Bioequivalence And Statistics in Clinical Pharmacology

by Patterson; Scott D.

• ISBN13: 9781584885306
• ISBN10: 1584885300
• Edition: 1st
• Format: Hardcover
• Copyright: 2005-11-10
• Publisher: Chapman & Hall/

Summary

Establishing techniques used in the assessment of bioequivalence, this work describes the use of statistics in clinical pharmacology studies of safety, ECG monitoring, efficacy, and population pharmacokinetics. The authors demonstrate study design, analysis, and interpretation of data using real-data examples from bioequivalence and clinical pharmacology studies. They feature a wide range of datasets, as well as SAS and SPLUS code (available for download) and examine regulatory considerations regarding the application of statistics in drug development. This work, as stated in a recent issue of Biometrics, "provides a springboard for all scientists from academia who are looking to do research in this area of medical applications."

Table of Contents

Preface	xi
List of figures	xiii
List of tables	xv
1 Drug Development and Clinical Pharmacology	1	(16)
1.1 Aims of This Book	2	(1)
1.2 Drug Development	3	(2)
1.3 Clinical Pharmacology	5	(6)
1.4 Statistics in Clinical Pharmacology	11	(3)
1.5 Structure of the Book	14	(3)
2 History and Regulation of Bioequivalence	17	(22)
2.1 When and How BE Studies Are Performed	19	(8)
2.2 Why Are BE Studies Performed?	27	(1)
2.3 Deciding When Formulations Are Bioequivalent	28	(4)
2.4 Potential Issues with TOST Bioequivalence	32	(4)
2.5 Current International Regulation	36	(3)
3 Testing for Average Bioequivalence	39	(40)
3.1 Background	39	(5)
3.2 Linear Model for 2 x 2 Data	44	(5)
3.3 Applying the TOST Procedure	49	(3)
3.4 Carry-over, Sequence, and Interaction Effects	52	(4)
3.5 Checking Assumptions Made about the Linear Model	56	(2)
3.6 Power and Sample Size for ABE in the 2 x 2 Design	58	(3)
3.7 Example Where Test and Reference Are Not ABE	61	(7)
3.8 Nonparametric Analysis	68	(8)
3.9 Some Practical Issues	76	(3)
4 BE Studies with More Than Two Periods	79	(54)
4.1 Background	80	(1)
4.2 Three-period Designs	81	(6)
4.3 Within-subject Variability	87	(3)
4.4 Robust Analyses for Three Period Designs	90	(2)
4.5 Four-period Designs	92	(4)
4.6 Designs with More Than Two Treatments	96	(6)
4.7 Nonparametric Analyses of Tmax	102	(14)
4.8 Technical Appendix: Efficiency	116	(4)
4.9 Tables of Data	120	(13)
5 Dealing with Unexpected BE Challenges	133	(44)
5.1 Restricted Maximum Likelihood Modelling	135	(3)
5.2 Failing BE and the DER Assessment	138	(5)
5.3 Simulation	143	(2)
5.4 Data-based Simulation	145	(2)
5.5 Carry-over	147	(7)
5.6 Optional Designs	154	(6)
5.7 Determining Trial Size	160	(5)
5.8 What Outliers Are and How to Handle Their Data	165	(2)
5.9 Bayesian BE Assessment	167	(3)
5.10 Technical Appendix	170	(7)
6 The Future and Recent Past of BE Testing	177	(12)
6.1 Brief History	178	(3)
6.2 Individual and Population BE	181	(5)
6.3 Scaled Average BE	186	(3)
7 Clinical Pharmacology Safety Studies	189	(54)
7.1 Background	191	(3)
7.2 First-time-in-humans	194	(14)
7.3 Sub-chronic Dosing Studies	208	(13)
7.4 Food-Effect Assessment and DDIs	221	(12)
7.5 Dose-Proportionality	233	(7)
7.6 Technical Appendix	240	(3)
8 QTc	243	(26)
8.1 Background	244	(3)
8.2 Modelling of QTc Data	247	(7)
8.3 Interpreting the QTc Modelling Findings	254	(5)
8.4 Design of a Thorough QTc Study in the Future	259	(3)
8.5 Technical Appendix	262	(7)
9 Clinical Pharmacology Efficacy Studies	269	(30)
9.1 Background	270	(4)
9.2 Sub-chronic Dosing	274	(8)
9.3 Phase IIa and the Proof of Concept	282	(12)
9.4 Methodology Studies	294	(5)
10 Population Pharmacokinetics	299	(34)
10.1 Population and Pharmacokinetics	300	(7)
10.2 Absolute and Relative Bioavailability	307	(4)
10.3 Age and Gender Pharmacokinetic Studies	311	(5)
10.4 Ethnicity	316	(5)
10.5 Liver Disease	321	(4)
10.6 Kidney Disease	325	(3)
10.7 Technical Appendix	328	(5)
11 Epilogue	333	(2)
Bibliography	335	(36)
Index	371