Handbook of Neuroemergency Clinical Trials (eBook)

Cover 3
Contents 7
Foreword 11
Acknowledgments 13
Introduction 15
Contributors 21
Chapter 1: Acute Ischemic Stroke 23
Stroke Thrombolysis 23
Antithrombotic Drugs 29
Neuroprotective Drugs in Acute Ischemic Stroke 29
Stumbling from the Bench to Bedside 32
Future Stroke Trials: The Stroke Therapy Academic Industry Roundtable 34
Conclusions 35
References 35
Chapter 2: Subarachnoid Hemorrhage 39
Etiology, Epidemiology, and Natural History 39
Diagnosis, Definition of Subpopulations, and Outcomes Assessment 42
Current Management of Aneurysmal Sah 44
Novel, Investigational, and Failed Therapeutics 50
Biological Markers, Surrogate Endpoints, and Outcomes 58
Why Do So Many Clinical Trials Fail? 58
Emergent Clinical Technologies and Methodologies 59
Conclusion 60
References 61
Chapter 3: Spontaneous Intracerebral Hemorrhage 67
Why Acute Ich Clinical Trials Are Difficult 67
Animal Models: Relevant Issues for Clinical Development Programs 68
Epidemiology and Natural History 70
Diagnosis and Subpopulations 73
Current Disease Management 74
Issues in Clinical Protocol Development 75
Outcomes 75
Efficacy Evaluation 76
Gold Standard Measures 77
Surrogate Endpoints 77
Safety Evaluation 78
References 78
Chapter 4: Traumatic Brain Injury 83
Historical Context of Traumatic Brain Injury Clinical Trials 83
Drug Development Programs for Traumatic Brain Injury 85
Traumatic Brain Injury Drugs and Treatments 86
Early Clinical Trials of Drugs and Biologics for Traumatic Brain Injury 87
Why Have Traumatic Brain Injury Clinical Trials Proved Difficult? 89
Current Environment of Traumatic Brain Injury Drug Development 91
Key Issues in Traumatic Brain Injury Clinical Trials Design and Analysis 91
Improved Classifications of Traumatic Brain Injury Populations 93
Damage and Outcome Measures 93
Shape of Outcome Distribution 96
Pharmacokinetic— Pharmacodynamic Correlations 97
Censoring Treatment Populations 97
Conclusion 97
References 98
Chapter 5: Acute Seizures and Status Epilepticus 103
Definitions 103
Animal Models: Relevant Issues for Clinical Development Programs 105
Epidemiology and Natural History 109
Mechanisms of Disease and Pathology 115
Diagnosis and Subpopulations 116
Current Disease Management and Controversies 120
Issues in Clinical Protocol Development 131
Outcome Measures 133
Surrogate Endpoints 137
Safety Evaluation 138
Conclusion 138
References 139
Chapter 6: Clinical Trials in Neuro-Ophthalmology 147
Optic Neuritis Treatment Trial 147
Ischemic Optic Neuropathy Decompression Trial 156
References 165
Chapter 7: Brain Resuscitation 169
Epidemiology and Natural History 170
Diagnosis and Subpopulations 171
Current Disease Management 174
Issues of Clinical Therapeutic Protocol Development 177
Outcomes of Resuscitation 178
Gold and Silver Standards 178
Conclusion 178
References 179
Chapter 8: Clinical Trials in Brain Injury After Cardiac Arrest 181
Epidemiology 181
Research and Practice Initiatives 181
Pathophysiology 183
Secondary Brain Injuries After Cardiac Arrest 192
Future Directions 194
Clinical Education and Trial Networks 195
References 195
Chapter 9: Efficient Dose-Response Finding Strategies for Acute Neuroemergency Treatments 201
Background: The ASTIN Study 201
Generalized Adaptive Dose Allocation Tool 205
Efficacy and Futility 205
Simulating a Stroke Trial 207
What We Need To Be Able To Simulate 215
What We Learn from Simulating 219
The Problems of Simulating 220
Adaptive Allocation 222
What Next? 224
Acknowledgment 225
References 225
Chapter 10: Biostatistical Issues in Neuroemergency Clinical Trials 227
Inherent Heterogeneity of Neuroemergency Populations 228
Clinical Testing of Novel Drugs and Treatments 229
Diagnosis and Subpopulations 231
Dosing and Timing Considerations 232
Key Design Features of Neuroemergency Trials 233
Handling Multiplicity of Endpoints 235
Precision of Outcome Measures 235
Variation in Prognostic Factors 236
Win–No Win Rules 237
Statistical Planning Considerations 239
Selection Bias 242
Minimizing Potential Sources of Bias 242
Approaches to Randomization 243
Handling Incomplete Data 244
Sequential Analysis and Stopping Rules 244
Data Analysis Considerations 244
Unresolved Biostatistical Issues 245
Concentration-Outcome Relationships 246
Surrogate Endpoints 246
Adaptive Trial Designs 246
Are Large Pragmatic Trials Necessary? 247
References 248
Chapter 11: Data Safety and Monitoring Board: Role in Acute Neurological Trials 251
Background on Data Safety Monitoring Boards 251
DSMBs in Neuroemergencies 252
DSMB Charter 260
Interactions 262
Summary 264
References 264
Appendix A. Sample DSMB Charter 265
Appendix B. Conflict of Interest Statement for DSMB Members 268
Chapter 12: Role of a Project Medical Officer in Acute Neuroemergency Clinical Trials 269
PMO Qualifications 270
Assessment of Study Feasibility 270
Study Design and Implementation 271
Review of CRF and CRF Guidelines 272
Providing Medical Input to Regulatory/Ethics and IRBs 272
Therapeutic Training for Sponsor’S Staff 273
Site Selection 274
Medical Support at Investigator’s Meeting 274
Managing Emerging Site Issues During Enrollment 274
Managing Site Initiation Process and Booster Activities 276
Guiding Sae and CRF Completion Issues 276
Coding of Medical Events for AES and SAEs 276
Writing/Contributing to the Clinical Trial Report 277
Supplementing Sponsor’s Staff at Regulatory Meetings 277
Summary 277
Chapter 13: Ethical Considerations in Neuroemergency Clinical Trials 279
The Concept of Risk 280
The Concept of Benefit 280
Study Design Considerations 282
Evaluation of a Therapeutic Hypothesis 282
Use of Placebo Control Subjects 283
Statutory Basis of Current Clinical Trials Regulations 283
General Role of the Institutional Review Board 283
Overview of Human Subjects Protection Regulations 284
Informed Consent Procedures 286
Waiver of Consent 287
Emergency Research Consent Waiver 288
Research Involving Children 288
Other Consent Mechanisms 289
Deferred Consent 289
IRB Knowledge of Local Conditions 290
Financial Compensation Issues 290
Important Resources for Research Ethics Training 293
References 294
Chapter 14: Industry Perspective on Drug Development 297
Selection of Pharmacological Targets and Necrosis Versus Apoptosis 297
Animal Models 298
Controlled Conditions of the Animal Experiment Versus Clinical Chaos 298
Time Window, Glucose, Temperature, and Brain Composition 299
Unmet Medical Needs and Drug Development 300
Risks to Neurotherapeutic Drug 301
Economics of CNS Drug Development 301
Factors Influencing Economic Feasibility in CNS Drug Development 302
Costs of Development 303
Industrial Investment and Productivity 305
Decreased Research Productivity 305
References 307
Chapter 15: Regulatory Perspective 309
Investigational New Drug Applications 309
Communicating with the FDA 312
Role of the Core Data Sheet 315
Fast Track Development Programs 316
Accelerated Approval 321
Subpart E Programs 323
Priority Review 324
Waiver of Prospective Informed Consent 324
Orphan Product Designation 328
Imaging Protocols 330
Health Insurance Portability and Accountability Act Privacy Regulations 331
License Application Process 332
Postapproval Issues: Marketing, Patient Registries, Advertising, and Promotional Materials 335
Conclusion 336
References 336
Index 341