Dose Finding in Drug Development (eBook)

Preface 6
Contents 9
Introduction and New Drug Development Process 15
1.1 Introduction 15
1.2 New Drug Development Process 18
1.3 Nonclinical Development 19
1.4 Premarketing Clinical Development 22
1.5 Clinical Development Plan 27
1.6 Postmarketing Clinical Development 28
1.7 Concluding Remarks 30
References 31
Dose Finding Based on Preclinical Studies 32
2.1 Introduction 32
2.2 Parallel Line Assays 34
2.3 Competitive Binding Assays 34
2.4 Anti-infective Drugs 39
2.5 Biologic 39
2.6 Preclinical Toxicology Studies 40
2.7 Extrapolating Dose from Animal to Human 42
References 43
Dose-Finding Studies in Phase I and Estimation of Maximally Tolerated Dose 44
3.1 Introduction 44
3.2 Basic Concepts 44
3.3 General Considerations for FIH Studies 46
3.4 Dose Selection 51
3.5 Assessments 56
3.6 Dose Selection for Phase II 60
References 60
Dose-Finding in Oncology - Nonparametric Methods 63
4.1 Introduction 63
4.2 Traditional or 3 + 3 Design 64
4.3 Basic Properties of Group Up-and-Down Designs 65
4.4 Designs that Use Random Sample Size: Escalation and A + B Designs 66
4.5 Designs that Use Fixed Sample Size 67
4.6 More Complex Dose-Finding Trials 69
4.7 Conclusion 70
Acknowledgements 70
References 70
Dose Finding in Oncology - Parametric Methods 73
5.1 Introduction 73
5.2 Escalation with Overdose Control Design 75
5.3 Adjusting for Covariates 77
5.4 Choice of Prior Distributions 82
5.5 Concluding Remarks 84
References 85
Dose Response: Pharmacokinetic - Pharmacodynamic Approach 87
6.1 Exposure Response 87
6.2 Time Course of Response 88
6.3 Pharmacokinetics 89
6.4 Pharmacodynamics 91
6.5 Delayed Effects and Response 91
6.6 Cumulative Effects and Response 94
6.7 Disease Progress 96
6.8 Modeling Methods 98
6.9 Conclusion 100
References 100
General Considerations in Dose- Response Study Designs 103
7.1 Issues Relating to Clinical Development Plan 103
7.2 General Considerations for Designing Clinical Trials 104
7.3 Design Considerations for Phase II Dose- Response Studies 110
7.4 Concluding Remarks 117
References 118
Clinical Trial Simulation - A Case Study Incorporating Efficacy and Tolerability Dose Response 120
8.1 Clinical Development Project Background 120
8.2 The Clinical Trial Simulation Project 122
8.3 Simulation Results and Design Recommendations 134
8.4 Conclusions 139
Acknowledgments 140
References 140
Analysis of Dose-Response Studies - Emax Model 141
9.1 Introduction to the Emax Model 141
9.2 Sensitivity of the Emax Model Parameters 143
9.3 Similar Models 148
9.4 A Mixed Effects Emax Model 148
9.5 Examples 149
9.6 Conclusions 155
References 155
Appendix 156
Analysis of Dose-Response Studies - Modeling Approaches 160
10.1 Introduction 160
10.2 Some Commonly Used Dose-Response Models 163
10.3 Estimation of Target Doses 167
10.4 Model Uncertainty and Model Selection 170
10.5 Combining Modeling Techniques and Multiple Testing 174
10.6 Conclusions 183
References 184
Multiple Comparison Procedures in Dose Response Studies 186
11.1 Introduction 186
11.2 Identifying the Minimum Effective Dose (MinED) 186
11.3 Identifying the Maximum Safe Dose (MaxSD) 191
11.4 Examples 191
11.5 Extensions 194
11.6 Discussion 195
Acknowledgments 196
References 196
Partitioning Tests in Dose-Response Studies with Binary Outcomes 198
12.1 Motivation 198
12.2 Comparing Two Success Probabilities in a Single Hypothesis 199
12.3 Comparison of Success Probabilities in Dose- Response Studies 202
12.4 An Example Using Partitioning Based Stepwise Methods 209
12.5 Conclusion and Discussion 211
References 212
Analysis of Dose-Response Relationship Based on Categorical Outcomes 214
13.1 Introduction 214
13.2 When the Response is Ordinal 215
13.3 When the Response is Binary 221
13.4 Multiple Comparisons 224
13.5 Discussion 227
References 230
Appendix: SAS Code for Performing Various Analyses 232
Power and Sample Size for Dose Response Studies 234
14.1 Introduction 234
14.2 General Approach to Power Calculation 235
14.3 Multiple-Arm Dose Response Trial 237
14.4 Phase I Oncology Dose Escalation Trial 247
14.5 Concluding Remarks 252
References 254
Index 256