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Table of Contents


	Preface to the Second Edition	xiii
	Preface to the First Edition	xvii
	Acknowledgements	xxi
1	Introduction	1
1.1	Drug Development	1
1.2	The Role of Statistics in Drug Development	2
1.3	The Object of this Book	3
1.4	The Author’s Knowledge of Statistics in Drug Development	4
1.5	The Reader and His or Her Knowledge of Statistics	4
1.6	How to Use the Book	5
	References	6
PART 1	FOUR VIEWS OF STATISTICS IN DRUG DEVELOPMENT: HISTORICAL, METHODOLOGICAL, TECHNICAL AND PROFESSIONAL	9
2	A Brief and Superficial History of Statistics for Drug Developers	11
2.1	Introduction	11
2.2	Early Probabilists	12
2.3	James Bernoulli (1654-1705)	13
2.4	John Arbuthnott (1667-1753)	14
2.5	The Mathematics of Probability in the Late 17th, the 18th and Early 19th Centuries	14
2.6	Thomas Bayes (1701-1761)	15
2.7	Adolphe Quetelet (1796-1874)	16
2.8	Francis Galton (1822-1911)	16
2.9	Karl Pearson (1857-1936)	17
2.10	‘Student’ (1876-1937)	17
2.11	R.A. Fisher (1890-1962)	17
2.12	Modern Mathematical Statistics	18
2.13	Medical Statistics	19
2.14	Statistics in Clinical Trials Today	20
2.15	The Current Debate	21
2.16	A Living Science	21
2.17	Further Reading	23
	References	23
3	Design and Interpretation of Clinical Trials as Seen by a Statistician	27
3.1	Prefatory Warning	27
3.2	Introduction	27
3.3	Defining Effects	28
3.4	Practical Problems in Using the Counterfactual Argument	28
3.5	Regression to the Mean	29
3.6	Control in Clinical Trials	33
3.7	Randomization	34
3.8	Blinding	36
3.9	Using Concomitant Observations	37
3.10	Measuring Treatment Effects	38
3.11	Data Generation Models	39
3.12	In Conclusion	41
3.13	Further Reading	41
	References	41
4	Probability, Bayes, P-Values, Tests of Hypotheses and Confidence Intervals	43
4.1	Introduction	43
4.2	An Example	44
4.3	Odds and Sods	44
4.4	The Bayesian Solution to the Example	45
4.5	Why Don’t We Regularly Use the Bayesian Approach in Clinical Trials?	46
4.6	A Frequentist Approach	47
4.7	Hypothesis Testing in Controlled Clinical Trials	48
4.8	Significance Tests and P-Values	49
4.9	Confidence Intervals and Limits and Credible Intervals	50
4.10	Some Bayesian Criticism of the Frequentist Approach	51
4.11	Decision Theory	51
4.12	Conclusion	52
4.13	Further Reading	52
	References	53
5	The Work of the Pharmaceutical Statistician	55
5.1	Prefatory Remarks	55
5.2	Introduction	56
5.3	In the Beginning	57
5.4	The Trial Protocol	57
5.5	The Statistician’s Role in Planning the Protocol	58
5.6	Sample Size Determination	59
5.7	Other Important Design Issues	60
5.8	Randomization	60
5.9	Data Collection Preview	61
5.10	Performing the Trial	61
5.11	Data Analysis Preview	61
5.12	Analysis and Reporting	62
5.13	Other Activities	63
5.14	Statistical Research	63
5.15	Further Reading	64
	References	65
PART 2	STATISTICAL ISSUES: DEBATABLE AND CONTROVERSIAL TOPICS IN DRUG DEVELOPMENT	67
6	Allocating Treatments to Patients in Clinical Trials	69
6.1	Background	69
6.2	Issues	71
	References	87
6.A	Technical Appendix	88
7	Baselines and Covariate Information	95
7.1	Background	95
7.2	Issues	98
	References	108
7.A	Technical Appendix	109
8	The Measurement of Treatment Effects	113
8.1	Background	113
8.2	Issues	114
	References	129
8.A	Technical Appendix	130
9	Demographic Subgroups: Representation and Analysis	133
9.1	Background	133
9.2	Issues	134
	References	144
9.A	Technical Appendix	145
10	Multiplicity	149
10.1	Background	149
10.2	Issues	150
	References	161
10.A	Technical Appendix	162
11	Intention to Treat, Missing Data and Related Matters	165
11.1	Background	165
11.2	Issues	167
	References	178
11.A	Technical Appendix	180
12	One-Sided and Two-Sided Tests and Other Issues to Do with Significance and P-Values	183
12.1	Background	183
12.2	Issues	184
	References	192
13	Determining the Sample Size	195
13.1	Background	195
13.2	Issues	198
	References	211
14	Multicentre Trials	213
14.1	Background	213
14.2	Issues	213
	References	230
14.A	Technical Appendix	231
15	Active Control Equivalence Studies	235
15.1	Background	235
15.2	Issues	237
	References	247
15.A	Technical Appendix	249
16	Meta-Analysis	251
16.1	Background	251
16.2	Issues	253
	References	268
16.A	Technical Appendix	270
17	Cross-Over Trials	273
17.1	Background	273
17.2	Issues	275
	References	284
18	n-of-1 Trials	287
18.1	Background	287
18.2	Issues	289
	References	293
19	Sequential Trials	295
19.1	Background	295
19.2	Issues	302
	References	313
20	Dose-Finding	317
20.1	Background	317
20.2	Issues	319
	References	334
21	Concerning Pharmacokinetics and Pharmacodynamics	337
21.1	Background	337
21.2	Issues	343
	References	358
22	Bioequivalence Studies	361
22.1	Background	361
22.2	Issues	362
	References	379
23	Safety Data, Harms, Drug Monitoring and Pharmaco-Epidemiology	383
23.1	Background	383
23.2	Issues	388
	References	403
24	Pharmaco-Economics and Portfolio Management	405
24.1	Background	405
24.2	Issues	407
	References	429
25	Concerning Pharmacogenetics, Pharmacogenomics and Related Matters	433
25.1	Background	433
25.2	Issues	437
	References	450
25.A	Technical Appendix	451
	Glossary	453
	Index	483