Table Of ContentSTATISTICS IN THE
PHARMACEUTICAL
INDUSTRY
THIRD EDITION
Biostatistics: A Series of References and Textbooks
Series Editor
Shein-Chung Chow
Duke University School of Medicine
Department of Biostatistics and Bioinformatics
Durham, NC, USA
1. Design and Analysis of Animal Studies in Pharmaceutical Development,
Shein-Chung Chow and Jen-pei Liu
2. Basic Statistics and Pharmaceutical Statistical Applications,
James E. De Muth
3. Design and Analysis of Bioavailability and Bioequivalence Studies,
Second Edition, Revised and Expanded, Shein-Chung Chow and Jen-pei Liu
4. Meta-Analysis in Medicine and Health Policy, Dalene K. Stangl and
Donald A. Berry
5. Generalized Linear Models: A Bayesian Perspective, Dipak K. Dey,
Sujit K. Ghosh, and Bani K. Mallick
6. Difference Equations with Public Health Applications, Lemuel A. Moyé
and Asha Seth Kapadia
7. Medical Biostatistics, Abhaya Indrayan and Sanjeev B. Sarmukaddam
8. Statistical Methods for Clinical Trials, Mark X. Norleans
9. Causal Analysis in Biomedicine and Epidemiology: Based on Minimal
Sufficient Causation, Mikel Aickin
10. Statistics in Drug Research: Methodologies and Recent Developments,
Shein-Chung Chow and Jun Shao
11. Sample Size Calculations in Clinical Research, Shein-Chung Chow, Jun Shao,
and Hansheng Wang
12. Applied Statistical Design for the Researcher, Daryl S. Paulson
13. Advances in Clinical Trial Biostatistics, Nancy L. Geller
14. Statistics in the Pharmaceutical Industry, 3rd Edition, Ralph Buncher
and Jia-Yeong Tsay
15. DNA Microarrays and Related Genomics Techniques: Design, Analysis, and
Interpretation of Experiments, David B. Allsion, Grier P. Page, T. Mark
Beasley, and Jode W. Edwards
STATISTICS IN THE
PHARMACEUTICAL
INDUSTRY
THIRD EDITION
EDITED BY
C. RALPH BUNCHER
University of Cincinnati Medical Center
Cincinnati, OH, U.S.A.
JIA-YEONG TSAY
Organon Pharmaceuticals U.S.A., Inc.
Roseland, NJ
Boca Raton London New York
DK219X_Discl.fm Page 1 Thursday, August 25, 2005 2:19 PM
Published in 2006 by
Chapman & Hall/CRC
Taylor & Francis Group
6000 Broken Sound Parkway NW, Suite 300
Boca Raton, FL 33487-2742
© 2006 by Taylor & Francis Group, LLC
Chapman & Hall/CRC is an imprint of Taylor & Francis Group
No claim to original U.S. Government works
Printed in the United States of America on acid-free paper
10 9 8 7 6 5 4 3 2 1
International Standard Book Number-10: 0-8247-5469-7 (Hardcover)
International Standard Book Number-13: 978-0-8247-5469-3 (Hardcover)
Library of Congress Card Number 2005043985
This book contains information obtained from authentic and highly regarded sources. Reprinted material is
quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts
have been made to publish reliable data and information, but the author and the publisher cannot assume
responsibility for the validity of all materials or for the consequences of their use.
No part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic,
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Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only
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Library of Congress Cataloging-in-Publication Data
Statistics in the pharmaceutical industry / [edited by] C. Ralph Buncher, Jia-Yeong Tsay.-- 3rd ed.
p. cm. -- (Biostatics ; 14)
ISBN 0-8247-5469-7 (alk. paper)
1. Pharmacy--Statistical methods. 2. Pharmaceutical industry--Statistical methods. 3. Drugs--
Testing. I. Buncher, C. Ralph (Charles Ralph), 1938- II. Tsay, Jia-Yeong, 1944- III. Biostatistics
(New York, N.Y.)
RS57.S8 2005 2005043985
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To Maxine and Tung-Ying
Series Introduction
The primary objectives of the Biostatistics Book Series are to provide useful
referencebooksforresearchersandscientistsinacademia,industry,andgovern-
ment,andalsotooffertextbooksforundergraduateorgraduatecoursesinthearea
ofbiostatistics.Thisbookserieswillprovidecomprehensiveandunifiedpresen-
tationsofstatisticaldesignsandanalysesofimportantapplicationsinbiostatistics,
such as those inbiopharmaceuticals. Awell-balancedsummarywillbegivenof
current and recently developed statistical methods and interpretations for both
statisticiansandresearchersorscientistswithminimalstatisticalknowledgewho
areengagedinthefieldofappliedbiostatistics.Theseriesiscommittedtoproviding
easy-to-understand,state-of-the-artreferencesandtextbooks.Ineachvolume,statis-
ticalconceptsandmethodologieswillbeillustratedthroughrealworldexamples.
As indicated by the authors of this volume, there is a rapid change in
pharmaceutical research and development since the publication of the second
editionofthisbook.Newconceptsandadvancedtechnologieshaveenabledmore
flexibleandefficientpharmaceuticalresearchanddevelopmentinthepastdecade.
These new concepts and advanced technologies include the use of adaptive (or
flexible) design in early phase of clinical research and development, the
determination of non-inferiority margin in non-inferiority trials for proving
superiorityoverplacebo,andtheestablishmentofapredictiveclinicalmodelusing
genomicdataforpersonalizedmedicine.Similartopreviouseditions,thisvolume
providesawell-balancedsummarizationofstatisticaldesignsandanalysesthatare
commonly encountered in pharmaceutical research and development. It covers
importanttopicsinpharmaceuticalresearchanddevelopmentsuchasclinicaltrial
designs, interim analysis and adaptive design in clinical trials, post-marking
studiesandadversedrugexperiences,statisticalchallengesinpharmacogenomics,
andglobalharmonizationofdrugdevelopment.Asaresult,itcanserveasnotonly
a textbook for a course in biopharmaceutical statistics at senior level of under-
graduateorgraduatelevelbutalsoasausefulreferencebookforpharmaceutical
scientistsandresearchersinthehealthrelatedarea.Inaddition,thisvolumealso
providespharmaceuticalscientistsandresearchersaninnovativewayofthinking
for evaluation of the effectiveness and safety of an investigational new drug or
therapy. It would be beneficial to biostatisticians and pharmaceutical scientists
and researchers who are engaged in the areas of pharmaceutical research and
development.
Shein-ChungChow
vii
Preface to the Third Edition
Wow—andwethoughtthatthedecadefromthefirsttothesecondeditionwas
one of rapid change. The changes in the pharmaceutical industry in the last
decade,fromthesecondtothisthirdedition,havebeenevenmoreenormous.For
example,theindustryandallofitsthinkinghavebecomeglobalsothatplanning
from the very beginning of a new drug to its marketing are done on an inter-
nationalbasis.Theregulatoryauthoritieshavemadegreatstridesinharmoniza-
tion so that there are fewer small and time consuming differences from one
countrytoanother.Computerpowerhaspermittedanincreasedlevelofstatistical
sophisticationinanalysesandinimprovedcommunicationovertheinternetand
intranet. Now one designs clinical trials that are adaptive and thus provide
flexibility and also raise interesting new statistical issues of validity. Proving
superiority over placebo is becoming less important and trials that show
equivalencewith(orsuperiorityto)aknowneffectivemedicationarethusmore
common andimportant.
Thisbookthentriestoconveytheexcitementofthepharmaceuticalindustry
to an audience including those who work there on the industry side or the
regulatory authorities who review the work of the industry and wish to learn
aboutadifferentarea,tothosewhomayworkthereinthefutureandwishtolearn
moreabouttheindustrybeforemakingthatdecision,andtothosewhojustwish
to understand more about the role of statistics in this research and these
companies.Thesechaptersarewrittenbythoseonthefrontlinesintheindustry
andattheregulatoryagencies.Theviewsofthosewhooriginatethestatisticsand
those who then evaluate the analysis are both here. While their roles may give
thesestatisticiansdifferentviewpoints,theirgoalsarethesame:seethatstudies
aredesignedtoprove safety andefficacy andgoodmanufacturing andfindnew
medicationsthataremarketablewhileweedingoutthechemicalcandidatesthat
have some defect. The answers vary with different classes of drugs and this
variety isalsoillustrated inthis volume.
Wetheeditorsexpressourthankstotheauthorsofthesechapterswhohave
recordedtheirknowledgeandexperiencetomakeiteasierforotherstoachieve
thesamelevelwithfewerhurdles.Thesophisticationoftheauthors’thinkinghas
been a blessingto the editors.
C. Ralph Buncher
Jia-YeongTsay
ix
