Clinical Trial Design Challenges in Mood Disorders (eBook)

Front Cover 1
Clinical Trial Design Challenges in Mood Disorders 4
Copyright Page 5
Contents 6
List of Contributors 10
Preface 12
1 Clinical Trial Design of Maintenance Treatments in Bipolar Disorder 14
Introduction 14
Design of Maintenance Treatment Trials in Bipolar Disorder 15
Need for a Uniform Nomenclature of Course and Outcome in Bipolar Disorders 15
Trial Duration 16
Definition of Outcome 18
Placebo-Controlled Maintenance Studies in Bipolar Disorder 18
Patient Recruitment 19
Course of Illness 19
Symptoms Ratings 20
Statistical Considerations 20
Regulatory Considerations 22
Conclusions 23
References 23
2 Meta-Analysis of Clinical Trials in Bipolar Disorder 26
Introduction 26
Reduction of Risk of Suicide With Lithium: An Example of Increased Statistical Power by Pooling 27
Publication Bias 29
Individual Patient Data Meta-Analyses 30
Multiple Treatments Meta-Analysis 32
Conclusions 34
References 34
3 Effectiveness Trials in Bipolar Disorders 36
Efficacy Versus Effectiveness: Two Words With the Same But Different Meanings 36
General Considerations 37
Systematic Treatment Enhancement Program for Bipolar Disorder 37
Bipolar Affective Disorder: Lithium/Anticonvulsant Evaluation Trial 38
Danish University Antidepressant Group Study 6 39
Lithium Moderate Dose Use Study 39
Bipolar Clinical Health Outcomes Initiative in Comparative Effectiveness Trial 39
Conclusions 40
References 40
4 Long-Term Treatment of Mood Disorders: Follow-Up of Acute Treatment Phase Studies Versus Continuation and Maintenance ... 42
Introduction 43
Requirements for Licensing Drugs in Mood Disorders 43
Long-Term Follow-Up of Randomized (Placebo-)Controlled Acute Treatment Studies 45
Randomized (Placebo-)Controlled Continuation Phase Withdrawal Studies 49
Randomized (Placebo-)Controlled Maintenance Phase Withdrawal Studies 52
Enriched Versus Nonenriched Designs 54
Conclusion 58
References 59
5 The Role of Noninferiority Designs in Bipolar Disorder Clinical Trials 62
Introduction 62
Trials for Drug Registration Versus Trials that are Most Clinically Informative 64
Why Superiority Designs are Preferred by Regulators in the Field of Bipolar Disorder 64
The Need of Clinically Informative Designs: Alternatives to Superiority Observational and Exploratory Trials 64
Noninferiority Designs 65
Conclusions 68
References 68
6 The Use of Mixed Methods in Drug Discovery: Integrating Qualitative Methods into Clinical Trials 72
Introduction 73
A Rationale for Mixed-Method Approaches to Clinical Trial Design 73
Qualitative Research Defined 74
Theoretical Perspectives in Qualitative Research 75
Ethnography 75
Phenomenology 76
Postmodernism 76
Hermeneutics 76
Middle-Range Theories 77
Mixed Methods Research Defined 78
Using Qualitative Methodologies in Clinical Trials 78
Research Strategy 79
Research Methods 79
Sampling and Analysis 80
Other Materials and Methods 81
An Example: N-Acetylcysteine in Schizophrenia 82
Benefits and Limitations in Using Mixed Methods in Clinical Trials 84
Conclusion 85
Conflicts of Interest Statement 85
References 86
7 Sequential Multiple Assignment Randomized Treatment (SMART): Designs in Bipolar Disorder Clinical Trials 88
Introduction 89
SMART Methodologies 90
SMART Study of Primary Lithium or Valproate in Clinically Symptomatic Bipolar Disorder Coupled with Second-Phase Randomizat ... 91
Synopsis of the 26-Week, Open, Randomized SMART Bipolar Disorder Study 92
Participants 92
Study Summary 92
Induction Phase 92
Maintenance Phase 92
Disposition of Subjects and Sample Size of Groups 93
Medications 93
Assessments 94
Criteria for Recovered Status 94
Hypothesis: A.2.1 94
Hypothesis A.3.1 95
Hypothesis A.2.2 95
Hypothesis A.2.3 95
Exploratory Analyses and Qualitative Aim 1 95
Power Analyses 96
Innovation and Significance 96
Approach and Feasibility 96
Consideration in Planning and Executing SMART Protocols 96
Selective Review of SMART Studies in Other Areas of Medicine 97
Prospective Design Considerations for SMART Studies 98
Matching the Statistical Analysis to the Rationale for a SMART 98
References 99
8 Novel Study Designs for Clinical Trials in Mood Disorders 100
Introduction 101
Overcoming the Problem of Excessive Placebo Responses 102
Standardizing Diagnostic Procedures 102
Restricting Enrollment to Selected Populations 103
Managing Clinicians’ Overestimation of Change 103
Rater Training 103
Requirement of Same Rater 104
Simplification of Study Visits and Assessments 104
Minimizing Nonspecific, Therapeutic Effects 104
Placebo Lead-in Phases 105
Extending Trial Duration 105
Reducing Number of Sites 105
Increasing the Sensitivity of Outcome Measures 106
Reducing the Number of Treatment Arms 106
Standard Parallel Comparison Design 106
Single-Blind Placebo Washout 107
Crossover Design 108
Adaptive Designs 109
Randomized Play-the-Winner Clinical Trials 109
Progressive Elimination of High Placebo Response Sites 110
Sequential, Parallel Comparison Design 111
An Example of Sequential, Parallel Comparison Design: L-Methylfolate as Adjunctive Therapy for Selective Serotonin Reuptake ... 113
Trial One 114
Trial Two 114
Pooled Response Rates 115
Conclusions 115
Dr. Maurizio Fava’s Lifetime Disclosures 115
References 116
9 Rating Scales in Bipolar Disorder 118
Introduction 119
Screening Instruments for Bipolar Disorder 120
General Behavioral Inventory 120
Manic Depressiveness Scale 120
Mood Disorder Questionnaire 120
Bipolar Affective Disorder Dimensional Scale 120
Bipolar Spectrum Diagnostic Scale 121
Screening Assessment of Depression-Polarity 121
Mania Scales 121
Review of Instruments 121
Description of Specific Instruments 121
Rater-Administered Mania Scales 121
Manic State Rating Scale 121
Modified Manic Rating Scale 122
Petterson Scale 122
Young Mania Rating Scale 122
Bech-Rafaelsen Scale 123
Mania Rating Scale 123
Mania Diagnostic and Severity Scale 123
Clinician Administered Rating Scale for Mania 123
Clinical Global Impression-Bipolar 124
Patient-Rated Mania Scales 124
Visual Analog Scales 124
M-D Scale 125
Self-Report Mania Inventory 125
Affective Self-Rating Scale 125
Altman Self-Report Mania Rating Scale 125
Mania Scales in Clinical Trials and Related Literature 125
Depression Scales in Bipolar Disorder 127
Review of Instruments 127
Description of Specific Instruments for Measuring Depressive Symptoms in Bipolar Disorder 128
Rater-Administered Depression Scales Used in Bipolar Studies 128
Hamilton Rating Scale for Depression 128
Montgomery Äsberg Depression Rating Scale 129
Inventory of Depressive Symptomatology 129
Bipolar Depression Rating Scale 130
Patient-Rated Depression Scales Used in Bipolar Studies 130
Quick Inventory of Depressive Symptomatology 130
Beck Depression Inventory 131
Depression Scales in Clinical Trials and Related Literature 131
Other Relevant Dimensions of Bipolar Outcome in Clinical Trials 131
Bipolar Response using Rating Scales 134
Bipolar Remission using Rating Scales 134
Bipolar Relapse, Recurrence, and Recovery using Rating Scales 134
Rating Scales to Assess Other Important Dimensions of Clinical Outcome among Bipolar Patients in Clinical Trials 137
Rating Scales in Bipolar Populations Across the Lifespan 138
Older Individuals with Bipolar Disorder 138
Children with Bipolar Disorder 139
Future Directions in Applications of Rating Scales in Bipolar Clinical Trials 140
References 141
10 Clinical Applicability of Results from Drug Trials in Bipolar Disorder – An Attempt to Shed Light on a Complex Issue 150
Introducing the Problem 151
Aims and Methods 152
Conceptual Framework 153
Unfolding the Basic Concepts 153
Selection of Subjects to Randomized Clinical Trials 154
Narrow Versus Broad Generalizability 156
Effect Size and Clinical Applicability of Trial Results 156
Generalizability Across Classification Systems 157
Generalizability Across Age 158
Generalizability Across Drugs 158
Generalizability and Adverse Effects 159
Industry-Driven Versus Investigator-Driven Trials in General 159
Generalizability and Clinical Applicability of Trial Results in Bipolar Disorder 160
Mania 160
Bipolar Depression 162
Mixed States 165
Maintenance 165
Differential Generalizability or Trial Results Based on Biologic Subgroups in Bipolar Disorder 169
Summarizing and Concluding Sections 170
Proper Clinical Applicability of Trial Results in Bipolar Disorder: A Brief Guidance 170
From Narrow Generalizability to Broad Applicability: Summarizing the Clinician’s Point of View 171
Approval Trials, Clinical Needs, and Future Perspectives 172
References 173
11 Clinical Trials in Developing Countries: Challenges in Design, Execution, and Regulation 180
Introduction 180
Clinical Trials in Developing Countries: Who Gains, and Why? 181
Clinical Trials in Developing Countries: Who Loses, and Why? 182
The Regulatory Environment 184
Special Issues 184
Discussion: Developments in India 185
Concluding Notes 186
References 186
Index 188