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Clinical Trial
Optimization
Using R
Editor-in-Chief
Shein-Chung Chow, Ph.D., Professor, Department of Biostatistics and Bioinformatics,
Duke University School of Medicine, Durham, North Carolina
Series Editors
Byron Jones, Biometrical Fellow, Statistical Methodology, Integrated Information Sciences,
Novartis Pharma AG, Basel, Switzerland
Jen-pei Liu, Professor, Division of Biometry, Department of Agronomy,
National Taiwan University, Taipei, Taiwan
Karl E. Peace, Georgia Cancer Coalition, Distinguished Cancer Scholar, Senior Research Scientist
and Professor of Biostatistics, Jiann-Ping Hsu College of Public Health,
Georgia Southern University, Statesboro, Georgia
Bruce W. Turnbull, Professor, School of Operations Research and Industrial Engineering,
Cornell University, Ithaca, New York
Published Titles
Adaptive Design Methods in Clinical Basic Statistics and Pharmaceutical
Trials, Second Edition Statistical Applications, Second Edition
Shein-Chung Chow and Mark Chang James E. De Muth
Adaptive Designs for Sequential Bayesian Adaptive Methods for
Treatment Allocation Clinical Trials
Alessandro Baldi Antognini Scott M. Berry, Bradley P. Carlin,
and Alessandra Giovagnoli J. Jack Lee, and Peter Muller
Adaptive Design Theory and Bayesian Analysis Made Simple:
Implementation Using SAS and R, An Excel GUI for WinBUGS
Second Edition Phil Woodward
Mark Chang Bayesian Designs for Phase I–II
Advanced Bayesian Methods for Clinical Trials
Medical Test Accuracy Ying Yuan, Hoang Q. Nguyen,
Lyle D. Broemeling and Peter F. Thall
Analyzing Longitudinal Clinical Trial Data: Bayesian Methods for Measures
A Practical Guide of Agreement
Craig Mallinckrodt and Ilya Lipkovich Lyle D. Broemeling
Applied Biclustering Methods for Big Bayesian Methods for Repeated Measures
and High-Dimensional Data Using R Lyle D. Broemeling
Adetayo Kasim, Ziv Shkedy, Bayesian Methods in Epidemiology
Sebastian Kaiser, Sepp Hochreiter, Lyle D. Broemeling
and Willem Talloen
Bayesian Methods in Health Economics
Applied Meta-Analysis with R Gianluca Baio
Ding-Geng (Din) Chen and Karl E. Peace
Bayesian Missing Data Problems: EM,
Applied Surrogate Endpoint Evaluation Data Augmentation and Noniterative
Methods with SAS and R Computation
Ariel Alonso, Theophile Bigirumurame, Ming T. Tan, Guo-Liang Tian,
Tomasz Burzykowski, Marc Buyse, and Kai Wang Ng
Geert Molenberghs, Leacky Muchene,
Nolen Joy Perualila, Ziv Shkedy,
and Wim Van der Elst
Published Titles
Bayesian Modeling in Bioinformatics Clinical Trial Optimization Using R

Dipak K. Dey, Samiran Ghosh, Alex Dmitrienko and Erik Pulkstenis
and Bani K. Mallick Computational Methods in Biomedical
Benefit-Risk Assessment in Research
Pharmaceutical Research and Ravindra Khattree and Dayanand N. Naik
Development Computational Pharmacokinetics
Andreas Sashegyi, James Felli, Anders Källén
and Rebecca Noel
Confidence Intervals for Proportions
Benefit-Risk Assessment Methods in and Related Measures of Effect Size
Medical Product Development: Bridging Robert G. Newcombe
Qualitative and Quantitative Assessments
Controversial Statistical Issues in
Qi Jiang and Weili He
Clinical Trials
Bioequivalence and Statistics in Clinical Shein-Chung Chow
Pharmacology, Second Edition
Data Analysis with Competing Risks
Scott Patterson and Byron Jones
and Intermediate States
Biosimilar Clinical Development: Ronald B. Geskus
Scientific Considerations and New
Data and Safety Monitoring Committees
Methodologies
in Clinical Trials, Second Edition
Kerry B. Barker, Sandeep M. Menon,
Jay Herson
Ralph B. D’Agostino, Sr., Siyan Xu, and Bo Jin
Design and Analysis of Animal Studies
Biosimilars: Design and Analysis of
in Pharmaceutical Development
Follow-on Biologics
Shein-Chung Chow and Jen-pei Liu
Shein-Chung Chow
Design and Analysis of Bioavailability
Biostatistics: A Computing Approach
and Bioequivalence Studies, Third Edition
Stewart J. Anderson
Shein-Chung Chow and Jen-pei Liu
Cancer Clinical Trials: Current and
Design and Analysis of Bridging Studies
Controversial Issues in Design and
Jen-pei Liu, Shein-Chung Chow,
Analysis
and Chin-Fu Hsiao
Stephen L. George, Xiaofei Wang,
and Herbert Pang Design & Analysis of Clinical Trials for
Economic Evaluation & Reimbursement:
Causal Analysis in Biomedicine and
An Applied Approach Using SAS & STATA
Epidemiology: Based on Minimal
Iftekhar Khan
Sufficient Causation
Mikel Aickin Design and Analysis of Clinical Trials
for Predictive Medicine
Clinical and Statistical Considerations in
Shigeyuki Matsui, Marc Buyse,
Personalized Medicine
and Richard Simon
Claudio Carini, Sandeep Menon, and Mark Chang
Design and Analysis of Clinical Trials with
Clinical Trial Data Analysis Using R
Time-to-Event Endpoints
Ding-Geng (Din) Chen and Karl E. Peace
Karl E. Peace
Clinical Trial Data Analysis Using R and SAS,
Design and Analysis of Non-Inferiority Trials
Second Edition
Mark D. Rothmann, Brian L. Wiens,
Ding-Geng (Din) Chen, Karl E. Peace,
and Ivan S. F. Chan
and Pinggao Zhang
Difference Equations with Public Health
Clinical Trial Methodology
Applications
Karl E. Peace and Ding-Geng (Din) Chen
Lemuel A. Moyé and Asha Seth Kapadia
Published Titles
DNA Methylation Microarrays: Interval-Censored Time-to-Event Data:
Experimental Design and Statistical Methods and Applications
Analysis Ding-Geng (Din) Chen, Jianguo Sun,
Sun-Chong Wang and Arturas Petronis and Karl E. Peace
DNA Microarrays and Related Genomics Introductory Adaptive Trial Designs:
Techniques: Design, Analysis, and A Practical Guide with R
Interpretation of Experiments Mark Chang
David B. Allison, Grier P. Page, Joint Models for Longitudinal and Time-
T. Mark Beasley, and Jode W. Edwards to-Event Data: With Applications in R
Dose Finding by the Continual Dimitris Rizopoulos
Reassessment Method Measures of Interobserver Agreement
Ying Kuen Cheung and Reliability, Second Edition
Dynamical Biostatistical Models Mohamed M. Shoukri
Daniel Commenges and Medical Biostatistics, Third Edition
Hélène Jacqmin-Gadda A. Indrayan
Elementary Bayesian Biostatistics Meta-Analysis in Medicine and
Lemuel A. Moyé Health Policy
Emerging Non-Clinical Biostatistics in Dalene Stangl and Donald A. Berry
Biopharmaceutical Development and Methods in Comparative Effectiveness
Manufacturing Research
Harry Yang Constantine Gatsonis and Sally C. Morton
Empirical Likelihood Method in Mixed Effects Models for the Population
Survival Analysis Approach: Models, Tasks, Methods
Mai Zhou and Tools
Essentials of a Successful Biostatistical Marc Lavielle
Collaboration Modeling to Inform Infectious Disease
Arul Earnest Control
Exposure–Response Modeling: Methods Niels G. Becker
and Practical Implementation Modern Adaptive Randomized Clinical
Jixian Wang Trials: Statistical and Practical Aspects
Frailty Models in Survival Analysis Oleksandr Sverdlov
Andreas Wienke Monte Carlo Simulation for the
Fundamental Concepts for New Clinical Pharmaceutical Industry: Concepts,
Trialists Algorithms, and Case Studies
Scott Evans and Naitee Ting Mark Chang
Generalized Linear Models: A Bayesian Multiregional Clinical Trials for
Perspective Simultaneous Global New Drug
Dipak K. Dey, Sujit K. Ghosh, and Development
Bani K. Mallick Joshua Chen and Hui Quan
Handbook of Regression and Modeling: Multiple Testing Problems in
Applications for the Clinical and Pharmaceutical Statistics
Pharmaceutical Industries Alex Dmitrienko, Ajit C. Tamhane,
Daryl S. Paulson and Frank Bretz
Inference Principles for Biostatisticians
Ian C. Marschner
Published Titles
Noninferiority Testing in Clinical Trials: Statistical Design and Analysis of Clinical

Issues and Challenges Trials: Principles and Methods
Tie-Hua Ng Weichung Joe Shih and Joseph Aisner
Optimal Design for Nonlinear Response Statistical Design and Analysis of
Models Stability Studies
Valerii V. Fedorov and Sergei L. Leonov Shein-Chung Chow
Patient-Reported Outcomes: Statistical Evaluation of Diagnostic
Measurement, Implementation and Performance: Topics in ROC Analysis
Interpretation Kelly H. Zou, Aiyi Liu, Andriy Bandos,
Joseph C. Cappelleri, Kelly H. Zou, Lucila Ohno-Machado, and Howard Rockette
Andrew G. Bushmakin, Jose Ma. J. Alvir, Statistical Methods for Clinical Trials
Demissie Alemayehu, and Tara Symonds Mark X. Norleans
Quantitative Evaluation of Safety in Drug Statistical Methods for Drug Safety
Development: Design, Analysis and Robert D. Gibbons and Anup K. Amatya
Reporting
Statistical Methods for Healthcare
Qi Jiang and H. Amy Xia
Performance Monitoring
Quantitative Methods for Traditional Alex Bottle and Paul Aylin
Chinese Medicine Development
Statistical Methods for Immunogenicity
Shein-Chung Chow
Assessment
Randomized Clinical Trials of Harry Yang, Jianchun Zhang, Binbing Yu,
Nonpharmacological Treatments and Wei Zhao
Isabelle Boutron, Philippe Ravaud,
Statistical Methods in Drug Combination
and David Moher
Studies
Randomized Phase II Cancer Wei Zhao and Harry Yang
Clinical Trials
Statistical Testing Strategies in the
Sin-Ho Jung
Health Sciences
Repeated Measures Design with Albert Vexler, Alan D. Hutson,
Generalized Linear Mixed Models for and Xiwei Chen
Randomized Controlled Trials
Statistics in Drug Research:
Toshiro Tango
Methodologies and Recent
Sample Size Calculations for Clustered Developments
and Longitudinal Outcomes in Clinical Shein-Chung Chow and Jun Shao
Research
Statistics in the Pharmaceutical Industry,
Chul Ahn, Moonseong Heo,
Third Edition
and Song Zhang
Ralph Buncher and Jia-Yeong Tsay
Sample Size Calculations in Clinical
Survival Analysis in Medicine and
Research, Second Edition
Genetics
Shein-Chung Chow, Jun Shao,
Jialiang Li and Shuangge Ma
and Hansheng Wang
Theory of Drug Development
Statistical Analysis of Human Growth
Eric B. Holmgren
and Development
Yin Bun Cheung Translational Medicine: Strategies and
Statistical Methods
Dennis Cosmatos and Shein-Chung Chow
Clinical Trial
Optimization
Using R
Edited by
Alex Dmitrienko
Erik Pulkstenis
Harry Yang
CRC Press
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Library of Congress Cataloging‑in‑Publication Data
Names: Dmitrienko, Alex. | Pulkstenis, Erik.

Title: Clinical trial optimization using R / Alex Dmitrienko, Erik Pulkstenis.
Description: Boca Raton : CRC Press, 2017. | Includes bibliographical
references and index.
Identifiers: LCCN 2016057709 | ISBN 9781498735070 (hardback : alk. paper)
Subjects: LCSH: Clinical trials--Statistical methods. | R (Computer program language)
Classification: LCC R853.C55 D6525 2017 | DDC 610.72/7--dc23
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Contents
Preface xiii
List of Contributors xvii
1 Clinical Scenario Evaluation and Clinical Trial Optimization 1

Alex Dmitrienko and Gautier Paux
1.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.2 Clinical Scenario Evaluation . . . . . . . . . . . . . . . . . . 2
1.2.1 Components of Clinical Scenario Evaluation . . . . . . 2
1.2.2 Software implementation . . . . . . . . . . . . . . . . 4
1.2.3 Case study 1.1: Clinical trial with a normally distributed
endpoint . . . . . . . . . . . . . . . . . . . . . . . . . . 16
1.2.4 Case study 1.2: Clinical trial with two time-to-event
endpoints . . . . . . . . . . . . . . . . . . . . . . . . . 20
1.3 Clinical trial optimization . . . . . . . . . . . . . . . . . . . . 28
1.3.1 Optimization strategies . . . . . . . . . . . . . . . . . 30
1.3.2 Optimization algorithm . . . . . . . . . . . . . . . . . 33
1.3.3 Sensitivity assessments . . . . . . . . . . . . . . . . . . 34
1.4 Direct optimization . . . . . . . . . . . . . . . . . . . . . . . 38
1.4.1 Case study 1.3: Clinical trial with two patient popula-
tions . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
1.4.2 Qualitative sensitivity assessment . . . . . . . . . . . . 43
1.4.3 Quantitative sensitivity assessment . . . . . . . . . . . 44
1.4.4 Optimal selection of the target parameter . . . . . . . 53
1.5 Tradeoff-based optimization . . . . . . . . . . . . . . . . . . 59
1.5.1 Case study 1.4: Clinical trial with an adaptive design 59
1.5.2 Optimal selection of the target parameter . . . . . . . 67
2 Clinical Trials with Multiple Objectives 71

2.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
2.2 Clinical Scenario Evaluation framework . . . . . . . . . . . . 73
2.2.1 Data models . . . . . . . . . . . . . . . . . . . . . . . 74
2.2.2 Analysis models . . . . . . . . . . . . . . . . . . . . . 74
2.2.3 Evaluation models . . . . . . . . . . . . . . . . . . . . 85
2.3 Case study 2.1: Optimal selection of a multiplicity adjustment 91
ix
x Contents
2.3.1 Clinical trial . . . . . . . . . . . . . . . . . . . . . . . 92

2.3.5 Conclusions and extensions . . . . . . . . . . . . . . . 120
2.4 Case study 2.2: Direct selection of optimal procedure parame-
ters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
2.4.1 Clinical trial . . . . . . . . . . . . . . . . . . . . . . . 121
2.4.2 Optimal selection of the target parameter in
Procedure B1 . . . . . . . . . . . . . . . . . . . . . . . 133
2.4.3 Optimal selection of the target parameters in Proce-
dure B2 . . . . . . . . . . . . . . . . . . . . . . . . . . 140
2.4.4 Sensitivity assessments . . . . . . . . . . . . . . . . . . 145
2.5 Case study 2.3: Tradeoff-based selection of optimal procedure
parameters . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156
2.5.1 Clinical trial . . . . . . . . . . . . . . . . . . . . . . . 156
2.5.2 Optimal selection of the target parameter in
Procedure H . . . . . . . . . . . . . . . . . . . . . . . 161
3 Subgroup Analysis in Clinical Trials 173

3.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . 173
3.2 Clinical Scenario Evaluation in confirmatory subgroup analysis 175
3.2.1 Clinical Scenario Evaluation framework . . . . . . . . 175
3.2.2 Multiplicity adjustments . . . . . . . . . . . . . . . . . 181
3.2.3 Decision-making framework . . . . . . . . . . . . . . . 184
3.3 Case study 3.1: Optimal selection of a multiplicity adjustment 188
3.3.1 Clinical trial . . . . . . . . . . . . . . . . . . . . . . . 189
3.3.2 Direct optimization based on disjunctive power . . . . 194
3.3.3 Direct optimization based on weighted power . . . . . 196
3.4 Case study 3.2: Optimal selection of decision rules to support
two potential claims . . . . . . . . . . . . . . . . . . . . . . . 215
3.4.1 Clinical trial . . . . . . . . . . . . . . . . . . . . . . . 215
3.4.2 Influence condition . . . . . . . . . . . . . . . . . . . . 215
3.4.3 Optimal selection of the influence threshold . . . . . . 219
Contents xi
3.5 Case study 3.3: Optimal selection of decision rules to support

three potential claims . . . . . . . . . . . . . . . . . . . . . . 228
3.5.1 Clinical trial . . . . . . . . . . . . . . . . . . . . . . . 228
3.5.2 Interaction condition . . . . . . . . . . . . . . . . . . . 233
3.5.3 Optimal selection of the influence and interaction thresh-
olds . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238
4 Decision Making in Clinical Development 251

Kaushik Patra, Ming-Dauh Wang, Jianliang Zhang, Aaron Dane, Paul
Metcalfe, Paul Frewer, and Erik Pulkstenis
4.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . 251
4.2 Clinical Scenario Evaluation in Go/No-Go decision making and
determination of probability of success . . . . . . . . . . . . 253
4.2.1 Clinical Scenario Evaluation approach . . . . . . . . . 253
4.2.2 Go/No-Go decision criteria . . . . . . . . . . . . . . . 255
4.2.3 Probability of success . . . . . . . . . . . . . . . . . . 258
4.2.4 Probability of success applications . . . . . . . . . . . 262
4.3 Motivating example . . . . . . . . . . . . . . . . . . . . . . . 264
4.3.1 Clinical trial . . . . . . . . . . . . . . . . . . . . . . . 265
4.4 Case study 4.1: Bayesian Go/No-Go decision criteria . . . . 269
4.4.1 Clinical trial . . . . . . . . . . . . . . . . . . . . . . . 269
4.4.2 General sensitivity assessments . . . . . . . . . . . . . 271
4.4.3 Bayesian Go/No-Go evaluation using informative priors 274
4.4.4 Sample size considerations . . . . . . . . . . . . . . . . 276
4.5 Case study 4.2: Bayesian Go/No-Go evaluation using an alter-
native decision criterion . . . . . . . . . . . . . . . . . . . . . 283
4.5.1 Clinical trial . . . . . . . . . . . . . . . . . . . . . . . 283
4.6 Case study 4.3: Bayesian Go/No-Go evaluation in a trial with
an interim analysis . . . . . . . . . . . . . . . . . . . . . . . . 286
4.6.1 Clinical trial . . . . . . . . . . . . . . . . . . . . . . . 287
4.7 Case study 4.4: Decision criteria in Phase II trials based on
Probability of Success . . . . . . . . . . . . . . . . . . . . . . 290
4.7.1 Clinical trial . . . . . . . . . . . . . . . . . . . . . . . 290
xii Contents
4.8 Case study 4.5: Updating POS using interim or external infor-
mation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294
4.8.1 Clinical trial . . . . . . . . . . . . . . . . . . . . . . . 295
Bibliography 301
Index 309
Preface
Clinical development is a strategic and operational, scientific process that

involves a significant level of multidimensional decision making, often in the
presence of incomplete information or considerable uncertainty. Along the
way, several key questions must be answered including selection of the right
dose and schedule, selection of the right patient population and selection of the
right analytical strategy to provide optimal treatment options for patients with
the highest probability of success. Against this backdrop, more fundamental
questions loom, e.g., whether the drug is even safe or effective at all and
whether the final risk-benefit profile will be acceptable.
Adding to the research burden is the desire to make correct decisions as
quickly and efficiently as possible. The rise in adaptive design science over
the past decade speaks to the increasing desire to learn in real time, and im-
mediately incorporate that learning into drug development, in an attempt to
eliminate or reduce the white space present in a traditional drug development
paradigm. Advances in multiplicity theory support the growing pressure to
definitively establish as many hypotheses/claims as possible within the con-
straints of Type I error rate control. At the same time clinical trial programs
are changing with the lines becoming increasingly blurred between traditional
phases of drug development, or individual trials that are increasing in com-
plexity to ask more questions (e.g., platform trials). External pressures also
exist, driven by the changes in reimbursement and increased expectations that
medications demonstrate their value to the patient and clinical community in
a more comprehensive way. The goal is simply no longer to conduct two large
Phase III trials with statistically significant p-values because the bar has been
raised.
Despite significant methodological advances provided by the statistical and
clinical community and associated computational advances, it remains clear
that development risk remains high, and that decision making has not yet been
universally optimized within clinical development. This can be seen by the
accumulating evidence that Phase II results often do not translate to Phase III
success (Brutti, De Santis, and Gubbiotti, 2008; Kirby et al., 2012; Kola and
Landis, 2004; Chuang-Stein and Kirby, 2014). One review of 253 published
Phase III oncology trials found that 62% of the trials failed to establish a
statistically significant treatment effect, mostly due to the fact that observed
treatment effects were simply smaller than expected based on previous data
(Gan et al., 2012).
This combination of increasing clinical trial complexity/options, coupled
xiii
xiv Preface
with increasing scrutiny on the risk-benefit profile that new treatments bring
to the table, against a backdrop of lackluster industry development perfor-
mance introduces both financial constraints, and a heightened level of urgency
around strategic drug development decision making in order to stop develop-
ment of inferior compounds early and accelerate development of promising
compounds (Arrowsmith and Miller, 2013; Paul et al., 2010). As a result,
clinical trial optimization is an absolute necessity in support of these objec-
tives, though quantitative methods to this end are frequently not part of the
drug development process.
Clinical trial optimization can be thought of at the trial level, or the de-
velopment plan level as clinical research designed to most efficiently and with
least risk answer the most important research questions to the developer. His-
torically the process has been fairly empiric, though the increasing availability
of computational resources and methods, along with the generally low success
rates, is driving an opportunity to marry clinical trial modeling and simulation
with decision making in a more comprehensive and holistic fashion, resulting
in evidence-based development which examines the operating characteristics
of development decisions themselves. In this book, we explore a promising
approach known as the Clinical Scenario Evaluation framework (Benda et al.,
2010) which endeavors to optimize clinical development considering a set of
objectives, design and analysis alternatives, underlying assumptions and, fi-
nally, quantitative metrics to facilitate decision making with better line of
sight into the decision space one is dealing with. We use specific common
clinical trial problems to elucidate the methodology in a case study setting. R
code is provided to both demonstrate common methods while providing some
preliminary tools for the practitioner. Examples include optimally spending
the Type I error rate across trial objectives or patient subgroups in the pres-
ence of multiple desired claims and optimally selecting associated decision
rules or analytical methods in Chapters 2 and 3. In addition, we present an
evaluation of Go/No-Go decision making at the proof-of-concept stage as well
as considerations for probability of success based on Bayesian principles in
Chapter 4. These case studies serve to scratch the surface regarding the po-
tential utility of modeling and simulation to optimize decision making within
a complex and highly dimensional development decision space.
The Clinical Scenario Evaluation paradigm is broadly flexible and applica-
ble to any scenario a clinical trial or researcher can envision and, as a result,
may impact the overall quality of the drug development process. It is a valu-
able tool available to the researcher and enables a move from empirical decision
making around myriads of options, to a more disciplined and evidence-based
approach to how one designs clinical trials and clinical trial programs.
Preface xv
Acknowledgments
We would like to thank the reviewers who have provided valuable comments
on selected chapters in the book: Thomas Brechenmacher (Novartis), Michael
Lee (Johnson and Johnson), Christoph Muysers (Bayer), Xin Wang (AbbVie).
We would also like to thank the book’s acquisitions editor, David Grubbs,
for his support and his work on this book publishing project.
Alex Dmitrienko, Mediana Inc.

Erik Pulkstenis, MedImmune.
List of Contributors
This book is based on a collaborative effort of nine statisticians from the

pharmaceutical industry:
Aaron Dane, Therapeutic Area Head for Infection, Biometrics and Infor-
mation Sciences, AstraZeneca; Independent Consultant, DaneStat Consulting
Limited.
Alex Dmitrienko, President, Mediana Inc.
Paul Frewer, Statistical Science Director, Biometrics and Information Sci-
ences, AstraZeneca.
Paul Metcalfe, Scientific Computing Director, Advanced Analytics Centre,
Biometrics and Information Sciences, AstraZeneca.
Kaushik Patra, Science Director, Biostatistics, MedImmune; Director, Bio-
statistics, Alexion.
Gautier Paux, Senior Statistician, Clinical Biostatistics Unit, Institut de
Recherches Internationales Servier.
Erik Pulkstenis, Vice President, Clinical Biostatistics and Data Manage-
ment, MedImmune.
Ming-Dauh Wang, Principal Research Scientist, Global Statistical Sciences,
Eli Lilly and Company.
Jianliang Zhang, Senior Director, Statistical Methods, MedImmune.
xvii
1
Clinical Scenario Evaluation and Clinical
Trial Optimization
Alex Dmitrienko
Mediana Inc.
Gautier Paux
Institut de Recherches Internationales Servier
1.1 Introduction
It was pointed out in the preface that clinical trial sponsors are actively look-
ing for ways to develop more efficient approaches to designing, conducting and
analyzing trials. This can be accomplished most effectively through a com-
prehensive quantitative assessment of available options, including innovative
trial designs and statistical methods. Clinical Scenario Evaluation (CSE) was
introduced in Benda et al. (2010), and subsequently refined in Friede et al.
(2010) and other publications, as an efficient quantitative approach to evalu-
ating trial designs and data analysis methods in individual clinical trials or,
more generally, in clinical development programs.
A general CSE-based approach to designing a clinical trial incorporates
a thorough assessment of multiple competing strategies which enables the
trial’s team to assess the pros and cons of the applicable trial designs and
analysis techniques and to examine their sensitivity to potential changes in
the underlying assumptions. This approach has the potential to help trial
sponsors set up more robust designs that avoid overly optimistic assumptions
that are still very common in Phase III trials (Gan et al., 2012) and, along
the same line, improve on simplistic or suboptimal analytical methods such as
inefficient multiplicity adjustments that are often employed in clinical trials;
see, for example, PREVAIL trial (Beer et al., 2014) or APEX trial (Cohen et
al., 2013; Cohen et al., 2014). In fact, CSE has been successfully leveraged
in multiple Phase II and III clinical trials and led to tangible improvements
compared to ad-hoc approaches to trial design and analysis. Examples and
references can be found in Benda et al. (2010), Friede et al. (2010), as well
1
2 Clinical Trial Optimization Using R
as more recent publications, including Dmitrienko, Paux and Brechenmacher

(2015) and Dmitrienko et al. (2016).
As a powerful approach to improving the probability of success and build-
ing robust trial designs and analysis strategies, the general CSE framework
will play a central role in this book. The guiding principles of CSE will be
introduced in Section 1.2 and will be applied in Chapters 2, 3 and 4. The
discussion of CSE applications in these chapters will focus mostly on efficacy
assessments in a single clinical trial. However, it is important to note that
many other applications fall within the CSE domain. This includes, for exam-
ple, a systematic assessment of safety signals as well as CSE-based evaluations
at the program level. For a discussion of key considerations related to apply-
ing CSE techniques to multiple clinical trials within the same development
program, see Benda et al. (2010).
It is important to explore the connections between CSE and clinical trial
optimization. As pointed out in Benda et al. (2010), due to its emphasis on
identifying best-performing designs and analysis strategies in clinical trials,
CSE provides a foundation for developing a holistic approach to optimizing
drug development. The key principles of CSE-based clinical trial optimiza-
tion will be introduced in Section 1.3 and illustrated throughout this book.
Practical and easy-to-implement clinical trial optimization strategies will be
emphasized in the book. The resulting strategies provide quantitative infor-
mation to support internal decision making and efficient dialog with external
clinical experts and regulators. To facilitate the application of CSE and opti-
mization methods to real-life trials, multiple case studies and R code will be
provided in Chapters 2, 3 and 4.
1.2 Clinical Scenario Evaluation

This section introduces the key principles and building blocks of the general
CSE approach with emphasis on the trial-level and analysis-level evaluations
introduced in Benda et al. (2010). The process of setting up a CSE frame-
work and defining its components in real clinical trials will be illustrated in
Section 1.2.2 using an R package that was designed to support CSE in clinical
trial applications (Mediana package).
1.2.1 Components of Clinical Scenario Evaluation

It is broadly recognized that evaluation of candidate trial designs and analysis
methods in clinical trials is, by nature, a multidimensional process. Benda et
al. (2010) proposed to decompose this complex problem into a small number of
components that define the core building blocks of the overall CSE framework.
These components were referred to as assumptions, options and metrics in the
Clinical Scenario Evaluation and Clinical Trial Optimization 3
Data Model Analysis Model
Assumption 1 Strategy 1
Clinical Scenario
. .
. .
. .
Data Model
. .
X
. .
Analysis Model
. .
. .
. .
Assumption a Strategy s
Evaluation Model
Criterion 1 . . . . . . Criterion c
Clinical Scenario Evaluation
Apply Evaluation Model to Clinical Scenario
FIGURE 1.1: General Clinical Scenario Evaluation framework.
original CSE publications. Dmitrienko et al. (2016) revised this terminology

to introduce more descriptive labels for each CSE component:
• Data models, previously known as assumptions, define the process of gen-
erating the trial data.
• Analysis models, previously known as options, specify the analysis strate-
gies applied to the trial data.
• Evaluation models, previously known as metrics, specify the criteria for
evaluating the performance of the analysis strategies applied to the trial
data.
Within the data and analysis models, multiple statistical assumptions or
analysis strategies can be specified and the combination of these two models
represents a clinical scenario. CSE focuses on the application of the criteria
defined in the evaluation model to the clinical scenarios of interest. A visual
representation of the CSE framework is provided in Figure 1.1.
This decomposition into three independent components provides a struc-
tured framework for clinical trial simulations which enables clinical trial re-
searchers to carry out a systematic quantitative assessment of the operating
characteristics of candidate designs and statistical methods to characterize
their performance in multiple settings. Ultimately, this assessment supports

the selection of a robust approach to clinical trial design and analysis which
demonstrates optimal performance.
It was emphasized in the introduction that, within the CSE framework,
emphasis is placed on realistic assumptions as opposed to simplistic assump-
tions that may be introduced to streamline the process of designing a clinical
trial or simplify the data analysis models. For example, when designing a
trial with a time-to-event endpoint, it is quite common to assume that this
endpoint follows an exponential distribution because this distribution sup-
ports the assumption of proportional hazards and leads to a straightforward
closed-form expression for the required number of events in the trial. CSE en-
courages clinical trial sponsors to take advantage of simulation-based methods
to facilitate an exhaustive performance assessment by exploring a multitude
of data models and analysis strategies, as well as a wide range of sensitivity
assessments to ultimately arrive at optimal and robust trial designs and data
analysis methods according to the pre-defined success criteria. In general,
simulation-based approaches have found numerous applications in clinical tri-
als and have been used to construct design and analysis evaluation frameworks
that are conceptually similar to CSE; see, for example, Westfall et al. (2008).
1.2.2 Software implementation

It was pointed out in Friede et al. (2010) that there may be an important gap
between the general set of CSE principles and their practical implementation.
This section introduces an R package (Mediana) that provides clinical trial
statisticians and drug developers in general with a powerful set of tools to
close this gap and enable CSE-based solutions in a broad range of clinical trial
applications. The package was developed by Paux and Dmitrienko (2016) and
is currently maintained by representatives from multiple biopharmaceutical
companies.
Mediana has been built to support a general framework for CSE-based
clinical trial simulations. This package is fully aligned with the CSE approach
and can be used to perform a systematic and critical review of options re-
lated to candidate trial designs and statistical methods or adjustments used
in the analysis. The package supports a broad class of data models, analysis
strategies and commonly used evaluation criteria. A full documentation of
this package can be found in the web-based manual at
http://gpaux.github.io/Mediana
This manual includes multiple case studies that have been created to facilitate
the implementation of simulation-based CSE approaches in multiple settings
and help the user understand individual features of the Mediana package. In
addition, for more information on other software tools that support CSE and
clinical trial optimization, visit the Biopharmnet web site at
http://biopharmnet.com/mediana
It is important to point out that this R package has been designed from
the ground up to be easily extensible. All options defined in each model
actually represent calls to R functions with the same name and thus users
can add their own options, e.g., new statistical tests, by developing custom R
functions. This important feature will be illustrated in Chapters 2 and 3.
The current version of the Mediana package supports the following com-
monly used types of trial designs:
• Fixed designs with a fixed follow-up period (period from a patient’s en-
rollment to discontinuation).
• Event-driven designs with a variable follow-up period. This setting is

common in trials with time-to-event outcomes and is characterized by the
fact that a patient may reach the primary endpoint before the end of the
follow-up period.
Other design options will be enabled in a future version of the package. This
includes support to adaptive designs in early-stage and late-stage clinical tri-
als.
This section provides a more formal description of the main components
of the CSE framework implemented in the Mediana package, which follows a
four-step process. The data, analysis and evaluation models are sequentially
specified using the DataModel, AnalysisModel and EvaluationModel objects,
respectively. The same process is used to set up each of the three models,
namely, a model is initialized and then specific components of each model
are added to it. Finally, Clinical Scenario Evaluation can be performed by
wrapping up the data, analysis and evaluation models into the CSE function,
along with the simulation parameters that are specified in the SimParamaters
object. Multiple examples of setting up CSE framework in real-life clinical
trials will be provided in Case studies 1.1 and 1.2.
Data model
As explained in Section 1.2.1, a data model defines the process of generating
patient data in a clinical trial. In particular, this model focuses on specify-
ing the parameters of the individual samples within a single trial, defined as
mutually exclusive groups of patients, such as treatment arms.
The first step is to initialize the data model. This is easily accomplished
by the command presented in Listing 1.1.
LISTING 1.1: Initialization of a data model

data . model = DataModel ()
It is highly recommended to use this command as it simplifies the spec-

ification of the data model components, i.e., the number of patients (sam-
ple size) (SampleSize) or number of events (Event), outcome distribution
(OutcomeDist), design parameters (Design) and sample parameters (Sample).

Each component is specified in a data model simply by adding it in one-by-one
to the DataModel object using the + operator.
SampleSize object
This object specifies the common number of patients enrolled in each sample
in a fixed-design trial with a balanced design (all samples are assumed to
have the same sample size). A SampleSize object is defined with a single
argument, denoted by sample.size, which specifies a list or vector of sample
sizes. Alternatively, if an unbalanced design is considered in a clinical trial,
the sample sizes need to be defined within each sample (see the Sample object
below).
Several equivalent specifications of the SampleSize object are presented
in Listing 1.2.
LISTING 1.2: Specification of SampleSize objects

SampleSize ( c (50 , 55 , 60 , 65 , 70) )
SampleSize ( seq (50 , 70 , 5) )
In this example, the sponsor would like to simulate a clinical trial with
a broad range of sample sizes in each sample, e.g., in each treatment arm.
Several sample sizes may be defined, as illustrated above, in a given sample
and represent the sample size sets evaluated in a particular clinical scenario.
Event object
This object specifies the total number of events (or target event counts) among
all samples in an event-driven clinical trial. An Event object has two argu-
ments:
• n.events defines a vector of target event counts.
• rando.ratio defines a vector of randomization ratios for each Sample
object defined in the DataModel object.
As for the number of events, several target event counts can be defined
as illustrated above and represent the number of event sets evaluated in the
current clinical scenario. Also, the specification of the randomization ratio
must respect the order of the samples in the data model, i.e., the first number
corresponds to the randomization ratio of the first sample included in the data
model.
OutcomeDist object
This object specifies the distribution of patient outcomes in a data model. An
OutcomeDist object is defined by two arguments:
• outcome.dist defines the outcome distribution, i.e., the distribution of the

trial endpoint, or, in a more general setting, the distribution of multiple
endpoints such as the primary endpoint and key secondary endpoints.
• outcome.type defines the outcome type (optional). There are two accept-
able values for this argument: standard (fixed-design setting, by default)
and event (event-driven design setting).
The Mediana package supports a wide variety of trial endpoints, including
continuous, binary, survival-type (time-to-event) and count-type outcomes, as
well as more complex settings involving simultaneous evaluation of multiple
endpoints with different marginal distributions. Data models with repeated
measures can be considered as well by assuming that each patient’s outcome
follows an appropriate multivariate distribution. Distributions supported in
the current version of the Mediana package are listed in Table 1.1 along with
the required parameters to be included in the outcome.par argument of the
Sample object. Note that parameters of multivariate distributions, such as
parameters of the marginal distributions and correlation matrix, need to be
defined using nested lists.
TABLE 1.1: Outcome distributions supported in the

current version of the Mediana package.
Outcome distribution outcome.dist outcome.par
Uniform UniformDist max
Normal NormalDist mean, sd
Exponential ExpoDist rate
Binomial BinomDist prop
Beta BetaDist prop
Poisson PoissonDist mean
Negative binomial NegBinomDist dispersion, mean
Multivariate normal MVNormalDist par, corr
Multivariate binomial MVBinomDist par, corr
Multivariate exponential MVExpoDist par, corr
Multivariate mixed MVMixedDist type, par, corr
The process of specifying parameters of outcome distributions in each sam-

ple will be illustrated in Case study 1.1 (see Listing 1.11) and Case study 1.2
(see Listing 1.19).
Note that the outcome’s type must be defined for each endpoint if a pa-
tient’s outcome follows a multivariate distribution, e.g., c("event","event")
if a bivariate exponential distribution is specified. The specification of the
outcome.type argument is essential to obtain censored events for time-to-
event endpoints if the SampleSize object is used to define the number of
patients instead of the number of events (Event object).
Finally, other outcome distributions can be enabled in a data model by
writing a custom R function which implements random number generation for
that particular distribution.
Design object
The Design object is optional and can be defined in event-driven designs if
the user is interested in modeling the enrollment (or accrual) and dropout
(or loss to follow up) processes. A Design object is defined by the following
arguments:
• enroll.period defines the duration of the enrollment period.
• enroll.dist defines the enrollment distribution. Any univariate distri-
bution included in the Mediana package or specified by the user can be
selected. The most popular distributions include the uniform, beta and
exponential distributions.
• enroll.dist.par defines the parameters of the enrollment distribution
(optional). No parameters are needed if the enrollment distribution is
assumed to be uniform over the accrual period.
• followup.period defines the length of the follow-up period for each pa-
tient in trial designs with a fixed follow-up period, i.e., the length of time
from the enrollment to planned discontinuation is constant across patients.
• study.duration defines the total trial duration in trial designs with a vari-
able follow-up period. The total trial duration is defined as the time from
the enrollment of the first patient to the discontinuation of the last patient.
The user must specify either followup.period or study.duration.
• dropout.dist defines the dropout distribution. As with the enrollment
distribution, any univariate built-in or user-specified distribution can be
chosen and the most popular choices include the uniform and exponential
distributions.
• dropout.dist.par defines the parameters of the dropout distribution (op-
tional).
Since CSE supports a thorough exploration of multiple options in a trial,
the user can define several sets of design parameters by adding multiple Design
objects to the data model. These sets are known as design parameter sets and
enable the user to compactly define multiple scenarios that can be evaluated
simultaneously. Also, the length of the enrollment period, total trial duration
and follow-up periods are measured using the same time units. Note that the
current version of Mediana supports only basic patient dropout models. More
advanced modeling options, including informative dropouts, and methods for
analyzing incomplete data in clinical trials (see, for example, Mallinckrodt
and Lipkovich, 2017) will be supported in a future version of the package.
Listing 1.3 gives an example of design parameters in a trial with a uniform
enrollment distribution and exponential dropout distribution. More informa-
tion on the specification of design parameters in clinical trials will be provided
in Case study 1.2 (see Listing 1.18).
LISTING 1.3: Specification of the Design object

Design ( enroll . period = 9 ,
study . duration = 21 ,
enroll . dist = " UniformDist " ,
dropout . dist = " ExpoDist " ,
dropout . dist . par = parameters ( rate = 0.0115) )
Sample object
This object specifies parameters of a sample in a data model. As explained
above, samples are defined as mutually exclusive groups of patients, for ex-
ample, treatment arms. Therefore, several Sample objects can be added to a
DataModel object. A Sample object is defined by three arguments:
• id defines the sample’s unique ID (label). This ID is used in the specifi-
cation of the trial’s analysis model.
• outcome.par defines the parameters of the outcome distribution for the
sample, including key data model parameters such as the treatment ef-
fects and additional parameters that play a supportive role, e.g., correla-
tion coefficients. The parameters depend on the endpoint’s distribution,
e.g., if the primary endpoint is normally distributed (outcome.dist =
"NormalDist"), two parameters (mean and sd) must be specified. The
parameters required for each distribution are listed in Table 1.1.
• sample.size defines the number of patients in the sample (optional). This
option is helpful for modeling unbalanced trial designs with unequal al-
location of patients to the treatment arms. The sample sizes must be
specified in the SampleSize object or in each individual Sample object.
Based on general CSE principles, the Mediana package makes it easy for
the user to specify several sets of assumptions in outcome.par. These sets may
correspond to a range of optimistic, realistic and pessimistic treatment effect
assumptions that support general sensitivity assessments. The assumptions
sets represent the outcome parameter sets that will be evaluated in the clinical
scenario. In this case, each assumption can be included in the outcome.par
argument, as illustrated in the specification of the Sample object in Case
study 1.1 (see Listing 1.11). Further, the specification of multivariate distri-
bution parameters will be illustrated in Chapter 2 (see Case study 2.2).
Analysis model
The analysis model defines the statistical methods (e.g., significance tests or
descriptive statistics) that are applied to the trial data. As in data models,
the first step in setting up an analysis model is to initialize the model as shown
in Listing 1.4.
LISTING 1.4: Initialization of an analysis model

analysis . model = AnalysisMode l ()
After that, the specification of an analysis model’s components can be

accomplished by adding appropriate objects to the AnalysisModel object
using the + operator. Components include the statistical test (Test), de-
scriptive statistics (Statistic), a single multiplicity adjustment procedure
(MultAdjProc), or a set of multiplicity adjustment procedures (MultAdj).
Test object
The Test object specifies a significance test that will be applied to one or more
samples included in a data model. This object is defined by the following four
arguments:
• id defines the test’s unique ID (label).
• method defines the significance test.
• samples defines the IDs of the samples (defined in the data model) that
the significance test is applied to.
• par defines the parameter(s) of the statistical test (optional).
Several commonly used significance tests are already implemented in the
Mediana package and are listed in Table 1.2. Note that all tests are set up
as one-sided tests and produce one-sided p-values. In addition, the user can
easily define other significance tests by implementing a custom function for
each test. If several significance tests need to be specified in an analysis model,
for example, in clinical trials with multiple endpoints, several Test objects can
be added to an AnalysisModel object.
TABLE 1.2: Statistical tests supported in the current version of

the Mediana package.
Test method par
Two-sample t-test TTest
Non-inferiority t-test TTestNI margin
Two-sample test for proportions PropTest yates
Non-inferiority test for proportions PropTestNI yates, margin
Wilcoxon-Mann-Whitney test WilcoxTest
Fisher exact test FisherTest
Log-rank test LogrankTest
Poisson regression test GLMPoissonTest
Negative-binomial regression test GLMNegBinomTest
Since the significance tests listed in Table 1.2 are one-sided tests, the sam-
ple order in the samples argument of a test is important. In particular, the
Mediana package assumes that a numerically larger value of the endpoint is
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possession of a Negro, called John Conny. Ships
constantly stop here to water, as the most convenient
Place for taking in any large Quantity, and pay, each
Ship, an Ounce of Gold for the Privilege.
W. Thence, and anchored the 15th at Dixcove, an 14.
English Factory. This, Succonda, Anamaboo, and
others, tho’ called Factories, are the Residence only of
two or three People from the principal one at Cape
Corso, who have Commission over and above their
Salary, for what Trade they transact.
W. Dixcove, and anchored next Day before Cape Corso 16.
Castle, our African Company’s chief Fort; the
Residence of their Governor, stiled Director General;
two Merchants, a Secretary, Chaplain, Surgeon,
Factors, Writers, Artificers, and a Company of
Soldiers; with Buildings and Conveniencies inside, for
themselves or Slaves.
A. Anamaboo (just below it) a noted Place of stopping, June
for all our Windward trading Ships, to compleat their 26.
Slave Cargoes.
A. and W. Montford; the 30th, Barkee, and then Shallo. 28.
Through the whole from Sierraleon, it may be
observed, that Wood, Candles, or any other Ships
Necessaries are hard to get; the former, not from a
Want in the Country (it being over-run) but an
impassable Beach, where there is no navigable River,
and the Diffidence of the Negroes, where it might be
best supplied; and the other, because Merchant-Ships
do not expect a Trade of that sort, and therefore
unprovided.
A. Whydah. The whole Coast runs in a strait Line July 4.
(without Gulphs or Bays) is thick set with Trees, a
Tendency of the Sea with the Wind, and every where a
very rough and turbulent Beach.
W. Whydah, and arrived the 28th at the Island of 20.
Princes, belonging to the Portuguese. In our
Approach, saw every Day abundance of Whale,
Thresher, and Petrel.——Cleaned our Ships, heaving
down by one another, but became exceeding sickly by
the Fatigue, each burying three and four Men a Day,
for six Weeks together.
W Princes, both having purchased their Anchors with Sep.
difficulty. 20.
A St. Thomas’s, another Portuguese Island (the 28.

principal of three) on this Coast, abounding with fresh
Provisions, especially Hogs and Fowls, exchanged like
other Places of Poverty, at very easy Rates.
W Hence, and stretched with our Starboard Tacks to Oct. 5.
the Westward, designing to reach as far to Windward
as possible, that if any Pyrates should be on the
Coast, we might have them under our Lee. The 20th
we fell in with Cape Apollonia, went from thence the
23d, and anchored at Axim.
W Axim, and came to Cape 3 Points, where neglecting 24.
to pay John Conny his Duties for Water, he panyarr’d
some of our Men, till satisfied.
Left Cape 3 Points, and arrived next Day in Cape Corso 30.
Road again; it being every where confirmed to us in this
Return down, that the Pyrates in August last (the time we were at
Princes) had committed great Ravages upon the Merchant Ships.
W. Cape Corso Road, leaving the Weymouth, (now too Nov.
disabled to weigh her Anchor,) and plying to 10.
Windward, fell in with Succonda the 15th, repeating
our Visits in a Month’s Cruise, to Dixcove, cquedah,
Cape 3 Points, Axim, Cape Apollonia, Assinee,
Bassam, Jaque a Jaques, &c. our Purpose in it being
to secure Trade, air a sickly Ship, be in the way of
Intelligence, and impress Men from the Merchant-
Ships. Many prevented this indeed, by escaping to us
themselves from ill Treatment (they said) bad or short
Diet; but then, as more again on the same Pretence
took on with the Pyrates, it shews Caprice and
Humour to be the principal Point that determines
Seamen to this or that Service.
A De Elmina, the Dutch African Company’s principal 1721/2
Fort, of great Trade, there being seldom less than 5
Jan. 6.
or 6 Sail of Dutch Ships in the Road, often more.
A. Cape Corso Road, and left it the 10th in pursuit of the 7.
Pyrates; the Governor here, having received two or three
Expresses, that they had chased and taken a Ship nigh Axim, a
Place we had just come from.
A Apong to Leeward, not following too fast lest we over- 11.
shot them, but after certain Intelligence that the
Rogues had passed this Road (off at Sea) we
followed.
A Accra, a considerable trading Place, (for Salt 12.
particularly) and where the Dane, the Dutch, and
English, have a Castle.
A Whydah, and learned that the Pyrates had plundered Jan 15.
and ransomed 11 Sail of Ships, and left the Place two
Days before, on the Report of our following them.
W. Thence, and followed the Pursuit, coming before the 19.
Isle of Princes the 29th, and found the Portuguese
Strangers to the News.
A. The Mouth of the River Gabone, a snug Harbor we Feb. 1.
thought, for their Reception, the Navigation being
difficult; but finding by our Boats we had missed them,
left it the 3d, and continued our Search to Cape
Lopez.
Made the Cape, and soon after discovered the three
Pyrate Ships at Anchor in that Bay. One of them upon
the Heel, righted at sight of us, slipped her Cable and
chased, bending some of her Sails as she came out,
by which we judged the Rashness of our Enemy, who
fell a Prize to us before Night.
Recovered the Cape again, and found the Prize’s 10.
Consorts (according to expectation) very easy in the
Bay, and stayed so long that we doubted whether they
would stir for us; but at length, as their Eyes cleared in
our nearer Advance, all mad and frightned, they cut
their Cable, set their Sails, up went the black Flag,
and down their Courage; they continued a running
Fight, while only our chace Guns could play upon
them, and struck presently when our Broadside
reached, without the least Damage done to us.
A. Cape Lopez Bay, seizing there the third Pyrate Ship, Feb.
that had been deserted for a better Escape or 12.
Defence in the other.
W. Thence, having wooded and watered, bound with 18.
our Prizes and Prisoners to Cape Corso; the General,
and chief Merchants there, being in the Commission,
(brought out of England with us) for the Tryal of them.
Stopped at Princes, from the 21st to the 24th.
A. Cape Corso Road; the Pyrates in this Passage were Mar.
very troublesome to us, from a Project or two they 15.
had formed for their Deliverance, and hoped by the
Weakness of our Ship’s Company, would have
succeeded.
W. Cape Corso, the General’s Daughter of the Coast 1722
taking a Passage with us to England, a fair, flaxen- May 1.
hair’d, young Lady, tho’ born of a Mulatto.
I shall here observe at leaving the Center, that in respect
to Trade, Guinea needs only this threefold Division,
viz. the Gold, the Ivory, and the Slave-Coast; all to
Windward of this, might be called the one, and all to
Leeward the other; not because either of these Parts
of Trade would be entirely wanted in such respective
Division, but each abounds more under that
Denomination.
A Whydah, and left it the 5th, arriving at Cape Lopez May 3.
the 26th, where both Ships wooded, watered, and
purchased Wax for making Candles, now exceeding
scarce; and is the most convenient Place for Ships of
War, at leaving the Country.
W. Cape Lopez, and after a few Days at Sea, by foggy June 5.
Weather lost Company with our Consort the Swallow.
Made Cape Augustine in Brasil, a Portuguese Colony, July 1.
and anchored the 4th in Pernambuca Road, the next
great Port of Trade in this Province, to Bahia.
W Brasil, having found the Trade-Winds blow home, 12.
and increased in their Strength to this Continent,
bringing a dangerous Swell into the Road.
A Barbados, took in a Supply of Rum and Provisions, August
and left it the 9th. 3.
A Port-Royal in Jamaica, where we found the Swallow 23.

had arrived, a Week before.
A Hurricane[39] that drove the Prize ashore, blew away Aug.
all our Masts, with other Damages that detained us 28.
here 6 Months to repair.
W Port-Royal, and anchored at the Kays. 1722/3
W. The Kays, bound for England. Jan. 1.
A Donna Maria Bay in Hispaniola (the Windward Feb. 7.
Passage) to water, &c. 19.
W. Thence, and arrived at Spithead, April 8th, whence 22.
we were ordered to Woolwich, and paid off May 11th,
1723.
F I N I S .
E R R ATA .
P. line
32 19 for to r. too.
67 22 for he r. they.
72 27 After r. Aft.
75 24 and will be paid not only &c.
115 4 Ch. x.
115 5 Ezion
125 16 r. some other Parts.
FOOTNOTES:
[1] Put metaphorically for a Ship’s Cockpit; and answers to the
dark Cellaring of a House.
[2] At the Changes of the Moon appears a Pillar of Fire in the
North, which darting its Rays every way, moves from Place to
Place, enlightning not only Greenland, but Iceland and Norway;
and sometimes further, till the returning Sun obscures it. (Harris,
p. 635. Vol. II.)
[3] Finis Terræ, the Westermost Extremity of Europe, and formerly
thought a Ne plus ultra.
[4]
Sold 2 half-worn Suits for a Pipe of Wine.
3 Second-hand Wigs — — Ditto.
Loaf-Sugar sells 20d. per lib.
Cheshire-Cheese, 8.
Bisket, 2.
Beef per piece 10.
Bought Citron at 15d.
Lemons per C. 20.
[5] Vide Harris’s Voyages.
[6] Ten-pounders are like Mullets, but full of small Bones, like
Herring-bones.
[7] Old-wives; a scaly, flat Fish, half as thick as long, called so
from some Resemblance the Face is fancied to have, with that of
a Nun’s.
[8] Cavalloes; a bright, silver-colour’d Fish, with a prickly Ridge on
each side, half its length.
[9] Barricudoes; a well-tasted Fish, one Foot and an half long, not
wholesome if the Roof of the Mouth be black.
[10] Sucking-Fish; something like the Dog-Fish; underneath he
has an oval Flat, of three Inches and an half over, granulated like
a Nutmeg-grater; with this he sticks so fast, as difficultly to be torn
from the Deck. He often infests the Shirk, sticks fast, and sucks
his Nourishment from him.
[11] Cat-Fish, so called from four slender Fibres like Whiskers,
sprouting from the under part of his Mouth.
[12] Lollas, are Places cleared of Wood, but barren; the
Habitations only of Bug a bugs, the Species of an Ant; build not
above a Foot and half high; are whitish, smaller than the common
sort, sting, and devour Cloaths.
[13] Lugars; open, clear Places, sowed with Rice, &c.
[14] Plantanes and Bananoes are a very common Fruit, shaped
like Cucumbers, but slender and longer; peeled of their Coat, they
are roasted and eat as Bread, fried, or eaten raw. The latter is the
juicier, and of a preferable Taste. The Plant bearing them grows
as high as a Cherry-tree, with a Leaf three Yards long, and one
over; an admirable Detergent in foul, sanious Ulcers, stripped of
the inner Skin, and applied as you do Housleek in Corns.
[15] The Pine-Apple is their Prince of Fruits; does not grow so
high, but about the Bigness of a Pæony; a beautiful green and
yellow; firm and juicy as a Melon; eaten with Wine and Sugar.
Some of strong Fancy, imagine all sorts of Fruit to be tasted in it;
to me, it always left a stinging abstergent Flavour.
[16] Lime-trees, about as big as our Apple, arise by several Roots,
and have an oval Leaf; the Fruit smaller, but of sharper Scent and
Flavour than Lemons. In the Woods also are many Sevil-Orange
Trees, the Fruit largest and best tasted of any I ever met.
[17] Papais, the Size of a moderate Melon, green as that, and full
of Seeds, which thrown out, and the outside pared, is used with
Meat, buttered and salted. They grow 20 or 30 Foot high. Bosman
says, Male and Female (the Alcoran, that all Fruits grow so, p.
213.) the Male blossoming, but bearing no Fruit.
[18] Rice is sown in swampy Grounds; grows the height of our
Wheat, and from the top of the Stems shoot very slender Stalks,
bearing the Rice grained one above another to a vast Increase; a
Peck yielding above 40 Bushels: Yet such is their Idleness, there
is often a Deficiency supplied from Sherbro, &c.
[19] The Civet is about as large as a Ram Cat, comes from about
Sherbro; it’s Head like a Foxes. The Male only affords this, at the
rate of 3 or 4 Grains a day, gathered with a Quill out of a little Cod
or Hole, near the Intestin. rectum.
[20] General Phips at Cape Corso, was so nettled at this (he
receiving but 19 for 21) that it took his Stomach off Victuals two or
three Days.
For as in Fight the Gun or Drum
Will make the Warriour’s Stomach come;
So eke in Play; if two miss Fire,
The Stomach palls with wax’ning Ire.
[21] The Word Fetish is used in a double Signification among the
Negroes: It is applied to Dress and Ornament, and to something
reverenced as a Deity (a Lake, a Stone, a Tree, &c.) both so far
agree, as to be regarded as a Charm. That by a Peculiarity, and
this by some inherent Essence, can attract Good, or divert Evil.
Here they sometimes hide the Fetish in secret parts of the Woods;
on urgent Occasions make a sort of Appeal to them, separating
some the Friday, some the Saturday, and keep within doors the
whole day, in a Moaning, or what you may call a Devotion to it.
[22] Salaries 80l. per Ann.
[23] Boiled by the Negroes to the bigness of half-penny Rolls, and
an Accy purchases nine a day of them for a Month. The English
bake it.
A lean Goat you may get by chance for five Accys; a Muscovy
Duck, a Parrot, or couple of Chickens, for one.
[24] Miscell. Curiosa. Vol. iii. has a Journal of the Weather at
Cape Corso for 12 Months, from Mr. Hillier, who says, that was a
Year of the most Rain that could be remembred.
[25] Tittwees, like a large Wolf or Mastive, very fierce, and rob
their Towns in the Night, of what Kid or Poultry they find.
Tigers, not so adventurous, but are seen by them sometimes:
There are two now in the Castle.
Serpents. I have heard the Gentlemen of the Factory say, they
have been seen here 30 foot long, able to swallow a Child whole;
(Bosman says, a Man, or a full-grown Deer.)
Deer. Those whose Feet are tipped, and used as Tobacco-
Stoppers, are the bigness of a large Cat. The General had one in
his Kitchen, the Feet as thick as the middle Finger; whence I
judge, those very slender ones we see, are the Abortives of this
Animal.
[26] These sort of Tryals have much the same View with the
Water of Jealousy among the Jews, or Ordeal with our Saxon
Ancestors, that is, a Tryal by Fire or Water: The former was
proving their Innocency by walking on hot Plough-Shears un-hurt:
The latter was used hot or cold. They run their Arm into it scalding
hot; or the Priest gave an Imprecation to a Draught of Holy-Water.
The Person swore to his Innocence, and being tied Hands and
Feet, was thrown into a River or Pond; if he sunk, he was
adjudged innocent, if he floated, guilty: And these ways continued
till K. Hen. III.
Another way with the Saxons, was single Combat; if a Woman,
she appointed her Champion.
Another, since we are upon Tryal, was by two Ounces of Bread
and Cheese taken after the Communion, the Priest thus
imprecating; May it stick in your Throat, turn pale, your Limbs
convulsed, &c. if guilty; but if innocent, may you swallow it easily,
&c.
Rapin.
[27] Hæmac is a Brasil word, and signifies a Net slung to rest in;
made there from the Rind of a Tree.
[28] Milton. B. 10, & 11.
[29] A Negrish Name.
[30] See the Appendix to the Navy-Surgeon, in which are Physical
Observations on the Moisture and Density of the Air.
[31] There is a square Fort on the Larboard Point of the Bay, and
Anchorings about a League from it.
[32] Some pretend to have found what they call a material
Thunder-bolt; such a one is said to have fell on the Turkish
Mosque at Adrianople A. D. 1693; and such are shewn in the
Museums of Princes. At Copenhagen they have a large piece of
metallick Substance, said to be Thunder-bolt.
[33] A Word used by our Sailors, for the Grout is made of it.
[34] Moquissin is a name given to any thing they think has an
incomprehensible Virtue. V. Geographic. Atlas.
[35] The Portuguese, who trade hither from Erasil, chuse their
Cargoes all Boys and Girls, if they can, as more ductile for
Conversion; there being Fathers appointed to instruct them in
their Creed, and to baptize them, on their arrival; but then they are
Papists.
[36] Made of a peculiar Earth from Germany, and bear (those that
are good) the most intense heat.
[37]
There’s but the twinkling of a Star,
Between a Man of Peace and War.
Hud.
[38] At this Place I would observe, in relation to heaving the Lead,
that there is a Nisus in Bodies of Water from below upwards,
which makes ’em to sink neither so fast, nor so direct, at any
considerable Depth, as near the Surface; all at 200 Fathom or
less, being bottomless; i. e. unfathomable.
This Nisus, or resisting Motion to the Descent of Bodies, is not
only perceptible in the Lead, but more sensibly declares itself,
first, in that black or green Skim, seen sometimes on the Surface
(even smelling) after long Calms, the Product of some intestine
Motion.
2. That Divers, or any floating Bodies, emerge with greater Force
than they sunk.
3. Mr. Boyle’s 20th Experiment observes, that a glass Bubble let
open into the Receiver, on the Exsuction of the Air, the Water in it
manifestly rises a greater Height; consequently the Expansion
and Rarefaction of the Air by the Heat of the Sun, makes room for
this Spring in the Water, to exert itself; and therefore the Tides
themselves would more difficultly yield to the distant Attractions of
the Sun and Moon (I should think) without adding to that Theory
this conjoined Force, or natural Propensity of the Sea, to swell
before.
In respect to sinking the Lead, also may be added, a greater
Coldness, and a greater Saltness of the Sea, in proportion to the
Depths; (both which are very probable,) and will create a greater
Buoyancy, or Resistance to sinking, as will likewise the drawing
out a greater Quantity of Line, (less apt to demerge.) So that
although falling Bodies in Air, have their Velocities encreased, the
nearer they approach the Earth, yet contrarily in Water, it
diminishes with the Descent.
[39] Depend much on the preceding Season, (hot and dry
Weather) apt to raise greater Plenty of elastick Vapours on the
Terra firma, and will explode themselves now here, now there, as
the greater Rarefaction of Air (more towards one Island than
another) may invite.
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TRANSCRIBER’S NOTE
The numerical dates in the Sidenotes (on pages 255 to 265) have all been
italicized for consistency eg Mar. 10..
Except for those changes noted below, all misspellings in the text, and
inconsistent or archaic usage, have been retained.
Pg 35: ‘some hunred Leagues’ replaced by ‘some hundred Leagues’.
Pg 48: the footnote anchor [16] was missing, and has been added to ‘[16]Limes,
Oranges’.
Pg 68: ‘weighed Auchor’ replaced by ‘weighed Anchor’.
Pg 97: ‘our Rigth of’ replaced by ‘our Right of’.
Pg 97: ‘The Heigth of’ replaced by ‘The Height of’.
Pg 104: ‘ars sold’ replaced by ‘are sold’.
Pg 132: ‘a Change full as bad’ replaced by ‘a Charge full as bad’.
Pg 193: ‘joined also in in a’ replaced by ‘joined also in a’.
Pg 199: ‘ridiculous, scaramouch’ replaced by ‘ridiculous, and scaramouch’
(catchword ‘and’ was missing).
Pg 202: ‘we re- our’ replaced by ‘we repeated our’.
Pg 207: ‘off the 1sland’ replaced by ‘off the Island’.
Pg 209: ‘Food or Necessarieis’ replaced by ‘Food or Necessaries’.
Pg 243: ‘Bitts of 7d½’ replaced by ‘Bitts of 7½d’.
Pg 261: ‘1721/2’ inserted before ‘Jan 6.’ as a new Sidenote.
Pg 263: ‘1722’ inserted before ‘May 1.’ as a new Sidenote.
Pg 265: ‘1722/3’ inserted before ‘Jan 1.’ as a new Sidenote.
Catalog: ‘by furnish- them’ replaced by ‘by furnishing them’.

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Clinical Trial Optimization Using R 1st

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Noninferiority Testing in Clinical Trials: Statistical Design and Analysis of Clinical

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No claim to original U.S. Government works

Printed on acid-free paper

International Standard Book Number-13: 978-1-4987-3507-0 (Hardback)

Library of Congress Cataloging‑in‑Publication Data

Names: Dmitrienko, Alex. | Pulkstenis, Erik.

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List of Contributors xvii

1 Clinical Scenario Evaluation and Clinical Trial Optimization 1

2 Clinical Trials with Multiple Objectives 71

2.3.1 Clinical trial . . . . . . . . . . . . . . . . . . . . . . . 92

3 Subgroup Analysis in Clinical Trials 173

3.5 Case study 3.3: Optimal selection of decision rules to support

4 Decision Making in Clinical Development 251

Clinical development is a strategic and operational, scientific process that

Alex Dmitrienko, Mediana Inc.

This book is based on a collaborative effort of nine statisticians from the

as more recent publications, including Dmitrienko, Paux and Brechenmacher

1.2 Clinical Scenario Evaluation

1.2.1 Components of Clinical Scenario Evaluation

Data Model Analysis Model

Clinical Scenario Evaluation

Apply Evaluation Model to Clinical Scenario

FIGURE 1.1: General Clinical Scenario Evaluation framework.

original CSE publications. Dmitrienko et al. (2016) revised this terminology

their performance in multiple settings. Ultimately, this assessment supports

1.2.2 Software implementation

• Event-driven designs with a variable follow-up period. This setting is

LISTING 1.1: Initialization of a data model

It is highly recommended to use this command as it simplifies the spec-

(OutcomeDist), design parameters (Design) and sample parameters (Sample).

LISTING 1.2: Specification of SampleSize objects

• outcome.dist defines the outcome distribution, i.e., the distribution of the

TABLE 1.1: Outcome distributions supported in the

The process of specifying parameters of outcome distributions in each sam-

LISTING 1.3: Specification of the Design object

LISTING 1.4: Initialization of an analysis model

After that, the specification of an analysis model’s components can be

TABLE 1.2: Statistical tests supported in the current version of

A St. Thomas’s, another Portuguese Island (the 28.

A Port-Royal in Jamaica, where we found the Swallow 23.

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