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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
Taylor & Francis Group
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Boca Raton, FL 33487-2742

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Version Date: 20170504

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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
LC record available at https://lccn.loc.gov/2016057709

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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

Alex Dmitrienko and Gautier Paux
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

2.3.2 Qualitative sensitivity assessment . . . . . . . . . . . . 99
2.3.3 Quantitative sensitivity assessment . . . . . . . . . . . 107
2.3.4 Software implementation . . . . . . . . . . . . . . . . 114
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
2.4.5 Software implementation . . . . . . . . . . . . . . . . 149
2.4.6 Conclusions and extensions . . . . . . . . . . . . . . . 154
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
2.5.3 Software implementation . . . . . . . . . . . . . . . . 168
2.5.4 Conclusions and extensions . . . . . . . . . . . . . . . 172

3 Subgroup Analysis in Clinical Trials 173

Alex Dmitrienko and Gautier Paux
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
3.3.4 Qualitative sensitivity assessment . . . . . . . . . . . . 199
3.3.5 Quantitative sensitivity assessment . . . . . . . . . . . 203
3.3.6 Software implementation . . . . . . . . . . . . . . . . 208
3.3.7 Conclusions and extensions . . . . . . . . . . . . . . . 213
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
3.4.4 Software implementation . . . . . . . . . . . . . . . . 225
3.4.5 Conclusions and extensions . . . . . . . . . . . . . . . 228
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
3.5.4 Software implementation . . . . . . . . . . . . . . . . 244
3.5.5 Conclusions and extensions . . . . . . . . . . . . . . . 249

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
4.3.2 Software implementation . . . . . . . . . . . . . . . . 268
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
4.4.5 Software implementation . . . . . . . . . . . . . . . . 279
4.4.6 Conclusions and extensions . . . . . . . . . . . . . . . 282
4.5 Case study 4.2: Bayesian Go/No-Go evaluation using an alter-
native decision criterion . . . . . . . . . . . . . . . . . . . . . 283
4.5.1 Clinical trial . . . . . . . . . . . . . . . . . . . . . . . 283
4.5.2 Software implementation . . . . . . . . . . . . . . . . 285
4.5.3 Conclusions and extensions . . . . . . . . . . . . . . . 286
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
4.6.2 Software implementation . . . . . . . . . . . . . . . . 289
4.6.3 Conclusions and extensions . . . . . . . . . . . . . . . 290
4.7 Case study 4.4: Decision criteria in Phase II trials based on
Probability of Success . . . . . . . . . . . . . . . . . . . . . . 290
4.7.1 Clinical trial . . . . . . . . . . . . . . . . . . . . . . . 290
4.7.2 Software implementation . . . . . . . . . . . . . . . . 292
4.7.3 Conclusions and extensions . . . . . . . . . . . . . . . 293
xii Contents

4.8 Case study 4.5: Updating POS using interim or external infor-
mation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294
4.8.1 Clinical trial . . . . . . . . . . . . . . . . . . . . . . . 295
4.8.2 Software implementation . . . . . . . . . . . . . . . . 298

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
4 Clinical Trial Optimization Using R

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
Clinical Scenario Evaluation and Clinical Trial Optimization 5

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
6 Clinical Trial Optimization Using R

(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:
Clinical Scenario Evaluation and Clinical Trial Optimization 7

• 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.
8 Clinical Trial Optimization Using R

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).
Clinical Scenario Evaluation and Clinical Trial Optimization 9

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.
10 Clinical Trial Optimization Using R

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
Exploring the Variety of Random
Documents with Different Content
The Project Gutenberg eBook of The Klan
Unmasked
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and most other parts of the world at no cost and with almost no
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Title: The Klan Unmasked

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Illustrator: J. A. Murdoch

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*** START OF THE PROJECT GUTENBERG EBOOK THE KLAN

UNMASKED ***
 WILLIAM JOSEPH SIMMONS
Founder of the Knights of the Ku Klux Klan and Emperor Invisible
Empire
 THE KLAN
UNMASKED
by

WILLIAM JOSEPH SIMMONS

Founder of

The Knights of The Ku Klux Klan

AND

Emperor of The Invisible Empire

PUBLISHED BY THE

Wm. E. THOMPSON PUBLISHING CO.

ATLANTA, GEORGIA.

COPYRIGHT, 1923

by

The Wm. E. Thompson

Publishing Company

Illustrations by J.A. Murdoch, Atlanta, Ga.

 TABLE OF CONTENTS
Chapter Page
Foreword: Why I Write a Book 7
PART ONE
Organization and Methods
I. The Klan Yesterday and To-day 18
II. We Americans—A Vanishing People 26
III. Fraternalism of The Klan 38
IV. The Klanishness of The Klan 46
V. Is The Klan Anti-Semitic? 55
VI. Is The Klan Anti-Catholic? 64
VII. The Terminology of The Klan 79
VIII. Symbolism of The Klan 87
IX. The Rendezvous 97
PART TWO
The Fading Hope of Democracy
X. Democracy as a Social System is on Trial 103
XI. Our Cities a Menace to Democracy 113
The Failure of Democracy in Central and
XII. 119
Eastern Europe
XIII. Foreign Outposts in The United States 126
XIV. The Racial Limitations of Democracy 139
The American Negro as Ward of The
XV. 147
Nation
XVI. We Americans are a Peculiar People 161
Giantism—The National Disease of
XVII. 174
America
XVIII. Drifting 184
 PART THREE
A Salvaging Policy for Americanism
"The Federal Union—It Must be
XIX. 198
Preserved"
XX. Our Country's Part Among the Nations 212
We English-Speaking People Must Stand
XXI. 219
Together
XXII. The Nemesis of Immigration 230
XXIII. The Problem of Restricting The Suffrage 248
XXIV. National Solidarity Through Education 260
XXV. The Conservation of The American Home 274
XXVI. "A Final Word 284

WHY I WRITE A BOOK

VARIOUS representatives of the press, as well as many of my
colleagues in the organization of which I have the honor to be the
Founder and head, have repeatedly asked me to make a public
statement, descriptive of our organization. It was anticipated in
certain quarters that we should at once make specific reply to the
embittered attacks upon the Klan. Although abundant space in the
press was placed at our disposal for this purpose, we did not take
advantage of the offer. It is no part of the policy of the Klan to enter
into heated public controversies—even in self-defense. We felt all
along that a clear and simple statement of facts concerning the form
of our organization, its methods and ultimate purposes, while
perhaps due the public, was not due the instigators of the attacks
upon us. We are not as yet aware of the exact source of these
attacks. Yet, I may say, the membership of the Klan universally
welcomed it, realizing that sooner or later the Klan must be under
fire. Whether or not we are enemies of our country and of freedom
we are quite willing to leave for the public to decide.
Meanwhile, the direct effect of these attacks upon the Klan will not
be without interest. Our ranks have been rendered more firm and
steady. The public has been rather amused than affected seriously by
the reams of villification which were heaped upon the Klan. It now
remains for us to tell what the Ku Klux Klan really is, how it came into
existence, and what it purposes to do through the organized power
of its membership.
We have been outrightly accused of maintaining secrecy in the
conduct of our organization. We ask, in rejoinder, for how long has it
been a crime or a misdemeanor in the United States for a fraternal
organization to employ secrecy in the conduct of its affairs? We have,
literally, hundreds of secret organizations in this country. The fact that
a number of persons draw themselves together in an organization for
mutual aid, for mutual confidences, and for mutual effort, implies
that they have something in common which they do not wish to
share fully with the public. So has every family and almost every
business. Then, too, the element of secrecy no doubt develops the
interest of the membership, adding to the charm as well as to the
value of their fellowship. Concerning this feature of our organization,
I feel assured that we might appeal to the common sense and
fairness which Americans are always and everywhere ready enough
to show. No one expects the Masonic fraternity or the Knights of
Columbus,—to mention two large, well-known and respected
fraternal organizations in this country,—to exhibit all their forms of
salutation and other formalities to the public. We simply claim the
same rights and privileges which other fraternal organizations share,
both under the law and in the esteem of the public mind.
New organizations and movements usually draw the fire of the
uninformed. People are inclined to be suspicious of that which they
do not understand. When Masonry first assumed its larger
importance in America it was the object of attacks so bitter that some
of the members were placed in danger of their lives. An Anti-Masonic
party, nearly a hundred years ago, acquired material importance and
sent several members to Congress. Just preceding the War Between
the States, the Know-Nothing, or Anti-Catholic party ran through its
brief but stormy career. This party was caused by the fact that the
Catholic Church was growing in certain parts of the country where it
had hitherto been almost unknown. When we Klansmen reflect upon
these historical facts we are much consoled. It remains only to say, in
this connection, that we bear our recent detractors not the slightest
ill will whatever. They do not understand us. That is all.
We confess that the Ku Klux Klan has been organized in order to help
in the accomplishment of a great task. Neither the magnitude of this
task nor its vital importance to the future of our country are yet
widely realized. Our American citizenship is usually earnest and active
with regard to the discharge of its more simple duties. With reference
to larger social problems, however, problems which sometimes
assume the form of great national dangers, our country is often
enough soundly asleep. The Ku Klux Klan proposes to wake the
sleeper and make him at least sit up, look around, and ask the time
of day.
Whether or not we are enabled to accomplish all that we have set out
to do remains for the future to decide. But I may say that the growth
of the Klan and the universal spirit and activity of its membership
indicate pretty clearly that neither our hopes nor our efforts, thus far,
have been in vain. The Klan is growing in the North and West more
rapidly than in the South. It has been carefully and permanently
grounded in nearly every large city. It will eventually spread to every
town, hamlet and country cross-roads. With our six years of
organized effort and our present status in mind, we may be pardoned
for saying that we feel that there must be some need for an
organization which has, in so short a time, shown such phenomenal
strength. The Klan exists because it satisfies a most vital need in our
national public life. Our opponents have tried to indicate that our
position and purposes are purely negative. Nothing is farther from
the truth. Any candid, logical and patriotic mind which will reflect
upon this and the following chapters of this book can not be our
enemy.
In order to first clear the way of the trivialities which have been
placed there to clog our footsteps, I wish in this foreword to state
most positively certain facts with reference to our organization. The
Ku Klux Klan has not been organized or conducted in opposition to
any religion or religious sect, or against the members of any race or
language group, either within or without the borders of our country.
Upon this point let no doubt be left in the mind of any American. It
has been falsely stated that we are fanning the flames of hatred
against the Negro race. Exactly the opposite is the truth. To our
fellow citizens of the Jewish or the Roman Catholic faith, and to other
groups too numerous to mention, we enter a flat denial to all those
pure fabrications which have seemingly given them so much alarm. It
is, indeed, quite true that our membership is restricted. It includes
only citizens of the white race. So does the membership of the Clan-
na-Gael and of B'rith Israel. If it may be truthfully said that our
membership is also restricted to Christians and to Protestants, this is
due purely to the fact that certain deductions may be made from
certain paragraphs in our Constitution and By-Laws. We have not yet
ceased wondering why attacks should be made upon us in the public
press on that score. The membership of the Knights of Columbus is, I
believe, restricted to members of the Roman Catholic Church. Is
there anything especially dangerous or wrong about that? I should
not say so. Catholic Churchmen have both a legal right and a moral
right to organize and conduct a fraternal order by and for themselves
alone. Moreover, the Knights of Columbus as an organization, and in
the personnel of its individual members, would be well within their
rights in demanding that they be saved from slander, villification and
unjust attacks of every sort, because of the restriction of their
membership to those of one faith. Since the end of the war various
German organizations, such as fraternal orders, singing societies,
etc., have begun to re-establish themselves. These organizations are
fully protected by the law and their members do not lack the esteem
of their English-speaking fellow citizens. Hence, I would most
candidly ask—and would that my voice could be heard throughout
the length and breadth of the land—since when has it become a
crime for a body of American-born, English-speaking, white citizens
to organize themselves into a fraternal order? What has happened in
our country which seems to bring our particular racial and social
group so much into disrepute? Since the House of Representatives in
Washington has investigated us, why is not a resolution presented
asking the House to investigate other institutions of a similar nature?
However that may be, since we have been duly investigated, and the
investigation has ended without the slightest accusation or criticism,
so far as we know, on the part of the House Committee, we would
now ask our accusers, in their turn, to be candid enough to do one of
two things. They must either present further facts to substantiate
their accusations or retract the accusations.
We repeat most emphatically—The members of the Ku Klux Klan, as
individuals or as Klansmen, are not the enemies of the Negro. We are
the best friends the Negro has, here or anywhere. Our organization
makes opposition to no religious sect or creed, as such. Our order is
based squarely upon the Constitution and laws of our country. We
hope never to be unmindful of the basic fact that both the Federal
and State Constitutions guarantee freedom of religious belief and
practice. We invite our fellow citizens of every faith to join us in the
protection of so valuable and sacred a right. Every statement made at
any time that we would deny this right to others than ourselves is an
absolute and unmitigated falsehood. In conclusion, let me emphasize
that the Ku Klux Klan conducts its activities not only within the law,
but in active support of the law. Our general organization would not
tolerate for a moment any illegal act on the part of any of our local
organizations. The Klan has not been formed to express little hatreds
but to study crucial problems and aid in the execution of large
national policies.
I might add a further word. We take pride in the fact that our
national and local organizations have conducted themselves,
generally, within the bounds of the strictest discipline. Perhaps it has
been because of the ease with which crimes might be committed and
our local organization unjustly blamed therefor that we have suffered
from a certain sort of criticism and attack from the uninformed and
the misinformed. We are now taking steps to make the Klan perfectly
secure against such criminal misuse of its name and regalia. Suffice it
to say here that we take the keenest pride in our record, and in
challenging our opponents and detractors to present the facts which
their allegations demand, we ask of them in the most kindly spirit.
We take much for granted. We can not be misunderstood for long.
We know that many of those who unknowingly oppose us to-day will
be our best friends, in many cases, indeed, our ardent companions of
to-morrow.

CHAPTER I
The Klan Yesterday and To-day
IN many questions, from all sources, I have been asked as to how
the Klan of the Sixties was related to the Klan of to-day. The original
Ku Klux Klan sprang from the urgent necessities of the Reconstruction
period. At the close of the War Between the States, the South was
prostrated and devastation was spread from the Potomac to the Rio
Grande. Following hard upon the collapse of the Southern
Confederacy, hordes of bad white men, generally termed "Carpet-
Baggers" and "Scalawags", came into the South to prey upon the
prostrated people of that section and to fatten on the ruins of war.
This crowd of men had been loyal to neither the Union nor the
Confederacy, and, in most instances, traitors to both. The
tremendous upheaval had thrown them from obscurity into publicity.
They availed themselves of the conditions that obtained to establish
themselves and utilized the recently emancipated race of slaves to
further their ends. Negroes everywhere were organized and taught to
hate the white people of the Southern states. Under martial law they
controlled all the elections that were held in the South. From these
was elevated to our legislatures and courts an alien race, untaught,
unskilled and incapable of government. White men in the South who
had borne arms in defense of the Confederacy had the hostility of the
so-called Union League directed against them. Their property was
invaded, their homes were menaced and in many instances the white
women of the South became the prey of Negroes who had been
inflamed by the teachings of "Carpet-Baggers" and "Scalawags." The
evident purpose was to establish for all time the supremacy of the
Negro over our Anglo-Saxon people and civilization.

LT. GEN. NATHAN BEDFORD FORREST

The Grand Wizard of the Original Ku Klux Klan.
To meet this condition and arrest this menace, the Ku Klux Klan
sprang into existence. The white man's civilization that had been
thousands of years in the building was imperilled. The blood of the
white man ran like lightning. Tremendous forces leaped from the
ashes of defeat and drove like the whirlwind throughout the land.
Civilization sounded the note of wild alarm. An empire covering half a
continent took form in an hour and more than a half million men
were mobilized in a single day in defense of the white man, his
home, his civilization and his freedom—against the rise and assaults
of an inferior race, many of which within the century, had been
cannibals, and some of which were still speaking the jargon of the
jungles of Africa.
In the formation of the original Ku Klux Klan there was no thought or
purpose in the mind of the white men of the South which made for
the suppression of the misguided Negroes by violence. Wise men
they were who founded the Invisible Empire and directed the
movements of its citizenry. They knew the superstition of the Negro.
Interwoven in the Negro's life, religious, social, industrial, was the
fantastic belief in the supernatural and the grotesque. To him the
ghost was very real and not at all unusual in appearance. In all their
folk tales there was a weird intermingling of ghostliness. Rather than
intercept by violence the movement of the Negro toward supremacy
in the South under the leadership of vicious white men, the Ku Klux
Klan devoted itself to thwarting the movement by overawing the
Negro through his superstitions. Had this plan not been adopted, the
Negro would have been largely exterminated.
This organization of the original Ku Klux Klan made a most thrilling
chapter in the history of the Anglo-Saxon civilization in America. It
has never been written. The organization has been maligned,
misrepresented, and misunderstood for more than fifty years. The
Congress of the United States instituted an investigation of the Klan
that totaled forty-six volumes in reports and findings, but not in a
solitary instance was an outrage or an atrocity in the South fastened
upon the organization. The supremacy of the white man was
established, the purity of the Anglo-Saxon race was maintained, and
both races, white and black, settled down side by side in peace and
contentment to work out their essentially different destinies.
The present Klan is a memorial to the original organization, the story
of whose valor has never been told, and the value of whose activities
to the American nation has never been appreciated. In a sense it is
the reincarnation among the sons of the spirit of the fathers. It is a
flaming torch of the genius and mission of the Anglo-Saxon
committed to the hands of the children which the Knights of the Ku
Klux Klan are again holding aloft.
The name of the old Klan has been taken by the new as a heritage.
The regalia and insignia of the old have been adopted by the new as
a mantle of one worthy generation might fall upon the shoulders of
its successor. Beyond this point the connection and similarity between
the two organizations do not extend. The ritual is not identical. The
purpose of each organization, while having a common impulsion, is
not the same in extent. The old Klan never intended to reach beyond
the horizon of the Southland. The present Klan has purposed the
supremacy of our heritage of ideals throughout the nation. There is
no intention on the part of the present Klan to intimidate or overawe
by spectral, ghostly garb, or to accomplish its aim by demonstrations
of force or acts of violence, or by a supergovernment under disguise,
or by moving in the darkness of the night. But there is a purpose
underlying the entire organization and pulsing in every fiber of its
being, to maintain Anglo-Saxon civilization on the American continent
from submergence due to the encroachment and invasion of alien
people of whatever clime or color. There was not in the old
organization a solitary motive except to save the civilization of the
white man that had been wrung out of the thousands of years of his
struggle upward. There is not a single motive actuating the new Klan
except to save the heritage which the fathers have left for us in the
present to transmit to the generation yet to come.
A moment's reflection will indicate how natural it is to see the new
Klan take form first in the South. With us the issue and the conflict is
an old one. Instinctively we scent dangers which our brethren in
other sections of the country are apt, as yet, to ignore. For centuries
we have been forced to deal, in one form or another, with a problem
which always seemed to us and still appears to some of us to be
insoluble. I mean the race problem. Yet in this, as in all else, our
kinship with our fellow citizens of the North was made evident by an
outstanding fact of Reconstruction days. The original Ku Klux Klan
was almost as strong in the Union army, maintaining martial law in
the defeated states, as among the men who wore the gray and went
down to glorious defeat. Had it not been for the active and
sympathetic co-operation of large numbers of the Union forces, the
achievements of the Ku Klux Klan in the Reconstruction period could
not have been accomplished. The time has now come, once more, to
bring to our whole country a sense of this great issue. And this issue,
the causes of this crisis, has broadened and deepened to a degree
which threatens the complete destruction of our civilization.

CHAPTER II
We Americans—A Vanishing People
WE Americans are nothing if not humanitarian. We have in the
United States many varieties of organization for the assistance of the
various foreign racial and national groups upon our soil. We have also
done not a little for the succor of the peoples of the old world who
are now in such great distress. The larger humanitarian motive is as
a guiding star to millions of Americans. It leads them and lights their
way. To many such it may seem unnecessary, to some preposterous,
for the organization of which I have the honor to be chief to be
founded and developed. But a sober second thought is required here.
Let us grant that a people which, in its weakness, faces permanent
injury, requires help that it may survive and grow. Then indeed, it
follows that we Americans, as a people, need to help ourselves first
of all. As a people and a nation we are face to face with dissolution.
In the Ku Klux Klan we have an institution designed to help in the
stupendous task of saving ourselves from failing and falling.
We Americans as a peculiar people face extinction upon our own soil.
Let me be fully understood. I do not wish in the least to appear
sensational. I wish only to state a few simple facts which should be
apparent to any American who investigates, ever so briefly, the true
condition of his country. So often, during the past twenty-two years, I
have been oppressed in heart as I have seen how little public interest
this crucial matter has aroused. If my tendency has, at times, been
somewhat pessimistic and fearful, I claim that there is cause enough
for fear and pessimism. Surely there is great need that intensest
sadness and sorrow strike deep into the hearts of Americans, if we
are now to help ourselves and live.
We Americans are a perishing people. From the point of view of
history we are being wiped from the face of the earth with a rapidity
which almost staggers hope. First let me clearly define what I mean
by the phase, "We American People." I mean by that phrase those
white, native-born citizens of this country whose ancestry, birth and
training has been such as to give them to-day a full share in the basic
principles, the ideals and the practice of our American civilization. I
do not mean that a foreign-born citizen can not be a good citizen. On
the contrary, many of our foreign-born are excellent citizens. Yet I
most positively mean what the title at the head of this chapter
distinctly suggests. We, the American people, we whose breed fought
through the Revolutionary War and the War Between the States, the
people by whose courage the great American wilderness was
penetrated, and by whose painstaking industry that wilderness was
subjugated and made fruitful—that this people, who gave to the
world Washington and Franklin, Jefferson and Hamilton, Andrew
Jackson and Daniel Webster, Robert E. Lee and Abraham Lincoln—this
people, our people, is on the downward way to the early ending of its
remarkable history. The mighty length and breadth of the soil made
sacred by our struggles and our victories is now being given over,
with ever greater rapidity, to various peoples of a totally different
mold. I am not saying that these other peoples are bad in character
or in any way unworthy. May Heaven witness for my colleagues and
myself of the Ku Klux Klan that we bear them no ill will whatsoever. I
hope that none of us as individuals or as an organization may do
them aught but good. We wish, above all, to be moved in all things
by that Christian spirit upon which our organization is founded, and
which, I trust, moves its humblest member. But we have come to
sound a warning throughout the length and breadth of the land—a
warning which everyone of our own people from Newfoundland to
California and from Florida to Alaska must hear and heed. We are
perishing as a people and the land of our fathers shall presently know
us no more. Emerson once said, "What you do speaks so loud I can
not hear what you say." Let me here change the words but not the
meaning. The facts cry out so loud that we can not hear the vain and
wordy opinions of the theorists and the sentimentalists. The prattle of
these sentimentalists, be it ever so noisy, can not prevent us from
both seeing and hearing the real drama. We are witnessing the
greatest tragedy of the ages.
 Only Americans May Pass
To place these facts in their proper relation, one to another, we must
study the map of the United States. That map, hanging on the wall of
the old school-house, or facing us over our desks in the library at
home, seems always to appear so big and brave and bold. To the
child at school it appears to flaunt its very bigness in the face of all
the world. My fellow American citizens in all the states, study that
map carefully. In terms of the civilization of the whole world it will
richly repay investigation. Let us move with the sun from the valley of
the river St. Johns in Maine, to the far-off mountains of our California.
Incoming masses by the hundred thousand flood New England. They
do not speak our language, can not know our laws, and do not mix
with our native people because there are hardly any natives in New
England left to mix with. In dozens of schools built for the children of
the great city of Boston and its suburbs the English language is not
even taught, not to speak of as being used as a means of acquiring
knowledge or of taking loyal and useful part in our national life.
Throughout twenty varieties of the stupendous foreign sections in all
our great industrial cities of the North, the very conditions of life
prevent millions from learning the English language or taking an
American breath into their nostrils. From St. Louis and Chicago and
Milwaukee on the West to New York and Boston on the East
democratic American political life is now almost impossible—
unthinkable. To this we shall recur in later chapters. Just now we
must proceed rapidly to other parts of our map. In our Far Western
territory, where a million square miles of mountain and valley are
beginning a marvelous development, we Americans are fighting one
of the most desperate and crucial social conflicts in the history of our
country and of European civilization. Our Western people are striving
for the very salvation of our soil as the heritage of the white
American. This conflict rages day by day—week by week—year by
year. Our brethren of the West are misunderstood and their crying
call for help is largely rejected by the East. There are counties in
California where more Japanese babies are being born each year
than white babies. The Japanese in California are multiplying at the
stupendous rate of sixty-nine per thousand, annually, while the white
people of California increase at the rate of eighteen per thousand.
But the eighteen per cent. includes the relatively high rate of the
foreign-born whites. The American white people of California increase
by an annual rate of less than ten per thousand. Look you well, fellow
Americans, to this part of our map. Go on in your indifference and
carelessness, and these western valleys and mountains will, in the
days of your children, be blood-soaked by one of the most desperate
of interracial wars—a war at once civil and international—in the
history of the world, and despite all your treaties of peace.
In the Southwest are over eighteen hundred miles of boundary line
between ourselves and the people of Mexico. I know that I am
expressing for my colleagues of the Ku Klux Klan who dwell along
that eighteen hundred miles of boundary line their inmost thought,
when I say that they wish only peace and fellowship and mutual aid
and generosity to mark all our relations with the simple and kindly
people of Mexico. But we are here marshalling the facts—the
staggering facts which the American people must know and ponder
well to-day. Nearly half a million Mexicans, speaking various dialects
of the Spanish and Indian languages, have recently come across our
Southwestern boundary line. Surely it is not with any ill will in our
hearts that we say with all the power we have that these thousands
can not share our American democracy with us in this generation. In
Mexico these people can be ruled in such a way and take such
measures of progress as may befit them. Granted time and they may
evolve a successful democracy all their own. But in this generation
they will make democracy impossible wherever large numbers of
them settle among us. If immigration continues through the next
generation THEY WILL FOREVER ENCROACH UPON AND OCCUPY
OUR SOUTHWEST. The native-born, white American will either
become a small ruling class, or fade from sight altogether. There are
factories in Texas with practically none but Mexicans employed. There
are sections of the Southwest where, in town and on the countryside,
there are many Negroes, Mexicans and Japanese, few Americans.
Finally, we come to the South. Leaving the burden of this argument
to future chapters, we can here take but a rapid glance at the
inexorable problem of the Southland. May Providence give to us men
and women of the South the power we need to place our problem
before our fellow citizens in other sections in such a way as to win
their minds and hearts by the goodness of our cause. If I but could, I
would move my hand along that ancient and deadly line which
separates us from our country-men and wipe it out forever. Our
problem of the Negro, men and women of the North, is your
problem. If we fail, you fail. We plead with you to join with us in
freeing all our minds from bigotry, all our hearts from unworthy
passions, and all our thoughts from sectional misunderstanding.
The larger fact which I seek in this connection to strike into the mind
and conscience of my country is as simple as the multiplication-table.
The Negro of to-day is less in numbers than the white inhabitants in
all states but one, for a single reason. That reason is the high
average mortality among the Negroes. The enormous birth rate of
the Negro population would rapidly submerge our white population if
the Negroes were not decimated by a high death rate. The Negroes'
numbers are kept within the number of our white population by
various dreadful diseases. Though these diseases afflict us all in the
South, the white people are generally far more immune than the
blacks. We are somewhat behind the North and West in the practice
of medicine, sanitation, and the general prevention of disease. But
we are making great strides in this as in other means of progress. As
all our people, including the Negroes, are progressively saved from
the ravages of disease, the Negroes' birth rate will be more and more
relentlessly shown in the census of the living. As night follows day,
the Negro will, in the future, move on toward larger and larger
comparative numbers in the South.
And so this map of our beloved land, which, as school children, we
gazed upon with deep longings toward the future greatness of our
country—this map to-day, section by section, is discolored and fading.
So do our hopes, too, fade and fail. We Americans are a perishing
people, and the things we have inherited and hold dearest in our
hearts are on the way to dissolution and total loss. Of all the greater
people of history, we Americans least deserve even the pity which is
the portion of those who fail. The glory of our rise, the large part that
is ours in the present, the majestic hope of the nation which
prophesies such a resplendent future—all this is our heritage. We lack
only understanding of ourselves and the public spirit required to take
action. The Ku Klux Klan, in garb of strange device, marshalled under
the flag of our country, has thrust itself as a dire warning across the
downward pathway of the American people—our own people, whom
we love.
 CHAPTER III
The Fraternalism of the Klan
SURELY there can not be in this frank statement of the principles and
the purposes of the Ku Klux Klan any ground for the criticism that the
organization was founded on racial and sectarian animosities and
hatreds. The Klan is neither anti-racial nor anti-sectarian. It is pro-
American. We concede to every distinctive organization in race and
religion the same rights of restricting and qualifying its membership
that we claim for ourselves. If, in the light of all the past, and in view
of the present, we are insisting upon an organization of native-born
white American citizens, we do not, by stipulating the conditions of
membership in the Ku Klux Klan, avow hostility to any one class or
company who may not, for one reason or another, qualify for
membership in our organization. Indeed, as Americans we not only
have the right to organize under the law and in keeping with the law,
but far more than that—in the exercise of that right the Klan is
positively committed to vouchsafing the same right to any other class
of people on the American continent who desire to organize
themselves for patriotic, social, fraternal or religious purposes. Only
this too is also stoutly maintained: Any organization that is formed
and fostered under the flag of our common country must not be
inimical to our democratic government and institutions.
There are numerous organizations in America to which members of
the Klan would not be admitted. These organizations are racial,
social, political and sectarian. There has never been any complaint
against these organizations. They have never been subjected to
scrutiny by the Department of Justice of the United States
Government. They have never been brought under Congressional
investigation. They have lived and grown and pursued their purposes
of organization without restraint or interference from the outside. All
this is in exact keeping with the freedom that is granted under the
Constitution and the laws. We realize only too well that when
organizations have arisen that have threatened the peace or morals
or health of our social life, or, for any purpose, inveighed against the
basic institutions of our country or the orderly conduct of our people
in obedience to constituted authority, such organizations have been
speedily suppressed. There are not a few of the leaders of such
movements in the penal institutions of our country to-day, designated
as political prisoners, because they undertook to obstruct the
machinery of the country in its war activities. The Ku Klux Klan is
committed so thoroughly—nothing remaining uncommitted—to the
full freedom of human life guaranteed under the Constitution to
American citizens that it can never interfere with the rights of groups
or individuals outside its ranks. It stands everywhere against
disorderly and disruptive movements which deny the authority of the
government and disobey its mandates whether in time of war or
peace. If there is one thing, more than any other, which we
Americans must now devoutly take to heart it is obedience to law.
Perhaps we are rightly accused by Europeans of being quite the most
lawless among civilized nations. This is indicated by nothing so much
as by the series of terrible race riots which have disgraced some of
our great cities during recent years—notably Atlanta, Washington,
East St. Louis, Chicago and Omaha. Space limits us here to the
description of a single case in which the Klan has been involved. At a
small town in Florida, a terrible race riot was precipitated on election
day, 1920. It was reported that one or more Negroes, disqualified by
law from voting, were nevertheless demanding that they be
permitted to vote. This incident led to others, and resulted in a
terrible race riot. More than a score of persons, mostly Negroes, were
killed. The white men, having defeated and dispersed the Negroes of
their own community, thoroughly inflamed, proceeded, late in the
day, to march upon ————, for the purpose of attacking the
Negroes of that community. The Klansmen notified by a member of
the —— Klan, of the approach of a force of armed whites, armed
themselves and placed their services at the disposal of the officers of
the law. They met the oncoming force just outside the limits of their
own town. Unhappily, the attackers were not turned back without an
armed conflict. In this affray two Klansmen were killed. The mob was
driven back. The Klansmen lost their lives in defense of the law and
while protecting the Negroes of their town.
On another occasion one of the largest and soundest local Klans ever
founded by our organizers was instantly dissolved, because our rules
and regulations in these things were violated. The Klan in question
wished to find a remedy for a serious local disorder. A tradesman in
the community was conducting a thriving bootlegging establishment
which grew to be a scandal to the whole town. The Klan, recently
organized, and not fully comprehending our methods, posted notices
warning the culprit to leave town. They emphasized their warning by
posting along side certain signs of the Ku Klux Klan. For this
interference with the orderly process of justice in this case the local
Klan in question was quickly disbanded by our headquarters.
With this and other similar incidents in mind the reader may well
imagine the thoughts and feelings of Klansmen everywhere when
they are told that their organization has been founded for the
purpose of "Lynching Niggers." We have been accused of crimes in
towns where we had no local Klan within hundreds of miles. In such
cases the lynching accusations are often carried on the wings of
great organizations of the press. Our denials we find ineffectual. But
of this I am certain: The truth will sometimes overtake the lies and
the evil will recoil on the heads of the evil-doers.
But in addition to the purely patriotic principles of the Klan, which are
fundamental, it is a fraternal organization. A Charter for the Klan was
granted by the State of Georgia. All of its activities are subject to
scrutiny by the State and review by properly constituted authority.
The Charter may be revoked at the will of the State. Where-ever
irregularities are shown in the conduct of the Klan, or wherever the
Klan departs from the purposes of its organization as set forth in the
Charter, the Klan may be disbanded by due process of law. It is
therefore not an organization that has sprung up over night, without
responsibility, claiming independence of the law of the land.
The Klan offers its membership a graduate course in fraternalism.
There are several orders administered and each of these orders
marks an advance in devotion to our common country and in those
fraternal relations and responsibilities which bind us to our fellow
men. There can be nothing in this organization, as there is nothing in
the many fraternal organizations in this country, that is inimical to the
highest sense of social order. Indeed, underlying the fraternalism of
the Klan is a consecration to the American home, the preservation of
its sanctity and the maintenance of ideal family life. From this a
sympathetic helpfulness flows out to those in distress and
discouragement, and a force of strong men is thrown about the weak
and helpless without respect to color or creed. This is the service of
love and sacrifice to our age and generation which is symbolized by
the fiery cross.

CHAPTER IV
The Klanishness of The Klan
IT is perhaps not only proper but also necessary, in view of the
vigorous and persistent attacks made on the Klan, to discuss more
fully the apparent exclusiveness of the organization. I desire to
reiterate with emphasis that the Klan is a purely American
organization assembled around the Constitution of the United States,
to safeguard its provisions, advance its purposes, and perpetuate its
democracy. This definition of the Klan in its organization necessarily
carries the idea of exclusiveness. All men without respect to race,
color and religion may not be organized into a democracy. Democracy
can not be established by outside pressure. It is something which
must be developed in the individual consciousness, and is of very
slow growth. We speak loosely when we talk of the Anglo-Saxon
having grown into a democracy through a thousand years of struggle.
Five thousand years would be a more accurate statement of the fact.
During all the slow processes of the development of the white man's
civilization, there was something inherent in his life that slowly
pushed its way up into the consciousness of the individual until it
found expression in constitutional government, in freedom of thought
and speech, and in all the elements of political and religious liberty.
One of the most developed expressions of this growth into
democracy is our American Government with all its complexities and
intricacies. It should go without saying that all men, without
reference to origin or history, can not be thrust into this country, and,
under restraint and repression, be forced into our ways of thinking
and living and so attain the true value of American citizenship. To
begin with, a great many people, living under one form of autocracy
or another, have never been awakened to a sense of and desire for
democracy. In others the sense has begun to stir, but has not had the
opportunity or the time for that sure growth that would transform
them into a citizenship capable of pure self-government.
This fact has been demonstrated by the futility of the attempts in
Russia, first under the administration of Kerensky and now under
Lenine and Trotsky. The bolshevist camarilla attempted to take that
nation, which has been subjected for ages to one of the simplest and
meanest despotisms on earth, and organize it into a sort of
democracy. This proposition is still further illuminated by the
experience of Germany in her attempt to build a democracy on the
ruins of her old autocracy. The best thinkers in the German nation,
notwithstanding the superior intellectual, economical and industrial
qualifications of the people, predict that a real democracy can not be
established in Germany in less than fifty years. If these two nations,
both white, the one having the most robust physical manhood in the
world, and the other the most vigorous mentality, can not rise from
autocracy into democracy, how absurd it appears that we should take
great masses of the untaught, underfed, inferior people of all the
lands and undertake to precipitate them, in masses, into our very
peculiar and intricate national democracy.
 The "Starry" Flag and the "Fiery" Cross Shall Not Fail
The Klan, organized to protect and advance the cause of our native
institutions, is therefore exclusive in the restriction of its membership
to white native-born Americans. We believe that only one born on
American soil, surrounded by American institutions, taught in the
American schools, harmonized from infancy with American ideals, can
become fully conscious of what our peculiar democracy means and
be adequately qualified for all the duties of citizenship in this republic.
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