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Dose Finding in Drug Development

:	Naitee Ting
:	Naitee Ting
:	Dose Finding in Drug Development
:	Springer-Verlag
:	9780387337067
:	1
:	CHF 132.60
:

:	Pharmazie
:	English

:	248
:	DRM
:	PC/MAC/eReader/Tablet
:	PDF

If you have ever wondered when visiting the pharmacy how the dosage of your prescription is determined this book will answer your questions. Dosing information on drug labels is based on discussion between the pharmaceutical manufacturer and the drug regulatory agency, and the label is a summary of results obtained from many scientific experiments. The book introduces the drug development process, the design and the analysis of clinical trials. Many of the discussions are based on applications of statistical methods in the design and analysis of dose response studies. Important procedural steps from a pharmaceutical industry perspective are also examined.

	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