Statistical Issues in Drug Development

Stephen Senn has worked for the NHS in England, as a lecturer in Scotland and in drug development in Switzerland (with CIBA-Geigy). Until recently he was Professor of Pharmaceutical and Health Statistics at University College London but since September 2003 he has been Professor of Statistics at Glasgow University. His books, Cross-over Trials in Clinical Research (1993, 2 nd edition 2002) and Statistical Issues in Drug Development (1997) are published by Wiley and his latest book, Dicing with Death (2003) by Cambridge University Press. In 2001, he was the first recipient of the George C Challis award for biostatistics of the University of Florida. He is a member of the editorial boards of Statistics in Medicine , Statistical Methods in Medical Research , Pharmaceutical Statistics and Applied Clinical Trials and is a section editor for the Wiley Statistics in Practice series.

Preface to the Second Edition. Preface to the First Edition. Acknowledgements. 1. Introduction. 1.1 Drug development. 1.2 The role of statistics in drug development. 1.3 The object of this book. 1.4 The author's knowledge of statistics in drug development. 1.5 The reader and his or her knowledge of statistics. 1.6 How to use the book. Part 1: Four Views of Statistics in Drug Development: Historical, Methodological, Technical and Professional. 2. A Brief and Superficial History of Statistics for Drug Developers. 2.1 Introduction. 2.2 Early Probabilists. 2.3 James Bernoulli (1654-1705). 2.4 John Arbuthnott (1667-1753). 2.5 The mathematics of probability in the late 17th, the 18th and early 19th centuries. 2.6 Thomas Bayes (1701-1761). 2.7 Adolphe Quetelet (1796-1874). 2.8 Francis Galton (1822-1911). 2.9 Karl Pearson (1857-1936). 2.10 'Student' (1876-1937). 2.11 R.A. Fisher (1890-1962). 2.12 Modern mathematical statistics. 2.13 Medical statistics. 2.14 Statistics in clinical trials today. 2.15 The current debate. 2.16 A living science. 2.17 Further reading. 3. Design and Interpretation of Clinical Trials as Seen by a Statistician. 3.1 Prefatory warning. 3.2 Introduction. 3.3 Defining effects. 3.4 Practical problems in using the counterfactual argument. 3.5 Regression to the mean. 3.6 Control in clinical trials. 3.7 Randomization. 3.8 Blinding. 3.9 Using concomitant observations. 3.10 Measuring treatment effects. 3.11 Data generation models. 3.12 In conclusion. 3.13 Further reading. 4. Probability, Bayes, P-values, Tests of Hypotheses and Confidence Intervals. 4.1 Introduction. 4.2 An example. 4.3 Odds and sods. 4.4 The Bayesian solution to the example. 4.5 Why don't we regularly use the Bayesian approach in clinical trials? 4.6 A frequentist approach. 4.7 Hypothesis testing in controlled clinical trials. 4.8 Significance tests and P-values. 4.9 Confidence intervals and limits and credible intervals. 4.10 Some Bayesian criticism of the frequentist approach. 4.11 Decision theory. 4.12 Conclusion. 4.13 Further reading . 5. The Work of the Pharmaceutical Statistician. 5.1 Prefatory remarks. 5.2 Introduction. 5.3 In the beginning. 5.4 The trial protocol. 5.5 The statistician's role in planning the protocol. 5.6 Sample size determination. 5.7 Other important design issues. 5.8 Randomization. 5.9 Data collection preview. 5.10 Performing the trial. 5.11 Data analysis preview. 5.12 Analysis and reporting. 5.13 Other activities. 5.14 Statistical research. 5.15 Further reading. Part 2: Statistical Issues: Debatable and Controversial Topics in Drug Development. 6. Allocating Treatments to Patients in Clinical Trials. 6.1 Background. 6.2 Issues. References. 6.A Technical appendix. 7. Baselines and Covariate Information. 7.1 Background. 7.2 Issues. 7.A Technical appendix. 8. The Measurement of Treatment Effects. 8.1 Background. 8.2 Issues. 8.A Technical appendix. 9. Demographic Subgroups: Representation and Analysis. 9.1 Background. 9.2 Issues. 9.A Technical appendix. 10. Multiplicity. 10.1 Background. 10.2 Issues. 10.A Technical appendix. 11. Intention to Treat, Missing Data and Related Matters. 11.1 Background. 11.2 Issues. 11.A Technical appendix. 12. One-sided and Two-sided Tests and Other Issues to Do with Significance and P-values. 12.1 Background. 12.2 Issues. 13. Determining the Sample Size. 13.1 Background. 13.2 Issues. 14. Multicentre Trials. 14.1 Background. 14.2 Issues. 14.A Technical appendix. 15. Active Control Equivalence Studies. 15.1 Background. 15.2 Issues. 15.A Technical appendix. 16. Meta-Analysis. 16.1 Background. 16.2 Issues. 16.A Technical appendix. 17. Cross-over Trials. 17.1 Background. 17.2 Issues. 18. n-of-1 Trials. 18.1 Background. 18.2 Issues. 19. Sequential Tr4ials. 19.1 Background. 19.2 Issues. 20. Dose-finding. 20.1 Background. 20.2 Issues. 21. Concerning Pharmacokinetics and Pharmacodynamics. 21.1 Background. 21.2 Issues. 22. Bioequivalence Studies. 22.1 Background. 22.2 Issues. 23. Safety Data, Harms, Drug Monitoring and Pharmaco-epidemiology. 23.1 Background. 23.2 Issues. 24. Pharmaco-economics and Portfolio Management. 24.1 Background. 24.2 Issues. 25. Concerning Pharmacogenetics, Pharmacogenomics and Related Matters. 25.1 Background. 25.2 Issues. 25.A Technical appendix. Glossary. Index.