Ting Dose Finding in Drug Development

1. Auflage 2006
ISBN: 978-0-387-33706-7
Verlag: Springer US
Format: PDF
Kopierschutz: 1 - PDF Watermark

E-Book, Englisch, 248 Seiten

Reihe: Statistics for Biology and Health

This book emphasizes dose selection issues from a statistical point of view. It presentsstatisticalapplicationsinthedesignandanalysisofdose–responsestudies. The importance of this subject can be found from the International Conference on Harmonization (ICH) E4 Guidance document. Establishing the dose–response relationship is one of the most important act- ities in developing a new drug. A clinical development program for a new drug can be broadly divided into four phases – namely Phases I, II, III, and IV. Phase I clinical trials are designed to study the clinical pharmacology. Information - tained from these studies will help in designing Phase II studies. Dose–response relationshipsareusuallystudiedinPhaseII.PhaseIIIclinicaltrialsarelarge-scale, long-term studies. These studies serve to con?rm ?ndings from Phases I and II. ResultsobtainedfromPhasesI,II,andIIIclinicaltrialswouldthenbedocumented and submitted to regulatory agencies for drug approval. In the United States, - viewers from Food and Drug Administration (FDA) review these documents and make a decision to approve or to reject this New Drug Application (NDA). If the new drug is approved, then Phase IV studies can be started. Phase IV clinical trials are also known as postmarketing studies.

Autoren/Hrsg.

Ting, Naitee

Inhaltsverzeichnis

1;Preface;6
2;Contents;9
3;Introduction and New Drug Development Process;15
3.1;1.1 Introduction;15
3.2;1.2 New Drug Development Process;18
3.3;1.3 Nonclinical Development ;19
3.4;1.4 Premarketing Clinical Development;22
3.5;1.5 Clinical Development Plan;27
3.6;1.6 Postmarketing Clinical Development;28
3.7;1.7 Concluding Remarks;30
3.8;References;31
4;Dose Finding Based on Preclinical Studies;32
4.1;2.1 Introduction;32
4.2;2.2 Parallel Line Assays;34
4.3;2.3 Competitive Binding Assays;34
4.4;2.4 Anti-infective Drugs;39
4.5;2.5 Biologic;39
4.6;2.6 Preclinical Toxicology Studies;40
4.7;2.7 Extrapolating Dose from Animal to Human;42
4.8;References;43
5;Dose-Finding Studies in Phase I and Estimation of Maximally Tolerated Dose;44
5.1;3.1 Introduction;44
5.2;3.2 Basic Concepts;44
5.3;3.3 General Considerations for FIH Studies;46
5.4;3.4 Dose Selection;51
5.5;3.5 Assessments ;56
5.6;3.6 Dose Selection for Phase II;60
5.7;References;60
6;Dose-Finding in Oncology - Nonparametric Methods;63
6.1;4.1 Introduction;63
6.2;4.2 Traditional or 3 + 3 Design;64
6.3;4.3 Basic Properties of Group Up-and-Down Designs;65
6.4;4.4 Designs that Use Random Sample Size: Escalation and A + B Designs ;66
6.5;4.5 Designs that Use Fixed Sample Size;67
6.6;4.6 More Complex Dose-Finding Trials ;69
6.7;4.7 Conclusion;70
6.8;Acknowledgements;70
6.9;References;70
7;Dose Finding in Oncology - Parametric Methods;73
7.1;5.1 Introduction;73
7.2;5.2 Escalation with Overdose Control Design;75
7.3;5.3 Adjusting for Covariates ;77
7.4;5.4 Choice of Prior Distributions;82
7.5;5.5 Concluding Remarks;84
7.6;References;85
8;Dose Response: Pharmacokinetic - Pharmacodynamic Approach;87
8.1;6.1 Exposure Response;87
8.2;6.2 Time Course of Response;88
8.3;6.3 Pharmacokinetics ;89
8.4;6.4 Pharmacodynamics ;91
8.5;6.5 Delayed Effects and Response;91
8.6;6.6 Cumulative Effects and Response ;94
8.7;6.7 Disease Progress;96
8.8;6.8 Modeling Methods;98
8.9;6.9 Conclusion;100
8.10;References;100
9;General Considerations in Dose- Response Study Designs;103
9.1;7.1 Issues Relating to Clinical Development Plan;103
9.2;7.2 General Considerations for Designing Clinical Trials;104
9.3;7.3 Design Considerations for Phase II Dose- Response Studies;110
9.4;7.4 Concluding Remarks;117
9.5;References;118
10;Clinical Trial Simulation - A Case Study Incorporating Efficacy and Tolerability Dose Response;120
10.1;8.1 Clinical Development Project Background;120
10.2;8.2 The Clinical Trial Simulation Project;122
10.3;8.3 Simulation Results and Design Recommendations;134
10.4;8.4 Conclusions;139
10.5;Acknowledgments;140
10.6;References;140
11;Analysis of Dose-Response Studies - Emax Model;141
11.1;9.1 Introduction to the Emax Model;141
11.2;9.2 Sensitivity of the Emax Model Parameters;143
11.3;9.3 Similar Models;148
11.4;9.4 A Mixed Effects Emax Model;148
11.5;9.5 Examples;149
11.6;9.6 Conclusions;155
11.7;References;155
11.8;Appendix ;156
12;Analysis of Dose-Response Studies - Modeling Approaches;160
12.1;10.1 Introduction;160
12.2;10.2 Some Commonly Used Dose-Response Models;163
12.3;10.3 Estimation of Target Doses;167
12.4;10.4 Model Uncertainty and Model Selection;170
12.5;10.5 Combining Modeling Techniques and Multiple Testing ;174
12.6;10.6 Conclusions;183
12.7;References;184
13;Multiple Comparison Procedures in Dose Response Studies;186
13.1;11.1 Introduction;186
13.2;11.2 Identifying the Minimum Effective Dose (MinED) ;186
13.3;11.3 Identifying the Maximum Safe Dose (MaxSD);191
13.4;11.4 Examples;191
13.5;11.5 Extensions;194
13.6;11.6 Discussion;195
13.7;Acknowledgments;196
13.8;References;196
14;Partitioning Tests in Dose-Response Studies with Binary Outcomes;198
14.1;12.1 Motivation;198
14.2;12.2 Comparing Two Success Probabilities in a Single Hypothesis;199
14.3;12.3 Comparison of Success Probabilities in Dose- Response Studies;202
14.4;12.4 An Example Using Partitioning Based Stepwise Methods;209
14.5;12.5 Conclusion and Discussion;211
14.6;References;212
15;Analysis of Dose-Response Relationship Based on Categorical Outcomes;214
15.1;13.1 Introduction;214
15.2;13.2 When the Response is Ordinal;215
15.3;13.3 When the Response is Binary;221
15.4;13.4 Multiple Comparisons;224
15.5;13.5 Discussion;227
15.6;References;230
15.7;Appendix: SAS Code for Performing Various Analyses;232
16;Power and Sample Size for Dose Response Studies;234
16.1;14.1 Introduction;234
16.2;14.2 General Approach to Power Calculation;235
16.3;14.3 Multiple-Arm Dose Response Trial;237
16.4;14.4 Phase I Oncology Dose Escalation Trial;247
16.5;14.5 Concluding Remarks;252
16.6;References;254
17;Index;256