Clinical Trials in Rheumatoid Arthritis and Osteoarthritis (eBook)

Contents 6
Contributors 8
Introduction 10
Why a Book About Clinical Trials in Rheumatoid Arthritis and Osteoarthritis? 10
How This Book Works 11
References 12
Historical and Current Perspectives on Management of Osteoarthritis and Rheumatoid Arthritis 14
Historical and Current Perspectives on Management of Osteoarthritis 14
Historical Aspects 15
Predisposing Factors 15
Pathogenesis 15
Treatment of OA 16
Nonpharmacological Therapies 16
Pharmacological Therapy 16
Surgical Treatments 20
Summary 21
Historical and Current Perspectives on Management of Rheumatoid Arthritis 21
Evolutional History of Pharmacotherapeutics in RA 22
Initial Assessment of Patients with RA 24
Further Management of RA Patients 24
Nonpharmacological Treatment of RA 25
Pharmacological Treatment of RA 26
Surgical Treatment of RA 34
Summary 35
References 35
Development of Biological Therapies for Inflammatory Arthritis 46
Tumor Necrosis Factor- 46
for Rheumatoid Arthritis 46
Ankylosing Spondylitis 48
Psoriatic Arthritis 49
Juvenile Idiopathic Arthritis 49
Safety Considerations 49
Economic Considerations 50
The Future 51
Other Biological Agents 51
References 56
Study Design and End Points for Rheumatoid Arthritis Trials 60
Introduction 60
Patient Selection 64
Types of Clinical Trials 65
End Points 67
Single End Points 68
Composite Measures 71
Adverse Events 75
Conclusion 75
References 76
Study Design and End Points in Ankylosing Spondylitis Clinical Trials 78
Introduction 78
Study Design 78
Scope of Patients 81
Type of End Points to Consider 82
Instruments for Various End Points 83
Assessment of Response/Improvement 86
Conclusion 87
References 87
Trial Design and Outcomes in Osteoarthritis 90
Introduction 90
Study Design 90
Scientific versus Pragmatic Trials 91
Study Duration 92
Patient Selection 92
Control Arm 93
Sample Size 95
Outcome Assessment 95
Compliance 97
Statistics 97
Presentation and Dissemination 98
Study Organization 98
Conclusion 98
References 99
Ethical Considerations 100
Introduction 100
Who Does What? 101
Sponsorship: Who’s Paying the Bill? 101
Placebo or Not Placebo? 102
Randomization 103
Who Can Take Part? 104
Trial Procedures 105
Ethical Review 109
Informed Consent 111
Dissemination 113
Conclusion 113
References 113
Appendix 1 115
What Is the Purpose of the Study? 115
Why Have I Been Chosen? 115
Do I Have to Take Part? 115
What Will Happen to Me if I Take Part? 115
What Do I Have to Do? 116
What Is the Drug That Is Being Tested? 117
What Are the Alternatives for Treatment? 117
What Are the Side Effects of Taking Part? 117
What Are the Possible Disadvantages and Risks of Taking Part? 117
What Are the Possible Benefits of Taking Part? 117
What if the New Information Becomes Available? 118
What Happens When the Research Study Stops? 118
What if Something Goes Wrong? 118
Will My Taking Part in This Study Be Kept Confidential? 118
What Will Happen to the Results of the Research Study? 119
Who Is Organizing and Funding the Research? 119
Contact for Further Information 119
Appendix 2 120
Organization of the Clinical Trial by the Sponsor 122
Introduction 122
Regulatory Guidance 122
Surrogate Markers 123
Couriers 125
Investigator Meetings 125
Cross-Calibration of Scanners 126
Inclusion and Exclusion Criteria 127
Data Flow 127
The Data Monitoring Committee 128
Trial Audit 129
Trial Closure 130
Conclusion 130
References 130
Organization of the Trial at the Investigator Site 132
Introduction 132
Site Resources 133
Study Budget and Clinical Trial Agreement 134
Ethics IRB and Informed Consent 135
Study Initiation and Conduct 136
Handling of Blood Samples: Central versus Local Laboratories 137
Pharmacy 138
Recruitment Methods 138
Monitoring Adverse Events 139
Informed Consent 140
Subject Retention and Compliance 141
Advocacy 141
Study Closeout 142
Conclusion 142
References 143
Role of the Imaging Core Laboratory in Rheumatoid Arthritis and Osteoarthritis Clinical Trials 144
Introduction 144
The Imaging Core Laboratory 144
Conclusion 158
References 158
Biochemical Markers of Rheumatoid Arthritis and Osteoarthritis: Clinical Utility and Practical Considerations 160
Introduction 160
Pathogenesis of RA and OA 161
Role of Biomarkers in RA and OA 161
Biochemical Markers of Joint Disease 162
Practical Considerations for Measurements of Biochemical Markers 169
Conclusion 174
References 174
Data Analysis and Presentation: Writing a Paper for Publication 180
Introduction 180
The CONSORT Statement 181
The Title 184
The Abstract 184
What Should Be in the Introduction? 186
Method 186
Issues with Outcome Measures in RA and OA 189
Results 191
The Conclusions 207
Summary 207
References 207
Radiographic Imaging End Points in Rheumatoid Arthritis Trials 210
Introduction 210
Radiographic Acquisition 210
Scoring Methods of Radiographs 211
Comparison of Scoring Methods 226
Reviewing Radiographs for a Clinical Trial 226
Scoring Radiographs for Repair 227
Analyzing and Reporting the Scores from Trials 227
Conclusion 228
References 228
Radiography in Clinical Trials Investigating Osteoarthritis 232
Introduction 232
The Acquisition of Radiographs 233
Measuring Joint SpaceWidth 236
Grading Disease Severity 237
Data from Clinical Trials 241
References 242
Use of Quantitative Magnetic Resonance Imaging in the Cross- Sectional and Longitudinal Evaluation of Structural Changes in Knee Osteoarthritis Patients 244
Introduction 244
Clinical Practice for MRI Acquisition of the Knee 245
MRI Acquisition Sequences to Identify Macromolecules Content in Articular Cartilage 247
Precision and Reliability of Knee Cartilage Quantification 248
Cross-sectional Quantitative Cartilage Measurements 250
Quantitative Cartilage Measurements in Longitudinal Studies 250
Comparing MRI Measurements with Joint Space Width and Narrowing on Standardized Knee Radiographs 251
Influence of Other Knee Structure Changes on OA Cartilage Loss 252
Redefining “Primary” OA 254
Conclusion 254
References 255
Biochemical Markers as Surrogate End Points of Joint Disease 258
Introduction 258
Osteoarthritis: The Disease and the Needs 258
Clinical Assessment and Biomarkers: Definitions and Classifications 262
The Status of OA Biomarkers: Strengths and Limitations 264
Potential Uses of Current Generation of OA Biomarkers 274
Bone Biomarkers and Osteoporosis Drug Development: A Role Model for Osteoarthritis? 276
Barriers to Validating OA Biomarkers as Surrogate End Points 276
The Promise That Broad Screens Can Identify New OA Biomarkers 277
References 278
Role of Genetics and Genomics in Clinical Trials in Osteoarthritis and Rheumatoid Arthritis 284
Introduction 284
Approaches to the Identification of Complex Disease Genes 284
Pharmacogenetics 288
Microarrays and Proteomics 288
Genetic Determinants in OA 290
Genetic Determinants in RA 291
Role of Pharmacogenetics in the Management of Arthritis 292
Application of Genetics and Pharmacogenetics in Clinical Trials 293
References 294
Cost-Effectiveness of New Biologics for Rheumatoid Arthritis and Osteoarthritis 298
Introduction 298
Background: The Role of Health Economics 299
Critical Appraisal of Economic Evaluations of New Biologics 303
Discussion 311
References 315
Abbreviations 318
Index 320