Dose Finding in Drug Development

Preface

Contents

Introduction and New Drug Development Process

1.1 Introduction

1.2 New Drug Development Process

1.3 Nonclinical Development

1.4 Premarketing Clinical Development

1.5 Clinical Development Plan

1.6 Postmarketing Clinical Development

1.7 Concluding Remarks

References

Dose Finding Based on Preclinical Studies

2.1 Introduction

2.2 Parallel Line Assays

2.3 Competitive Binding Assays

2.4 Anti-infective Drugs

2.5 Biologic

2.6 Preclinical Toxicology Studies

2.7 Extrapolating Dose from Animal to Human

References

Dose-Finding Studies in Phase I and Estimation of Maximally Tolerated Dose

3.1 Introduction

3.2 Basic Concepts

3.3 General Considerations for FIH Studies

3.4 Dose Selection

3.5 Assessments

3.6 Dose Selection for Phase II

References

Dose-Finding in Oncology - Nonparametric Methods

4.1 Introduction

4.2 Traditional or 3 + 3 Design

4.3 Basic Properties of Group Up-and-Down Designs

4.4 Designs that Use Random Sample Size: Escalation and A + B Designs

4.5 Designs that Use Fixed Sample Size

4.6 More Complex Dose-Finding Trials

4.7 Conclusion

Acknowledgements

References

Dose Finding in Oncology - Parametric Methods

5.1 Introduction

5.2 Escalation with Overdose Control Design

5.3 Adjusting for Covariates

5.4 Choice of Prior Distributions

5.5 Concluding Remarks

References

Dose Response: Pharmacokinetic - Pharmacodynamic Approach

6.1 Exposure Response

6.2 Time Course of Response

6.3 Pharmacokinetics

6.4 Pharmacodynamics

6.5 Delayed Effects and Response

6.6 Cumulative Effects and Response

6.7 Disease Progress

6.8 Modeling Methods

6.9 Conclusion

References

General Considerations in Dose- Response Study Designs

7.1 Issues Relating to Clinical Development Plan

7.2 General Considerations for Designing Clinical Trials

7.3 Design Considerations for Phase II Dose- Response Studies

7.4 Concluding Remarks

References

Clinical Trial Simulation - A Case Study Incorporating Efficacy and Tolerability Dose Response

8.1 Clinical Development Project Background

8.2 The Clinical Trial Simulation Project

8.3 Simulation Results and Design Recommendations

8.4 Conclusions

Acknowledgments

References

Analysis of Dose-Response Studies - Emax Model

9.1 Introduction to the Emax Model

9.2 Sensitivity of the Emax Model Parameters

9.3 Similar Models

9.4 A Mixed Effects Emax Model

9.5 Examples

9.6 Conclusions

References

Appendix

Analysis of Dose-Response Studies - Modeling Approaches

10.1 Introduction

10.2 Some Commonly Used Dose-Response Models

10.3 Estimation of Target Doses

10.4 Model Uncertainty and Model Selection

10.5 Combining Modeling Techniques and Multiple Testing

10.6 Conclusions

References

Multiple Comparison Procedures in Dose Response Studies

11.1 Introduction

11.2 Identifying the Minimum Effective Dose (MinED)

11.3 Identifying the Maximum Safe Dose (MaxSD)

11.4 Examples

11.5 Extensions

11.6 Discussion

Acknowledgments

References

Partitioning Tests in Dose-Response Studies with Binary Outcomes

12.1 Motivation

12.2 Comparing Two Success Probabilities in a Single Hypothesis

12.3 Comparison of Success Probabilities in Dose- Response Studies

12.4 An Example Using Partitioning Based Stepwise Methods

12.5 Conclusion and Discussion

References

Analysis of Dose-Response Relationship Based on Categorical Outcomes

13.1 Introduction

13.2 When the Response is Ordinal

13.3 When the Response is Binary

13.4 Multiple Comparisons

13.5 Discussion

References

Appendix: SAS Code for Performing Various Analyses

Power and Sample Size for Dose Response Studies

14.1 Introduction

14.2 General Approach to Power Calculation

14.3 Multiple-Arm Dose Response Trial

14.4 Phase I Oncology Dose Escalation Trial

14.5 Concluding Remarks

References

Index