Handbook Of Neuroemergency Clinical Trials

by Skolnick; Alves

• ISBN13: 9780126480825
• ISBN10: 0126480826
• Format: Hardcover
• Copyright: 2005-12-15
• Publisher: Elsevier Science

Summary

"This book is intended to initiate the sharing of neuroemergency clinical trial experiences between the various indications typically studied by neurology and neurosurgical sub-specialties. The goal is to extend lessons learned from various therapeutic areas to be able to improve upon the methodologies and strategies for the development of innovative therapies. Authors from both private and public sectors focus on the "state of the practice" of neuroemergency clinical trials, exploring the issues we face and the strategies that might lead to future successes in this critical area of unmet medical need."--BOOK JACKET.

Table of Contents

Foreword	ix
Acknowledgments	xi
Introduction	xiii
Acute Ischemic Stroke
Christopher Bladin
Stephen Davis
Stroke Thrombolysis	1	(6)
Antithrombotic Drugs	7	(1)
Neuroprotective Drugs in Acute Ischemic Stroke	7	(3)
Stumbling from the Bench to Bedside	10	(2)
Future Stroke Trials: The Stroke Therapy Academic Industry Roundtable	12	(1)
Conclusions	13	(1)
References	13	(4)
Subarachnoid Hemorrhage
Nader Pouration
Aaron S. Dumont
Neal F. Kassell
Etiology, Epidemiology, and Natural History	17	(3)
Diagnosis, Definition of Subpopulations, and Outcomes Assessment	20	(2)
Current Management of Aneurysmal SAH	22	(6)
Novel, Investigational, and Failed Therapeutics	28	(8)
Biological Markers, Surrogate Endpoints, and Outcomes	36	(1)
Why Do So Many Clinical Trials Fail?	36	(1)
Emergent Clinical Technologies and Methodologies	37	(1)
Conclusion	38	(1)
References	39	(6)
Spontaneous Intracerebral Hemorrhage
Michael D. Hill
Why Acute ICH Clinical Trials Are Difficult	45	(1)
Animal Models: Relevant Issues for Clinical Development Programs	46	(1)
Epidemiology and Natural History	47	(4)
Diagnosis and Subpopulations	51	(1)
Current Disease Management	52	(1)
Issues in Clinical Protocol Development	53	(1)
Outcomes	53	(1)
Efficacy Evaluation	54	(1)
Gold Standard Measures	55	(1)
Surrogate Endpoints	55	(1)
Safety Evaluation	56	(1)
References	56	(5)
Traumatic Brain Injury
Wayne M. Alves
Lawrence F. Marshall
Historic Context of Traumatic Brain Injury Clinical Trials	61	(2)
Drug Development Programs for Traumatic Brain Injury	63	(1)
Traumatic Brain Injury Drugs and Treatments	64	(1)
Early Clinical Trials of Drugs and Biologics for Traumatic Brain Injury	65	(2)
Why Have Traumatic Brain Injury Clinical Trials Proved Difficult?	67	(2)
Current Environment of Traumatic Brain Injury Drug Development	69	(1)
Key Issues in Traumatic Brain Injury Clinical Trials Design and Analysis	69	(2)
Improved Classifications of Traumatic Brain Injury Populations	71	(1)
Damage and Outcome Measures	71	(3)
Shape of Outcome Distribution	74	(1)
Pharmacokinetic---Pharmacodynamic Correlations	75	(1)
Censoring Treatment Populations	75	(1)
Conclusion	75	(1)
References	76	(5)
Acute Seizures and Status Epilepticus
Susan Herman
Definitions	81	(2)
Animal Models: Relevant Issues for Clinical Development Programs	83	(4)
Epidemiology and Natural History	87	(6)
Mechanisms of Disease and Pathology	93	(1)
Diagnosis and Subpopulations	94	(4)
Current Disease Management and Controversies	98	(11)
Issues in Clinical Protocol Development	109	(2)
Outcome Measures	111	(4)
Surrogate Endpoints	115	(1)
Safety Evaluation	116	(1)
Conclusion	116	(1)
References	117	(8)
Clinical Trials in Neuro-Ophthalmology
Madhura Tamhankar
Laura Balcer
Optic Neuritis Treatment Trial	125	(9)
Ischemic Optic Neuropathy Decompression Trial	134	(9)
References	143	(5)
Brain Resuscitation
Edwin Nemoto
Charles C. King
Epidemiology and Natural History	148	(1)
Diagnosis and Subpopulations	149	(3)
Current Disease Management	152	(3)
Issues of Clinical Therapeutic Protocol Development	155	(1)
Outcomes of Resuscitation	156	(1)
Gold and Silver Standards	156	(1)
Conclusion	156	(1)
References	157	(2)
Clinical Trials in Brain Injury After Cardiac Arrest
Romergryko G. Geocadin
Daniel F. Hanley
Epidemiology	159	(1)
Research and Practice Initiatives	159	(2)
Pathophysiology	161	(9)
Secondary Brain Injuries After Cardiac Arrest	170	(2)
Future Directions	172	(1)
Clinical Education and Trial Networks	173	(1)
References	173	(6)
Efficient Dose-Response Finding Strategies for Acute Neuroemergency Treatments
Tom Parke
Michael Krams
Peter Mueller
Don Berry
Background: The ASTIN Study	179	(4)
Generalized Adaptive Dose Allocation Tool	183	(1)
Efficacy and Futility	183	(2)
Simulating a Stroke Trial	185	(8)
What We Need To Be Able To Simulate	193	(4)
What We Learn from Simulating	197	(1)
The Problems of Simulating	198	(2)
Adaptive Allocation	200	(2)
What Next?	202	(1)
Acknowledgment	203	(1)
References	203	(3)
Biostatistical Issues in Neuroemergency Clinical Trials
Wayne M. Alves
Inherent Heterogeneity of Neuroemergency Populations	206	(1)
Clinical Testing of Novel Drugs and Treatments	207	(2)
Diagnosis and Subpopulations	209	(1)
Dosing and Timing Considerations	210	(1)
Key Design Features of Neuroemergency Trials	211	(2)
Handling Multiplicity of Endpoints	213	(1)
Precision of Outcome Measures	213	(1)
Variation in Prognostic Factors	214	(1)
Win--No Win Rules	215	(2)
Statistical Planning Considerations	217	(3)
Selection Bias	220	(1)
Minimizing Potential Sources of Bias	220	(1)
Approaches to Randomization	221	(1)
Handling Incomplete Data	222	(1)
Sequential Analysis and Stopping Rules	222	(1)
Data Analysis Considerations	222	(1)
Unresolved Biostatistical Issues	223	(1)
Concentration-Outcome Relationships	224	(1)
Surrogate Endpoints	224	(1)
Adaptive Trial Designs	224	(1)
Are Large Pragmatic Trials Necessary?	225	(1)
References	226	(3)
Data Safety and Monitoring Board: Role in Acute Neurological Trials
Brett E. Skolnick
Background on Data Safety Monitoring Boards	229	(1)
DSMBs in Neuroemergencies	230	(8)
DSMB Charter	238	(2)
Interactions	240	(2)
Summary	242	(1)
References	242	(1)
Appendix A. Sample DSMB Charter	243	(3)
Appendix B. Conflict of Interest Statement for DSMB Members	246	(2)
Role of a Project Medical Officer in Acute Neuroemergency Clinical Trials
Joseph A. Kwentus
PMO Qualifications	248	(1)
Assessment of Study Feasibility	248	(1)
Study Design and Implementation	249	(1)
Review of CRF and CRF Guidelines	250	(1)
Providing Medical Input to Regulatory/Ethics and IRBs	250	(1)
Therapeutic Training for Sponsor's Staff	251	(1)
Site Selection	252	(1)
Medical Support at Investigator's Meeting	252	(1)
Managing Emerging Site Issues During Enrollment	252	(2)
Managing Site Initiation Process and Booster Activities	254	(1)
Guiding SAE and CRF Completion Issues	254	(1)
Coding of Medical Events for AEs and SAEs	254	(1)
Writing/Contributing to the Clinical Trial Report	255	(1)
Supplementing Sponsor's Staff at Regulatory Meetings	255	(1)
Summary	255	(3)
Ethical Considerations in Neuroemergency Clinical Trials
Wayne M. Alves
The Concept of Risk	258	(1)
The Concept of Benefit	258	(2)
Study Design Considerations	260	(1)
Evaluation of a Therapeutic Hypothesis	260	(1)
Use of Placebo Control Subjects	261	(1)
Statutory Basis of Current Clinical Trials Regulations	261	(1)
General Role of the Institutional Review Board	261	(1)
Overview of Human Subjects Protection Regulations	262	(2)
Informed Consent Procedures	264	(1)
Waiver of Consent	265	(1)
Emergency Research Consent Waiver	266	(1)
Research Involving Children	266	(1)
Other Consent Mechanisms	267	(1)
Deferred Consent	267	(1)
IRB Knowledge of Local Conditions	268	(1)
Financial Compensation Issues	268	(3)
Important Resources for Research Ethics Training	271	(1)
References	272	(3)
Industry Perspective on Drug Development
Thomas C. Wessel
Christopher Gallen
Selection of Pharmacological Targets and Necrosis Versus Apoptosis	275	(1)
Animal Models	276	(1)
Controlled Conditions of the Animal Experiment Versus Clinical Chaos	276	(1)
Time Window, Glucose, Temperature, and Brain Composition	277	(1)
Unmet Medical Needs and Drug Development	278	(1)
Risks to Neurotherapeutic Drug Developers	279	(1)
Economics of CNS Drug Development	279	(1)
Factors Influencing Economic Feasibility in CNS Drug Development	280	(1)
Costs of Development	281	(2)
Industrial Investment and Productivity	283	(1)
Decreased Research Productivity	283	(2)
References	285	(2)
Regulatory Perspective
Lisa L. Travis
Investigational New Drug Applications	287	(3)
Communicating with the FDA	290	(3)
Role of the Core Data Sheet	293	(1)
Fast Track Development Programs	294	(5)
Accelerated Approval	299	(2)
Subpart E Programs	301	(1)
Priority Review	302	(1)
Waiver of Prospective Informed Consent	302	(4)
Orphan Product Designation	306	(2)
Imaging Protocols	308	(1)
Health Insurance Portability and Accountability Act Privacy Regulations	309	(1)
License Application Process	310	(3)
Postapproval Issues: Marketing, Patient Registries, Advertising, and Promotional Materials	313	(1)
Conclusion	314	(1)
References	314	(5)
Index	319