Publisher Summary
BACKGROUND: THE ASTIN STUDY
GENERALIZED ADAPTIVE DOSE ALLOCATION TOOL
EFFICACY AND FUTILITY
SIMULATING A STROKE TRIAL
WHAT WE NEED TO BE ABLE TO SIMULATE
WHAT WE LEARN FROM SIMULATING
THE PROBLEMS OF SIMULATING
ADAPTIVE ALLOCATION
WHAT NEXT?
ACKNOWLEDGMENT
Chapter 10: Biostatistical Issues in Neuroemergency Clinical Trials
Publisher Summary
INHERENT HETEROGENEITY OF NEUROEMERGENCY POPULATIONS
CLINICAL TESTING OF NOVEL DRUGS AND TREATMENTS
DIAGNOSIS AND SUBPOPULATIONS
DOSING AND TIMING CONSIDERATIONS
KEY DESIGN FEATURES OF NEUROEMERGENCY TRIALS
HANDLING MULTIPLICITY OF ENDPOINTS
PRECISION OF OUTCOME MEASURES
VARIATION IN PROGNOSTIC FACTORS
WIN-NO WIN RULES
STATISTICAL PLANNING CONSIDERATIONS
SELECTION BIAS
MINIMIZING POTENTIAL SOURCES OF BIAS
APPROACHES TO RANDOMIZATION
HANDLING INCOMPLETE DATA
SEQUENTIAL ANALYSIS AND STOPPING RULES
DATA ANALYSIS CONSIDERATIONS
UNRESOLVED BIOSTATISTICAL ISSUES
CONCENTRATION-OUTCOME RELATIONSHIPS
SURROGATE ENDPOINTS
ADAPTIVE TRIAL DESIGNS
ARE LARGE PRAGMATIC TRIALS NECESSARY?
Chapter 11: Data Safety and Monitoring Board: Role in Acute Neurological Trials
Publisher Summary
BACKGROUND ON DATA SAFETY MONITORING BOARDS
DSMBs IN NEUROEMERGENCIES
DSMB CHARTER
INTERACTIONS
Chapter 12: Role of a Project Medical Officer in Acute Neuroemergency Clinical Trials
Publisher Summary
PMO QUALIFICATIONS
ASSESSMENT OF STUDY FEASIBILITY
STUDY DESIGN AND IMPLEMENTATION
REVIEW OF CRF AND CRF GUIDELINES
PROVIDING MEDICAL INPUT TO REGULATORY/ETHICS AND IRBS
THERAPEUTIC TRAINING FOR SPONSOR’S STAFF
SITE SELECTION
MEDICAL SUPPORT AT INVESTIGATOR’S MEETING
MANAGING EMERGING SITE ISSUES DURING ENROLLMENT
MANAGING SITE INITIATION PROCESS AND BOOSTER ACTIVITIES
GUIDING SAE AND CRF COMPLETION ISSUES
CODING OF MEDICAL EVENTS FOR AES AND SAES
WRITING/CONTRIBUTING TO THE CLINICAL TRIAL REPORT
SUPPLEMENTING SPONSOR’S STAFF AT REGULATORY MEETINGS
SUMMARY
Chapter 13: Ethical Considerations in Neuroemergency Clinical Trials
Publisher Summary
THE CONCEPT OF RISK
THE CONCEPT OF BENEFIT
STUDY DESIGN CONSIDERATIONS
EVALUATION OF A THERAPEUTIC HYPOTHESIS
USE OF PLACEBO CONTROL SUBJECTS
STATUTORY BASIS OF CURRENT CLINICAL TRIALS REGULATIONS
GENERAL ROLE OF THE INSTITUTIONAL REVIEW BOARD
OVERVIEW OF HUMAN SUBJECTS PROTECTION REGULATIONS
INFORMED CONSENT PROCEDURES
WAIVER OF CONSENT
EMERGENCY RESEARCH CONSENT WAIVER
RESEARCH INVOLVING CHILDREN
OTHER CONSENT MECHANISMS
DEFERRED CONSENT
IRB KNOWLEDGE OF LOCAL CONDITIONS
FINANCIAL COMPENSATION ISSUES
IMPORTANT RESOURCES FOR RESEARCH ETHICS TRAINING
Chapter 14: Industry Perspective on Drug Development
Publisher Summary
SELECTION OF PHARMACOLOGICAL TARGETS AND NECROSIS VERSUS APOPTOSIS
ANIMAL MODELS
CONTROLLED CONDITIONS OF THE ANIMAL EXPERIMENT VERSUS CLINICAL CHAOS
TIME WINDOW, GLUCOSE, TEMPERATURE, AND BRAIN COMPOSITION
UNMET MEDICAL NEEDS AND DRUG DEVELOPMENT
RISKS TO NEUROTHERAPEUTIC DRUG DEVELOPERS
ECONOMICS OF CNS DRUG DEVELOPMENT
FACTORS INFLUENCING ECONOMIC FEASIBILITY IN CNS DRUG DEVELOPMENT
COSTS OF DEVELOPMENT
INDUSTRIAL INVESTMENT AND PRODUCTIVITY
DECREASED RESEARCH PRODUCTIVITY
Chapter 15: Regulatory Perspective
Publisher Summary
INVESTIGATIONAL NEW DRUG APPLICATIONS
COMMUNICATING WITH THE FDA
ROLE OF THE CORE DATA SHEET
FAST TRACK DEVELOPMENT PROGRAMS
ACCELERATED APPROVAL
SUBPART E PROGRAMS
PRIORITY REVIEW
WAIVER OF PROSPECTIVE INFORMED CONSENT
ORPHAN PRODUCT DESIGNATION
IMAGING PROTOCOLS
HEALTH INSURANCE PORTABILITY AND ACCOUNTABILITY ACT PRIVACY REGULATIONS
LICENSE APPLICATION PROCESS
POSTAPPROVAL ISSUES: MARKETING, PATIENT REGISTRIES, ADVERTISING, AND PROMOTIONAL MATERIALS
CONCLUSION
Index
No. of pages: 360
Language: English
Edition: 1
Published: December 15, 2005
Imprint: Academic Press
Hardback ISBN: 9780126480825
eBook ISBN: 9780080454351
WA
Wayne M. Alves
Dr. Alves is Vice President of Clinical Operations at Evoke Pharmaceuticals, Inc. in Solana, California. He has held academic positions conducting basic clinical research in neuroemergency populations, and has served as consultant to numerous companies seeking to develop novel drugs.
Affiliations and expertise
Valeant Pharmaceuticals Inc., Costa Mesa, CA, USA
BS
Brett E. Skolnick
Dr. Skolnick is a Clinical Associate Professor of Neurosurgery at North Shore-LIJ School of Medicine in Manhasset, New York. He has a broad based experience with development responsibilities in neurology that includes Intracerebral hemorrhage, traumatic brain injury and stroke as well as more recently in the area of inflammation having worked on the development of multiple monoclonal antibodies in Psoriasis, Rheumatoid Arthritis, Crohn’s disease and Ulcerative Colitis. Dr. Skolnick has previously worked as a clinical development consultant to pharmaceutical companies with a focus on early novel drug development.
Affiliations and expertise
Novo Nordisk Pharmaceuticals, Inc., Princeton, NJ, USA
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