Applied Statistics in the Pharmaceutical Industry978-1-4757-3466-9/1.pdf · Applied Statistics in...
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Applied Statistics in the Pharmaceutical Industry
Transcript of Applied Statistics in the Pharmaceutical Industry978-1-4757-3466-9/1.pdf · Applied Statistics in...
Applied Statistics in the Pharmaceutical Industry
Springer Science+Business Media, LLC
Steven P. Millard Andreas Krause Editors
Applied Statistics in the Pharmaceutical Industry
With Case Studies Using S-PLUS
With 131 Illustrations
" Springer
Steven P. Millard Probability, Statistics & Information 7723 44th Avenue NE Seattle, WA 98115-5117 USA
Andreas Krause Novartis Pharma AG Biostatistics P.O. Box 4002 Basel Switzerland
Library of Congress Cataloging-in-Publication Data Applied statistics in the pharmaceutical industry : with case studies using S-PLus I editors, Steven P. Millard, Andreas Krause.
p. cm. Includes bibliographical references and index. ISBN 978-1-4419-3166-5 ISBN 978-1-4757-3466-9 (eBook) DOI 10.1007/978-1-4757-3466-9 1. Drugs-Research-Statistical methods. I. MilIard, Steven P. II. Krause, Andreas.
RS122 .A66S 2001 615'. 19'0727---dc21 00-053767
Printed on acid-free paper.
S-PLus is a registered trademark of Insightful Corporation. @ 2001 Springer Science+Business Media New York Originally published by Springer-Verlag New Y orle, Inc. in 2001 Softcover reprint ofthe hardcover Ist edition 2001
A1l rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Springer Science+Business Media, LLC), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieva1, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter deve10ped is forbidden. The use of general descriptive names, trade names, trademarks, etc., in this publication, even if The former are not especially identified, is not to be taken as a sign that such names, as understood By the Trade Marks and Merchandise Marks Act, may accordingly be used freely by anyone.
Production managed by Timothy Taylor; manufacturing supervised by Jerome Basma. Camera-ready copy prepared from the authors' JnEX2e and Microsoft Word files.
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ISBN 978-1-4419-3166-5 SPIN 10716954
Preface Each year, hundreds of new drugs are approved for the marketplace. The approval of a single new drug is the result of years of screening tens of thousands of compounds, performing preclinical research on their effects, and designing, implementing, and analyzing the results of clinical trials. Statisticians are involved in every phase of this process. Between the years 1960 and 2000, the number of statisticians working in the pharmaceutical industry grew from less than 100 to over 2500.
This book provides a general (but not exhaustive) guide to statistical methods used in the pharmaceutical industry, and illustrates how to use S-PLUS to implement these methods. Specifically, each chapter in this book:
• Illustrates statistical applications in the pharmaceutical industry. • Illustrates how the statistical applications can be carried out using
S-PLUS (each chapter except the first contains an appendix with S-PLUS code).
• Illustrates why S-PLUS is a useful software package for carrying out these applications.
• Discusses the results and implications of a particular application.
The target audience for this book is very broad, including:
• Graduate students in biostatistics. • Statisticians who are involved in the industry as research scientists,
regulators, academics, and/or consultants who want to know more about how to use S-PLUS and learn about other subfields within the industry that they may not be familiar with.
• Statisticians in other fields who want to know more about statisti-cal applications in the pharmaceutical industry.
The data and code from each chapter are available on the following web site: http://www2.active.ch/-krause.aldoc/statistics-in-pharmal. (Due to confidentiality, the raw data are not available for some chapters.)
Part 1 of this book includes Chapter 1, which is an introductory chapter explaining the history and current state of statistics in the drug development process. Following Chapter 1, this book is divided into six more sections that follow the sequence of the drug development process (see Figure 1.2). Part 2 encompasses basic research and preclinical studies and Chapter 2 within this section discusses one-factor comparative studies. Part 3 covers preclinical safety assessment. Chapter 3 discusses analysis of animal carcinogenicity data, and Chapter 4 toxicokinetic and pharmacokinetic data. Part 4 involves Phase I studies. Chapter 5 discusses the analysis of pharmacokinetic data in humans, Chapter 6 illustrates graphical presentations of single patient results, Chapter 7 explains the design and analysis of Phase I oncology trials, Chapter 8 discusses
vi Preface
the analysis of analgesic trials, Chapter 9 points out problems with patient compliance and how this affects pharmacokinetic analysis, and Chapter 10 discusses the classic 2,2,2 crossover design. Part 5 includes chapters on Phase IT and ill clinical trials. Chapter 11 discusses power and sample size calculations, Chapter 12 compares how S-PLUS and SAS handle analysis of variance, Chapter 13 explains a technique for sample size reestimation, Chapter 14 discusses permutation tests for Phase ill clinical trials, Chapter 15 discusses comparing two treatments in a Phase ill clinical trial, and Chapter 16 covers meta-analysis of clinical trials. Part 6 covers Phase IV studies, and includes Chapter 17 on the analysis of health economic data. Finally, Part 7 encompasses manufacturing and production. Chapter 18 discusses the decimal reduction time of a sterilization process, and Chapter 19 covers acceptance sampling plans by attributes.
A Note about S-PLUS Versions The chapters in this book were written when the current versions of S-PLUS were Version 3.4 and then 5.1 for UNIX, and Version 4.5 and then 2000 for Windows. The Windows version of S-PWS includes a graphical user interface (GUI) with pull-down menus and buttons. By the time this book is published, both S-PWS 6.0 for UNIX and S-PWS 6.0 for Windows will be available, and both of these versions of S-PWS will have GUIs. All of the chapters in this book, however, illustrate how to use S-PLUS by writing S-PLUS commands and functions, rather than using pull-down menus.
Typographic Conventions Throughout this book, S-PWS commands and functions are displayed in a ftxedwidth font, for example: summary (aov .psize). Within chapters, S-PLUS commands are preceded with> (the "greater than" sign), which is the default S-PWS prompt. Rather than use the S-PWS continuation prompt (+ by default) for continuation lines, we follow Venables and Ripley (1999) and use indentation instead. Within appendices, S-PWS prompts are omitted.
Companion Web Site for This Book For more information about the authors, datasets, software, and related links, please refer to http://www2.active.ch/-krause.aldoc/statistics-in-pharmal.
Information on S-PLUS
For infonnation on S-PLUS, please contact Insightful Corporation:
Insightful Corporation 1700 Westlake Ave N, Suite 500 Seattle, W A 98lO9-3044 USA 800-569-0123 [email protected] www.insightful.com
Insightful Corporation Knightway House Park Street Bagshot, Surrey GU195AQ United Kingdom +44 1276 452 299 [email protected] www.uk.insightful.com
Acknowledgments In the Spring of 1997, one of us (Steve) taught a course on using S-PLUS at two different branches of Merck Research Laboratories. The course was organized by Charles Liss and Thomas Bradstreet of Merck, and Charles (Chuck) Taylor of MathSoft, Inc. (now Insightful Corporation), and revolved around using S-PLUS to analyze three different data sets from the pharmaceutical industry. That course was the seed for this book.
Thomas Bradstreet put Steve in touch with several statisticians and provided early guidance on the scope and direction of this book. Andreas, who works in the pharmaceutical industry, had already published a book with Melvin Olson on using S-PLUS (The Basics of Sand S-PLUS), and therefore knew several people who became contributors to this book. Weare grateful to all of the authors who generously donated their time and efforts to writing chapters for this book. We would also like to thank John Kimmel for his help and guidance throughout the process of editing this book. Steve Millard would like to thank Aleksandr Aravkin, Sam Coskey, and Jeannine Silkey for their help in formatting many of the chapters. Finally, we would like to thank all of the statisticians in the pharmaceutical industry; you have devoted yourselves to improving the health of the world.
Contents Preface ........................................................................................................ v A Note About S-PLUS Versions ................................................................ vii Typographic Conventions ......................................................................... vii Companion Web Site for This Book ........................................................ vii Information on S-PLUS ............................................................................. ix Acknowledgments ..................................................................................... xi List of Contributors .................................................................................. xv
Part 1: Introduction .................................................................................... 1 1. Statistics and the Drug Development Process
Bruce Rodda, Steven P. Millard, and Andreas Krause ...................... 3
Part 2: Basic Research and Preclinical Studies ....................................... 15 2. One-Factor Comparative Studies
Bill Pikounis ..................................................................................... 17
Part 3: Pre-Clinical Safety Assessment .................................................... 41 3. Analysis of Animal Carcinogenicity Data
Hongshik Ahn and Ralph L. Kodell ................................................. 43 4. Analysis of Toxicokinetic and Pharmacokinetic Data from
Animal Studies Wherly P. Hoffman, Michael A. Heathman, James Z. Chou, and Darrel L. Allen ................................................ 75
Part 4: Phase I Studies ............................................................................ 107 5. Analysis ofPharmacokinetic Data
Ha Nguyen and Dhammika Amaratunga ....................................... 109 6. Graphical Presentation of Single Patient Results
Jiirgen Bock ................................................................................... 135 7. Graphical Insight and Data Analysis for the
2,2,2 Crossover Design Bill Pikounis, Thomas E. Bradstreet, and Steven P. Millard ......... 153
8. Design and Analysis of Phase I Trials in Clinical Oncology Axel Benner, Lutz Edler, and Gemot Hartung .............................. 189
9. Patient Compliance and its Impact on Steady State Pharmacokinetics Wenping Wang ............................................................................... 217
10. Analysis of Analgesic Trials Ene 1. Ette, Peter Lockwood, Raymond Miller, and Jaap Mandema ........................................................................ 237
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Part 5: Phase II and Phase III Clinical Trials ....................................... 267 11. Power and Sample Size Calculations
Jiirgen Bock ................................................................................... 269 12. Comparing Two Treatments in a Large Phase III Clinical Trial
Michaela Jahn ............................................................................... 299 13. Analysis of Variance: A Comparison Between SAS and S-Pws
Melvin Olson .................................................................................. 321 14. Permutation Tests for Phase III Clinical Trials
Vance Berger and Anastasia Ivanova ............................................ 349 15. Sample Size Reestimation
Wenping Wang and Andreas Krause ............................................. 375 16. Meta-Analysis of Clinical Trials
Keith O'Rourke, Beverley Shea, and George A. Wells .................. 397
Part 6: Phase IV Studies ......................................................................... 425 17. Analysis of Health Economic Data
John R. Cook, George W. Carides, and Erik J. Dasbach .............. 427
Part 7: Manufacturing and Production ................................................. 455 18. Evaluation of the Decimal Reduction Time ofa
Sterilization Process in Pharmaceutical Production Jeffrey Eisele, Mauro Gasparini, and Amy Racine ........................ 457
19. Acceptance Sampling Plans by Attributes Harry Yang and David Carlin ....................................................... 475
Index .......................................................................................................... 503
List of Contributors The following is a list of contact infonnation for chapter authors that was current at the time this book was published. Note that author affiliation may differ between what is listed here and what is listed at the beginning of a chapter. Mfiliation listed at the beginning of a chapter reflects author affiliation at the time the chapter was written.
Hongshik Ahn Department of Applied Mathematics and Statistics
State University of New York Stony Brook, NY 11794-3600, USA [email protected]
Darrel L. Allen Toxicology and Drug Disposition Research Laboratories
Lilly Research Laboratories 2001 West Main Street Indianapolis, IN 46140, USA allen_darreC/@lilly.com
Dhammika Amaratunga The R. W. Johnson Pharmaceutical Research Institute
OMPC Building, Room 2196, Route 202
P.D. Box 300 Raritan, NJ 08869-0602, USA [email protected]
Axel Benner Biostatistics Unit German Cancer Research Center Heidelberg, Germany [email protected]
Vance Berger Biometry Research Group, DCP National Cancer Institute Executive Plaza North, Suite 344 Bethesda, MD 20892-7354, USA [email protected]
Jiirgen Bock F. Hoffmann-La Roche AG PDBS 74/0G-W, 4070 Basel, Switzerland [email protected]
Tom Bradstreet Department of Clinical
Pharmacology Statistics Merck Research Laboratories 10 Sentry Parkway, BL 3-2 Blue Bell, PA 19422, USA [email protected]
George W. Carides Department of Health Economic
Statistics Merck Research Laboratories 10 Sentry Parkway, BL 2-3 Blue Bell, P A 19422, USA [email protected]
David Carlin MedImmune, Inc. 35 West Watkins Mill Road Gaithersburg, MD 20878, USA [email protected]
James Z. Chou TAP Pharmaceutical Products Inc. 675 North Field Drive Lake Forest, IL 60045, USA [email protected]
xvi List of Contributors
JohnR. Cook Department of Health Economic
Statistics Merck Research Laboratories 10 Sentry Parkway, BL 2-3 Blue Bell, PA 19422, USA [email protected]
Erik J. Dasbach Department of Health Economic
Statistics Merck Research Laboratories 10 Sentry Parkway, BL 2-3 Blue Bell, PA 19422, USA [email protected]
Lutz Edler Biostatistics Unit German Cancer Research Center Heidelberg, Germany edler@dkft·de
Jeffrey Eisele Department of Biostatistics Novartis Pharma AG CH-4002 Basel, Switzerland [email protected]
Ene I. Ette Clinical Pharmacology Vertex Pharmaceuticals, Inc. Cambridge, MA 02139, USA [email protected]
Mauro Gasparini Dipartimento di Matematica Politecnico di Torino 1-10129 Torino, Italy [email protected]
Gemot Hartung Oncological Center Mannheim Medical School Heidelberg, Germany [email protected]
Michael A. Heathman Department of Pharmacokinetics and
Pharmacodynamics Lilly Research Laboratories 2001 West Main Street Indianapolis, IN 46140, USA [email protected]
Whedy P. Hoffman Division of Statistics and
Information Sciences Lilly Research Laboratories 2001 West Main Street Indianapolis, IN 46140, USA [email protected]
Pulastasialvanova Department of Biostatistics School of Public Health, CB# 7400 University of North Carolina Chapel Hill, NC 27599-7400, USA [email protected]
Michaela Jahn F. Hoffmann-La Roche AG PDBS, Building 74, 4-W, 4070 Basel, Switzerland [email protected]
Ralph L. Kodell Division of Biometry and
Risk Assessment National Center for Toxicological Research
Food and Drug Administration Jefferson, AR 72079, USA [email protected]
Andreas Krause Novartis Pharma AG P.O. Box 4002 Basel Switzerland [email protected]
Peter Lockwood Department of Pharmacokinetics, Dynamics and Metabolism
PfIZer Global Research and Development
2800 Plymouth Road Ann Arbor, MI48I05, USA [email protected]
Jaap Mandema Pharsight Corporation 800 West El Camino Real, Suite 200 Mountain View, CA 94040, USA [email protected]
Steven P. Millard Probability, Statistics & Information 7723 44th Avenue NE Seattle, WA 98115-5117, USA [email protected]
Raymond Miller Department of Pharmacokinetics,
Dynamics and Metabolism Pfizer Global Research and Development
2800 Plymouth Road Ann Arbor, MI48105, USA [email protected]
HaNguyen Global Medical Affairs Aventis Pharmaceuticals, Inc. P.o. Box 6800 Bridgewater, NJ 08807, USA [email protected]
Keith O'Rourke Clinical Epidemiology Unit and DepartmentofSurge~
Ottawa Hospital University of Ottawa Ottawa, Ontario K1 Y-4E9, Canada [email protected]
Melvin Olson Allergan, Inc. 2525 Dupont Drive Irvine, CA 92623-9534, USA [email protected]
Bill Pikounis Biometrics Research Merck Research Laboratories 126 East Lincoln Avenue Mail Stop RY70-38 Rahway, NJ 07065-0900, USA [email protected]
Amy Racine Department of Biostatistics Novartis Pharma AG CH-4002 Basel, Switzerland [email protected]
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xviii List of Contributors
Bruce Rodda Health Services & Research Southwest Texas State University 601 University Drive San Marcos, TX 78666-4616, USA bruce][email protected]
Beverley Shea Clinical Epidemiology Unit and Department of Medicine
Ottawa Hospital University of Ottawa Ottawa, Ontario Kl Y-4E9, Canada [email protected]
Wenping Wang Pharsight Corporation 5520 Dillard Drive, Suite 210 Cary, NC 27511, USA [email protected]
George A. Wells Department of Epidemiology and
Community Medicine University of Ottawa Ottawa, Ontario Kl Y-4E9, Canada [email protected]
Harry Yang MedImmune, Inc. 35 West Watkins Mill Road Gaithersburg, MD 20878, USA [email protected]
