Introduction to Statistics in Pharmaceutical Clinical Trials

by Durham, Todd A.; Turner, J. Rick

Edition: 1st

ISBN13: 9780853697145

ISBN10: 0853697140

Format: Paperback

Pub. Date: 2008-03-01

Publisher(s): Pharmaceutical Pr

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Summary

Introduction to Statistics in Pharmaceutical Clinical Trials is an ideal introduction to statistics presented in the context of clinical trials conducted during pharmaceutical drug development. This novel approach both teaches the computational steps needed to conduct analyses and provides a conceptual understanding of how these analyses provide information that forms the rational basis for decision making throughout the drug development process.

Author Biography

Todd A Durham is Senior Director of Biostatistics and Data Management, Inspire Pharmaceuticals, Durham, North Carolina, USA J Rick Turner is Chairman, Department of Clinical Research, Campbell University School of Pharmacy, North Carolina, USA

Foreword	p. x
Preface	p. xii
Dedications	p. xiv
The discipline of Statistics: Introduction and terminology	p. 1
Introduction	p. 1
The discipline of Statistics	p. 2
The term "statistic" and the plural form "statistics"	p. 3
The term "statistical analysis"	p. 3
Association versus causation	p. 3
Variation and systematic variation	p. 4
Compelling evidence	p. 4
The terms "datum" and "data"	p. 5
Results from statistical analyses as the basis for decision-making	p. 5
Blood pressure and blood pressure medication	p. 5
Organization of the book	p. 6
Some context before reading Chapters 2-11	p. 7
Review	p. 8
References	p. 8
The role of clinical trials in new drug development	p. 9
Introduction	p. 9
Drug discovery	p. 9
Regulatory guidance and governance	p. 10
Pharmaceutical manufacturing	p. 13
Nonclinical research	p. 14
Clinical trials	p. 15
Postmarketing surveillance	p. 18
Ethical conduct during clinical trials	p. 19
Review	p. 20
References	p. 20
Research questions and research hypotheses	p. 23
Introduction	p. 23
The concept of scientific research questions	p. 23
Useful research questions	p. 23
Useful information	p. 24
Moving from the research question to the research hypotheses	p. 24
The placebo effect	p. 24
The drug treatment group and the placebo treatment group	p. 25
Characteristics of a useful research question	p. 25
The reason why there are two research hypotheses	p. 26
Other forms of the null and alternate hypotheses	p. 27
Deciding between the null and alternate hypothesis	p. 28
An operational statistical definition of "more"	p. 29
The concept of statistically significant differences	p. 30
Putting these thoughts into more precise language	p. 30
Hypothesis testing	p. 31
The relationship between hypothesis testing and ethics in clinical trials	p. 31
The relationship between research questions and study design	p. 32
Review	p. 33
References	p. 33
Study design and experimental methodology	p. 35
Introduction	p. 35
Basic principles of study design	p. 36
A common design in therapeutic exploratory and confirmatory trials	p. 38
Experimental methodology	p. 40
Why are we interested in blood pressure?	p. 41
Uniformity of blood pressure measurement	p. 43
Measuring change in blood pressure over time	p. 43
The clinical study protocol	p. 44
Review	p. 45
References	p. 45
Data, central tendency, and variation	p. 47
Introduction	p. 47
Populations and samples	p. 47
Measurement scales	p. 48
Random variables	p. 49
Displaying the frequency of values of a random variable	p. 49
Central tendency	p. 52
Dispersion	p. 53
Tabular displays of summary statistics of central tendency and dispersion	p. 55
Review	p. 56
References	p. 56
Probability, hypothesis testing, and estimation	p. 57
Introduction	p. 57
Probability	p. 57
Probability distributions	p. 60
Binomial distribution	p. 61
Normal distribution	p. 62
Classical probability and relative frequency probability	p. 67
The law of large numbers	p. 68
Sample statistics and population parameters	p. 69
Sampling variation	p. 69
Estimation: General considerations	p. 70
Hypothesis testing: General considerations	p. 74
Hypothesis test of a single population mean	p. 78
The p value	p. 80
Relationship between confidence intervals and hypothesis tests	p. 81
Brief review of estimation and hypothesis testing	p. 82
Review	p. 83
References	p. 83
Early phase clinical trials	p. 85
Introduction	p. 85
A quick recap of early phase studies	p. 85
General comments on study designs in early phase clinical studies	p. 86
Goals of early phase clinical trials	p. 86
Research questions in early phase clinical studies	p. 87
Pharmacokinetic characteristics of interest	p. 87
Analysis of pharmacokinetic and pharmacodynamic data	p. 89
Dose-finding trials	p. 91
Bioavailability trials	p. 92
Other data acquired in early phase clinical studies	p. 93
Limitations of early phase trials	p. 94
Review	p. 95
References	p. 95
Confirmatory clinical trials: Safety data I	p. 97
Introduction	p. 97
The rationale for safety assessments in clinical trials	p. 97
A regulatory view on safety assessment	p. 98
Adverse events	p. 99
Reporting adverse events	p. 99
Using all reported AEs for all participants	p. 100
Absolute and relative risks of participants reporting specific AEs	p. 101
Analyzing serious AEs	p. 102
Concerns with potential multiplicity issues	p. 102
Accounting for sampling variation	p. 103
A confidence interval for a sample proportion	p. 103
Confidence intervals for the difference between two proportions	p. 105
Time-to-event analysis	p. 107
Kaplan-Meier estimation of the survival function	p. 109
Review	p. 114
References	p. 115
Confirmatory clinical trials: Safety data II	p. 117
Introduction	p. 117
Analyses of clinical laboratory data	p. 117
Vital signs	p. 123
QT interval prolongation and torsades de pointes liability	p. 124
Concluding comments on safety assessments in clinical trials	p. 125
Review	p. 126
References	p. 126
Confirmatory clinical trials: Analysis of categorical efficacy data	p. 127
Introduction: Regulatory views of substantial evidence	p. 127
Objectives of therapeutic confirmatory trials	p. 130
Moving from research questions to research objectives: Identification of endpoints	p. 131
A brief review of hypothesis testing	p. 132
Hypothesis tests for two or more proportions	p. 133
Concluding comments on hypothesis tests for categorical data	p. 145
Review	p. 145
References	p. 146
Confirmatory clinical trials: Analysis of continuous efficacy data	p. 147
Introduction	p. 147
Hypothesis test of two means: Two-sample t test or independent groups t test	p. 147
Hypothesis test of the location of two distributions: Wilcoxon rank sum test	p. 150
Hypothesis tests of more than two means: Analysis of variance	p. 152
A worked example with a small dataset	p. 155
A statistical methodology for conducting multiple comparisons	p. 159
Bonferroni's test	p. 160
Employing Bonferroni's test in our example	p. 161
Tukey's honestly significant difference test	p. 163
Implications of the methodology chosen for multiple comparisons	p. 164
Additional considerations about ANOVA	p. 166
Nonparametric analyses of continuous data	p. 167
The Kruskal-Wallis test	p. 167
Hypothesis test of the equality of survival distributions: Logrank test	p. 169
Review	p. 171
References	p. 172
Additional statistical considerations in clinical trials	p. 173
Introduction	p. 173
Sample size estimation	p. 173
Multicenter studies	p. 181
Analysis populations	p. 182
Dealing with missing data	p. 184
Primary and secondary objectives and endpoints	p. 185
Evaluating baseline characteristics	p. 186
Equivalence and noninferiority study designs	p. 187
Additional study designs	p. 189
Review	p. 190
References	p. 190
Concluding comments	p. 191
Reference	p. 191
Appendices	p. 193
Standard normal distribution areas	p. 195
Percentiles of t distributions	p. 205
Percentiles of X[superscript 2] distributions	p. 207
Percentiles of F distributions ([alpha] = 0.05)	p. 209
Values of q for Tukey's HSD test ([alpha] = 0.05)	p. 211
Review exercise solutions by chapter	p. 215
Index	p. 219
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