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DESIGN AND ANALYSIS OF
CLINICAL TRIALS
Concepts and Methodologies

Second Edition

SHEIN-CHUNG CHOW
Millennium Pharmaceuticals, Inc.
Cambridge, MA

JEN-PEI LIU
National Cheng-kung University
Tainan, Taiwan
National Health Research Institutes
Taipei, Taiwan

A John Wiley & Sons, Inc., Publication

DESIGN AND ANALYSIS OF CLINICAL TRIALS

Second Edition
WILEY SERIES IN PROBABILITY AND STATISTICS

Established by WALTER A. SHEWHART and SAMUEL S. WILKS

Editors: David J. Balding, Noel A. C. Cressie,

Nicholas I. Fisher, Iain M. Johnstone, J. B. Kadane, Geert Molenberghs, Louise M. Ryan,
David W. Scott, Adrian F. M. Smith, Jozef L. Teugels;
Editors Emeriti: Vic Barnett, J. Stuart Hunter, David G. Kendall

A complete list of the titles in this series appears at the end of this volume.
DESIGN AND ANALYSIS OF
CLINICAL TRIALS
Concepts and Methodologies

Second Edition

SHEIN-CHUNG CHOW
Millennium Pharmaceuticals, Inc.
Cambridge, MA

JEN-PEI LIU
National Cheng-kung University
Tainan, Taiwan
National Health Research Institutes
Taipei, Taiwan

A John Wiley & Sons, Inc., Publication

Copyright © 2004 by John Wiley & Sons, Inc. All rights reserved.

Published by John Wiley & Sons, Inc., Hoboken, New Jersey.

Published simultaneously in Canada.

No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by
any means, electronic, mechanical, photocopying, recording, scanning, or otherwise, except as permitted
under Section 107 or 108 of the 1976 United States Copyright Act, without either the prior written
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to the Permissions Department, John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, (201) 748-
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Limit of Liability/Disclaimer of Warranty: While the publisher and author have used their best efforts in
preparing this book, they make no representations or warranties with respect to the accuracy or
completeness of the contents of this book and specifically disclaim any implied warranties of
merchantability or fitness for a particular purpose. No warranty may be created or extended by sales
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For general information on our other products and services please contact our Customer Care Department
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Wiley also publishes its books in a variety of electronic formats. Some content that appears in print, however,
may not be available in electronic format.

Library of Congress Cataloging-in-Publication Data is available.

ISBN 0-471-24985-8

Printed in the United States of America

10 9 8 7 6 5 4 3 2 1
CONTENTS

Preface ix
Preface to the First Edition xi
1. Introduction 1
1.1 What are Clinical Trials?, 1
1.2 History of Clinical Trials, 3
1.3 Regulatory Process and Requirements, 7
1.4 Investigational New Drug Application, 15
1.5 New Drug Application, 22
1.6 Clinical Development and Practice, 31
1.7 Aims and Structure of the Book, 35

2. Basic Statistical Concepts 43

2.1 Introduction, 43
2.2 Uncertainty and Probability, 44
2.3 Bias and Variability, 47
2.4 Confounding and Interaction, 55
2.5 Descriptive and Inferential Statistics, 65
2.6 Hypothesis Testing and p-Values, 71
2.7 Clinical Significance and Clinical Equivalence, 77
2.8 Reproducibility and Generalizability, 82

3. Basic Design Considerations 88

3.1 Introduction, 88
3.2 Goals of Clinical Trials, 89
v
vi CONTENTS

3.3 Target Population and Patient Selection, 93

3.4 Selection of Controls, 100
3.5 Statistical Considerations, 109
3.6 Other Issues, 116
3.7 Discussion, 118

4. Randomization and Blinding 120

4.1 Introduction, 120
4.2 Randomization Models, 122
4.3 Randomization Methods, 127
4.4 Implementation of Randomization, 149
4.5 Generalization of Controlled Randomized Trials, 154
4.6 Blinding, 158
4.7 Discussion, 165

5. Designs for Clinical Trials 167

5.1 Introduction, 167
5.2 Parallel Group Designs, 169
5.3 Cluster Randomized Designs, 174
5.4 Crossover Designs, 179
5.5 Titration Designs, 188
5.6 Enrichment Designs, 194
5.7 Group Sequential Designs, 200
5.8 Placebo-Challenging Design, 202
5.9 Blinded Reader Designs, 208
5.10 Discussion, 212

6. Designs for Cancer Clinical Trials 215

6.1 Introduction, 215
6.2 General Considerations for Phase I Cancer Clinical Trials, 217
6.3 Single-Stage Up-and-Down Phase I Designs, 218
6.4 Two-Stage Up-and-Down Phase I Designs, 220
6.5 Continual Reassessment Method Phase I Designs, 223
6.6 Optimal/Flexible Multiple-Stage Designs, 226
6.7 Randomized Phase II Designs, 232
6.8 Discussion, 236

7. Classification of Clinical Trials 239

7.1 Introduction, 239
7.2 Multicenter Trial, 240
7.3 Superiority Trials, 247
7.4 Active Control and Equivalence/Noninferiority Trials, 250
7.5 Dose-Response Trials, 265
7.6 Combination Trials, 270
7.7 Bridging Studies, 283
7.8 Vaccine Clinical Trials, 289
7.9 Discussion, 296
 CONTENTS vii

8. Analysis of Continuous Data 300

8.1 Introduction, 300
8.2 Estimation, 301
8.3 Test Statistics, 305
8.4 Analysis of Variance, 311
8.5 Analysis of Covariance, 316
8.6 Nonparametrics, 320
8.7 Repeated Measures, 326
8.8 Discussion, 337

9. Analysis of Categorical Data 339

9.1 Introduction, 339
9.2 Statistical Inference for One Sample, 344
9.3 Inference of Independent Samples, 356
9.4 Ordered Categorical Data, 362
9.5 Combining Categorical Data, 366
9.6 Model-Based Methods, 372
9.7 Repeated Categorical Data, 379
9.8 Discussion, 384

10. Censored Data and Interim Analysis 386

10.1 Introduction, 386
10.2 Estimation of the Survival Function, 388
10.3 Comparison between Survival Functions, 394
10.4 Cox’s Proportional Hazard Model, 402
10.5 Calendar Time and Information Time, 417
10.6 Group Sequential Methods, 422
10.7 Discussion, 435

11. Sample Size Determination 438

11.1 Introduction, 438
11.2 Basic Concept, 439
11.3 Two Samples, 443
11.4 Multiple Samples, 452
11.5 Censored Data, 464
11.6 Dose-Response Studies, 468
11.7 Crossover Designs, 474
11.8 Equivalence and Noninferiority Trials, 481
11.9 Multiple-Stage Design in Cancer Trials, 492
11.10 Comparing Variabilities, 493
11.11 Discussion, 508

12. Issues in Efficacy Evaluation 510

12.1 Introduction, 510
12.2 Baseline Comparison, 512
viii CONTENTS

12.3 Intention-to-Treat Principle and Efficacy Analysis, 517

12.4 Adjustment for Covariates, 523
12.5 Multicenter Trials, 529
12.6 Multiplicity, 537
12.7 Data Monitoring, 546
12.8 Use of Genetic Information for Evaluation of Efficacy, 552
12.9 Sample Size Re-estimation, 558
12.10 Discussion, 560

13. Safety Assessment 562

13.1 Introduction, 562
13.2 Extent of Exposure, 564
13.3 Coding of Adverse Events, 569
13.4 Analysis of Adverse Events, 584
13.5 Analysis of Laboratory Data, 591
13.6 Discussion, 600

14. Preparation and Implementation of a Clinical Protocol 602

14.1 Introduction, 602
14.2 Structure and Components of a Protocol, 603
14.3 Points to Be Considered and Common Pitfalls during
Development and Preparation of a Protocol, 609
14.4 Common Departures for Implementation of a Protocol, 612
14.5 Monitoring, Audit, and Inspection, 617
14.6 Quality Assessment of a Clinical Trial, 620
14.7 Discussion, 626

15. Clinical Data Management 628

15.1 Introduction, 628
15.2 Regulatory Requirements, 630
15.3 Development of Case Report Forms, 633
15.4 Database Development, 636
15.5 Data Entry, Query, and Correction, 638
15.6 Data Validation and Quality, 641
15.7 Database Lock, Archive, and Transfer, 642
15.8 Discussion, 645

Bibliography 649
Appendices 683
Index 713
PREFACE

In recent years, there has been an explosive growth of literature in clinical trials. As
indicated in the first edition, the purpose of this book is to provide a comprehensive and
unified presentation of the principles and methodologies in designs and analyses utilized for
various clinical trials and to give a well-balanced summary of current regulatory
requirements and recently developed statistical methods in this area. Since the first edition
was published in 1998, it has been well received by clinical scientists/researchers and is
now widely used as a reference source and a graduate textbook in clinical research and
development. It is our continuing goal to provide a complete, comprehensive, and updated
reference and textbook in the area of clinical research.
The second edition can be distinguished from the first in three ways. First, we have
revised and/or updated sections to reflect good clinical practice in regulatory review/
approval process and recent developments in design and analysis in clinical research. For
example, the second edition provides an update of the status of clinical trials and
regulations, especially ICH (International Conference on Harmonization) guidelines for
clinical trials since 1998. Second, the second edition is expanded to 15 chapters.
Additional new topics and three new chapters are added to provide a total account of the
most recent development in clinical trials. To name just a few, the second edition includes
new topics such as clinical significance and reproducibility and generalizability (Chapter
2); goals of clinical trials and target population (Chapter 4); clustered randomized design,
group sequential design, placebo-challenging design, and blinded reader design (Chapter
5); superiority trials, active control and equivalence/noninferiority trials, dose-response
trials, bridging studies, and vaccine clinical trials (Chapter 7); sample size determination
on equivalence and noninferiority trials and comparing variabilities (Chapter 11); and use
of genomic information for evaluation of efficacy (Chapter 12). The three new chapters
include “Designs for Cancer Clinical Trials” (Chapter 6), “Preparation and Implementation
of a Clinical Protocol” (Chapter 14), and “Clinical Data Management” (Chapter 15).

ix
x PREFACE

Finally, the second edition includes more than 280 new references from clinical-related
literature. We believe that this revised and expanded second edition will benefit clinical
scientists/researchers from the medical-pharmaceutical industry, regulatory agencies, and
academia by serving as an extremely useful reference source in clinical research.
From John Wiley and Sons, I would like to thank Steve Quigley for providing us the
opportunity to work on this edition, and Susanne Steitz for her outstanding efforts in
preparing this edition. The first author would like to thank support from colleagues from
StarPlus, Inc. and Millennium Pharmaceuticals, Inc. during the preparation of this edition.
The second author wishes to express his gratitude to his wife, Dr. Wei-Chu Chie, and their
daughter Angela for their support, patience, and understanding during the preparation of
this edition.
Finally, the views expressed are those of the authors and not necessarily those of
Millennium Pharmaceuticals, Inc., and National Cheng-Kung University and National
Health Research Institutes, Taiwan. We are solely responsible for the contents and errors of
this edition. Any comments and suggestions will be very much appreciated.

SHEIN-CHUNG CHOW
JEN-PEI LIU

Cambridge, Massachusetts
Tainan, Taiwan
September, 2003
PREFACE TO THE FIRST EDITION

Clinical trials are scientific investigations that examine and evaluate safety and efficacy of
drug therapies in human subjects. Biostatistics has been recognized and extensively
employed as an indispensable tool for planning, conduct, and interpretation of clinical
trials. In clinical research and development, the bio-statistician plays an important role that
contributes toward the success of the trial. An open and effective communication among
clinician, biostatistician, and other related clinical scientists will result in a successful
clinical trial. The mutual communication, however, is a two-way street: not only (1) the
biostatistician must effectively deliver statistical concepts and methodologies to his/her
colleagues but also (2) the clinician must communicate thoroughly clinical and scientific
principles embedded in clinical research to the biostatistician. The biostatistician can then
formulate these clinical and scientific principles into valid statistical hypotheses, models,
and methodologies for data analyses. The integrity, quality, and success of a clinical trial
depend on the interaction, mutual respect, and understanding among the clinician, the
biostatistician, and other clinical scientists.
There are many books on clinical trials already on the market. These books, however,
emphasize either statistical or clinical aspects. None of these books provides a balanced
view of statistical concepts and clinical issues. Therefore the purpose of this book is not
only to fill the gap between clinical and statistical disciplines but also to provide a
comprehensive and unified presentation of clinical and scientific issues, statistical
concepts, and methodologies. Moreover this book focuses on the interactions among
clinicians, biostatisticians, and other clinical scientists that often occur during the various
phases of clinical research and development. This book is intended to give a well-balanced
overview of current and emerging clinical issues and newly developed statistical
methodologies. Although this book is written from a viewpoint of pharmaceutical research
and development, the principles and concepts presented in this book can be applied to
nonbiopharmaceutical settings.

xi
xii PREFACE TO THE FIRST EDITION

It is our goal to provide a concise and comprehensive reference book for physicians,
clinical researchers, pharmaceutical scientists, clinical or medical research associates,
clinical programmers or data coordinators, and biostatisticians in the areas of clinical
research and development, regulatory agencies, and academe. Hence this book is written
for readers with minimal mathematical and statistical backgrounds. Although it is not
required, an introductory statistics course that covers the concepts of probability, sampling
distribution, estimation, and hypothesis testing would be helpful. This book can also serve
as a textbook for graduate courses in the areas of clinical and pharmaceutical research and
development. Readers are encouraged to pay attention to clinical issues and their statistical
interpretations as illustrated through real examples from various phases of clinical research
and development.
The issues covered in this book may occur during the various phases of clinical trials in
pharmaceutical research and development, and their corresponding statistical interpreta-
tions, concepts, designs, and analyses. All the important clinical issues are addressed in
terms of the concepts and methodologies of the design and analysis of clinical trials. For
this reason this book is composed of clinical concepts and methodologies. Each chapter
with different topics is self-contained.
Chapter 1 provides an overview of clinical development for pharmaceutical entities, the
process of drug research and development in pharmaceutical industry, and regulatory
processes and requirements. The aim and structure of the book is also discussed in this
chapter. The concepts of design and analysis of clinical trials are covered from Chapters 2
through 6. Basic statistical concepts such as uncertainty, bias, variability, confounding,
interaction, and statistical versus clinical significance are introduced in Chapter 2. Funda-
mental considerations for the selection of a suitable design in achieving certain objectives
of a particular trial under various circumstances are provided in Chapter 3. Chapter 4
illustrates the concepts and different methods of randomization and blinding that are
indispensable to the success and integrity of a clinical trial. Chapter 5 introduces different
types of statistical designs for clinical trials such as parallel, crossover, titration, and
enrichment designs and discusses their relative advantages and drawbacks. Various types
of clinical trials, which include multicenter, active control, combination, and equivalence
trials, are the subject of Chapter 6.
Methodologies and the issues for clinical data analysis are addressed in Chapters 7
through 12. Since clinical endpoints can generally be classified into three types,
continuous, categorical, and censored data, various statistical methods for analyses of
these three types of clinical data and their advantages and limitations are provided in
Chapters 7, 8, and 9, respectively. In addition, group sequential procedures for interim
analysis are given in Chapter 9. Different procedures for sample size determination are
provided in Chapter 10 for data under different designs. Statistical issues in analyzing
efficacy data are discussed in Chapter 11. These issues include baseline comparisons,
intention-to-treat analyses versus evaluable or per-protocol analyses, adjustment of
covariates, multiplicity issues, and data monitoring. Chapter 12 focuses on the issues of
analysis of safety data, including the extent of exposure, coding, and analysis of adverse.
events, and analysis of laboratory data.
For each chapter, whenever possible, real examples from clinical trials are included to
demonstrate the clinical and statistical concepts, interpretations, and their relationships and
interactions. Comparisons of the relative merits and disadvantages of statistical methodo-
logy for addressing different clinical issues in various therapeutic areas are discussed in
appropriate chapters. In addition, if applicable, topics for future development are provided.
 PREFACE TO THE FIRST EDITION xiii

All computations in this book were performed using SAS. Other statistical packages such
as SPSS, BMDP, or MINTAB may also be applied.
At John Wiley, we would like to thank Acquisition Editor Steve Quigley for providing
us with the opportunity to work on this book and for his outstanding effort in preparing this
book for publication. We are greatly indebted to the Bristol-Myers Squibb Company and
Covance, Inc. for their support, in particular, to S. A. Henry, L. Meinert, and H. Koffer. We
are grateful for A. P. Pong, C. C. Hsieh, and G. Y. Han for their assistance in preparing the
many charts, figures, graphs, and tables in this book. We are grateful to Y. C. Chi, F. Ki,
and C. S. Lin for many helpful discussions and for reviewing the manuscript. We also wish
to thank A. P. Pong, M. L. Lee, and E. Nordbrock for their constant support and
encouragement. The first author also wishes to express his appreciation to his wife, Yueh-Ji,
and their daughters, Emily and Lilly, for their patience and understanding during the
preparation of this book.
Finally, we are fully responsible for any errors remaining in the book. The views
expressed are those of the authors and are not necessarily those of Covance, Inc. and the
National Cheng-Kung University.

SHEIN-CHUNG CHOW
JEN-PEI LIU

Princeton, New Jersey

Tainan, Taiwan
October 1997
1
INTRODUCTION

1.1 WHAT ARE CLINICAL TRIALS?

Clinical trials are clinical investigations. They have evolved with different meanings by
different individuals and organizations at different times. For example, Meinert (1986)
indicates that a clinical trial is a research activity that involves administration of a test
treatment to some experimental unit in order to evaluate the treatment. Meinert (1986) also
defines a clinical trial as a planned experiment designed to assess the efficacy of a treat-
ment in humans by comparing the outcomes in a group of patients treated with the test
treatment with those observed in a comparable group of patients receiving a control treat-
ment, where patients in both groups are enrolled, treated, and followed over the same time
period. This definition indicates that a clinical trial is used to evaluate the effectiveness of
a treatment. Piantadosi (1997) simply defined a clinical trial as an experimental testing
medical treatment on human subject. On the other hand, Spilker (1991) considers clinical
trials as a subset of clinical studies that evaluate investigational medicines in phases I, II,
and III, the clinical studies being the class of all scientific approaches to evaluate medical
disease preventions, diagnostic techniques, and treatments. This definition is somewhat
narrow in the sense that it restricts to the clinical investigation conducted by pharmaceuti-
cal companies during various stages of clinical development of pharmaceutical entities
which are intended for marketing approval. The Code of Federal Regulations (CFR)
defines a clinical trial as the clinical investigation of a drug that is administered or dis-
pensed to, or used involving one or more human subjects (21 CFR 312.3). Three important
key words in these definitions of clinical trials are experimental unit, treatment, and evalu-
ation of the treatment.

Design and Analysis of Clinical Trials: Concepts and Methodologies, Second Edition
By Shein-Chung Chow and Jen-pei Liu
ISBN 0-471-24985-8 Copyright © 2004 John Wiley & Sons, Inc.

1
2 INTRODUCTION

Experimental Unit
An experimental unit is usually referred to as a subject from a targeted population under
study. Therefore the experimental unit is usually used to specify the intended study popu-
lation to which the results of the study are inferenced. For example, the intended popula-
tion could be patients with certain diseases at certain stages or healthy human subjects. In
practice, although a majority of clinical trials are usually conducted in patients to evaluate
certain test treatments, it is not uncommon that some clinical trials may involve healthy
human subjects. For example, at very early phase trials of clinical development, initial
investigation of a new pharmaceutical entity may only involve a small number of healthy
subjects, say fewer than 30. Large primary prevention trials are often conducted with
healthy human subjects with size in tens of thousand subjects. See, for example, Physi-
cian’s Health Study (PHSRG, 1988), Helsinki Health Study (Frick et al., 1987), and
Women Health Trial (Self et al., 1988).

Treatment
In clinical trials a treatment can be a placebo or any combinations of a new pharmaceutical
identity (e.g., a compound or drug), a new diet, a surgical procedure, a diagnostic test, a
medial device, a health education program, or no treatment. For example, in the Physi-
cian’s Health Study, one treatment arm is a combination of low-dose aspirin and beta
carotene. Other examples include lumpectomy, radiotherapy, and chemotherapy as a com-
bination of surgical procedure and drug therapy for breast cancer; magnetic resonance
imaging (MRI) with a contrast imaging agent as a combination of diagnostic test and a
drug for enhancement of diagnostic enhancement; or a class III antiarrhythmic agent and
an implanted cardioverter defibrillator as a combination of a drug and a medical device for
treatment of patients with ventricular arrhythmia. As a result, a treatment is any interven-
tion to be evaluated in human subjects regardless that it is a new intervention to be tested
or serves as a referenced control group for comparison.

Evaluation
In his definition of clinical trials, Meinert (1986) emphasizes the evaluation of efficacy of
a test treatment. It, however, should be noted that the assessment of safety of an interven-
tion such as adverse experiences, elevation of certain laboratory parameters, or change in
findings of physical examination after administration of the treatment is at least as impor-
tant as that of efficacy. Recently, in addition to the traditional evaluation of effectiveness
and safety of a test treatment, clinical trials are also designed to assess quality of life, phar-
macogenomics, and pharmacoeconomics such as cost-minimization, cost-effectiveness,
and cost-benefit analyses to human subjects associated with the treatment under study. It is
therefore recommended that clinical trials should not only evaluate the effectiveness and
safety of the treatment but also assess quality of life, impact of genetic factors, pharma-
coeconomics, and outcomes research associated with the treatment.
Throughout this book we will define a clinical trial as a clinical investigation in which treat-
ments are administered, dispensed, or used involving one or more human subjects for evalua-
tion of the treatment. By this definition, the experimental units are human subjects either with
a pre-existing disease under study or healthy. Unless otherwise specified, clinical trials in this
book are referred to as all clinical investigations in human subjects that may be conducted by
 HISTORY OF CLINICAL TRIALS 3

pharmaceutical companies, clinical research organizations such as the U.S. National Institutes
of Health (NIH), university hospitals, or any other medical research centers.

1.2 HISTORY OF CLINICAL TRIALS

We humans since our early days on earth have been seeking or trying to identify some inter-
ventions, whether they be a procedure or a drug, to remedy ailments that inflict ourselves
and our loved ones. In this century the explosion of modern and advanced science and tech-
nology has led to many successful discoveries of promising treatments such as new medi-
cines. Over the years there has been a tremendous need for clinical investigations of these
newly discovered and promising medicines. In parallel, different laws have been enacted and
regulations imposed at different times to ensure that the discovered treatments are effective
and safe. The purpose for imposing regulations on the evaluation and approval of treatments
is to minimize potential risks that they may have for human subjects, especially for those
treatments whose efficacy and safety are unknown or are still under investigation.
In 1906, the United States Congress passed the Pure Food and Drug Act. The purpose
of this act is to prevent misbranding and adulteration of food and drugs. However, the
scope of this act is rather limited. No preclearance of drugs is required. Moreover the act
does not give the government any authority to inspect food and drugs. Since the act does
not regulate the claims made for a product, the Sherley Amendment to the act was passed
in 1912 to prohibit labeling medicines with false and fraudulent claims. In 1931, the U.S.
Food and Drug Administration (FDA) was formed. The provisions of the FDA are intended
to ensure that (1) food is safe and wholesome, (2) drugs, biological products, and medical
devices are safe and effective, (3) cosmetics are unadulterated, (4) the use of radiological
products does not result in unnecessary exposure to radiation, and (5) all of these products
are honestly and informatively labeled (Fairweather, 1994).
The concept of testing marketed drugs in human subjects did not become a public issue
until the Elixir Sulfanilamide disaster occurred in the late 1930s. The disaster was a safety
concern of a liquid formulation of a sulfa drug that caused more than 100 deaths. This
drug had never been tested in humans before its marketing. This safety concern led to the
pass of the Federal Food, Drug and Cosmetic Act (FD&C Act) in 1938. The FD&C Act
extended its coverage to cosmetics and therapeutic devices. More important, the FD&C
Act requires the pharmaceutical companies to submit full reports of investigations regard-
ing the safety of new drugs. In 1962, a significant Kefauver-Harris Drug Amendment to
the FD&C Act was passed. The Kefauver-Harris Amendment not only strengthened the
safety requirements for new drugs but also established an efficacy requirement for new
drugs for the first time. In 1984, the Congress passed the Price Competition and Patent
Term Restoration Act to provide for increased patent protection to compensate for patent
life lost during the approval process. Based on this act, the FDA was also authorized to
approve generic drugs only based on bioavailability and bioequivalence trials on healthy
male subjects. It should be noted that the FDA also has the authority for designation of
prescription drugs or over-the counter drugs. In the United States, on average, it will take
a pharmaceutical company about 10 to 12 years for development of a promising pharma-
ceutical entity with an average cost between $350 millions to $450 millions US. Drug
development is a lengthy and costly process. This lengthy process is necessary to ensure
the safety and efficacy of the drug product under investigation. On average, it may take
more than two years for regulatory authorities such as the FDA to complete the review of
4 INTRODUCTION

the new drug applications submitted by the sponsors. This lengthy review process might
be due to limited resources available at the regulatory agency. As indicated by the U.S.
FDA, they will be able to improve the review process of new drug applications if
additional resources are available. As a result, in 1992, the U.S. Congress passed the
Prescription Drug User Fee Act (PDUFA), which authorizes the FDA to utilize the
so-called user fee financed by the pharmaceutical industry to provide additional resources
for the FDA’s programs for development of drug and biologic products. From 1992 to
1997, this program has enabled the FDA to reduce the average time required for review of
a new drug application from 30 months to 15 months. In 1997, the U.S. Congress also
passed the Food and Drug Administration Modernization Act (FDAMA) to enhance the
FDA’s missions and its operations for the increasing technological, trade, and public
health complexities in the 21st Century by reforming the regulation of food, drugs,
devices, biologic products, and cosmetics.
The concept of randomization in clinical trials was not adapted until the early 1920s
(Fisher and Mackenzie, 1923). Amerson et al. (1931) first considered randomization of
patients to treatments in clinical trials to reduce potential bias and consequently to increase
statistical power for detection of a clinically important difference. At the same time a Com-
mittee on Clinical Trials was formed by the Medical Research Council of the Great Britain
(Medical Research Council, 1931) to promulgate good clinical practice by developing
guidelines governing the conduct of clinical studies from which data will be used to support
application for marketing approval. In 1937, the NIH awarded its first research grant in
clinical trial. At the same time the U.S. National Cancer Institute (NCI) was also formed to
enhance clinical research in the area of cancer. In 1944, the first publication of results from a
multicenter trial appeared in Lancet (Patulin Clinical Trials Committee, 1944). Table 1.2.1
provides a chronic accounts of historical events for both clinical trials and the associated
regulations for treatments intended for marketing approval. Table 1.2.1 reveals that the
advance of clinical trials goes hand in hand with the development of regulations.
Oklin (1995) indicated that there are at least 8,000 randomized controlled clinical trials
conducted each year whose size can include as many as 100,000 subjects. As more clinical
trials are conducted worldwide each year, new service organization and/or companies have
emerged to provide information and resources for the conduct of clinical trials. Table 1.2.2
provides a summary of resources available for clinical trials from a web-based clinical trial
listing service called CenterWatch.® These trials are usually sponsored by the pharmaceutical
industry, government agencies, clinical research institutions, or more recently a third party
such as health maintenance organizations (HMO) or insurance companies. In recent years
clinical trials conducted by the pharmaceutical industry for marketing approval have become
more extensive. However, the sizes of clinical trials funded by other organizations are even
larger. The trials conducted by the pharmaceutical industry are mainly for the purpose of reg-
istration for marketing approval. Therefore, they follow a rigorously clinical development
plan which is usually carried out in phases (e.g., phases I, II, and III trials, which will be dis-
cussed later in this chapter) that progress from very tightly controlled dosing of a small num-
ber of normal subjects to less tightly controlled studies involving large number of patients.
According to USA Today (Feb. 3, 1993), the average time that a pharmaceutical com-
pany spends getting a drug to market is 12 years and 8 months. Of this figure, six years and
8 months are spent in clinical trials to obtain the required information for market registra-
tion. The FDA review takes 2 years and 6 months. As a result of PDUFA, the review time
at the U.S. FDA has been reduced considerably. Table 1.2.3 provides a summary of median
review time at the Center for Drug Review and Research (CDER) at the U.S. FDA in 2001.
 Table 1.2.1 Significant Historical Events in Clinical Trials and Regulations
Year Clinical Trials Regulations
1906 Pure Food and Drug Act (Dr. Harvey Wiley)
1912 Sherley Amendment
1923 First randomization to experiments (Fisher and Mackenzie, 1923)
1931 First randomization of patients to treatments in clinical trials Formation of U.S. Food and Drug Administration
(Amberson, et al., 1931)
Committee on clinical trials by the Medical Research Council
of Great Britain (Medical Research Council, 1931)
1937 Formation of National Cancer Institute and First Research
Grant by National Institutes of Health (National Institutes
of Health, 1981)
1938 U.S. Federal Food, Drug and Cosmetic Act (Dr. R. Tugwell)
1944 First publication of results from a multicenter
trial (Patulin Clinical Trial Committee, 1944)
1952 Publication of Elementary Medical Statistics (Mainland, 1952) FDA makes designation of Prescription Drug or OTC
1962 Publication of Statistical Methods in Clinical and Amendment to the U.S. Food, Drug, and Cosmetic Act
Preventive Medicine (Hill, 1962)
1966 Mandated creation of the local boards (IRB) for Funding by U.S. Public Health Service
1976 Medical Device Amendment to the U.S. Food, Drug Cosmetic Act (1976)
1977 Publications of General Considerations for Clinical Evaluation of Drugs (HEW (FDA), 1977)
1984 Drug Price Competition and Patent Term Restoration Act (Waxman and Hatch, 1984)
1985 NDA rewrite
1988 Publication of Guidelines for the Format and Content of the Clinical and Statistical Section
of an Application (FDA, 1988)
1990 Publication of Good Clinical Practice for Trials on Medicinal Products in the European
Community (EC Commission, 1990)
1987 Treatment IND (FDA, 1987)
1992 Parallel track and accelerated approval (FDA, 1992)
Prescription Drug User Fee Act
1997 Publication of Good Clinical Practice: Consolidated Guidelines (ICH, 1996)
U.S. FDA Modernization Act

5
6 INTRODUCTION

Table 1.2.2 Summary of Resources for Clinical Trials

Description Resources
Number of Clinical Trials 41,000
Clinical Investigators 25,000
Academic Clinical Research Center 600
Pharmaceutical, Biotechnology, and Medical Device Companies 275
Contract Research Organization (CRO) 250
Companies Provides Services to Clinical Trials 130
Financial and Investment Professionals for Clinical Trials 100
Source: CenterWatch® Clinical Trials Listing Service (http://www.centerwatch.com).

For example, for the 10 drugs receiving priority status, the median review time is only
6 months. The median overall approval time is 14 months. However, it is not surprising
that new molecular entities requires about more than 7 months to review. This lengthy clin-
ical development process is necessary to assure the efficacy and safety of the drug product.
As a result, this lengthy development period sometimes does not allow the access of prom-
ising drugs or therapies to subjects with serious or life-threatening illnesses. Kessler and
Feiden (1995) point out that the FDA may permit promising drugs or therapies currently
under investigation to be available to patients with serious or life-threatening diseases
under the so-called treatment IND in 1987. The Parallel Track Regulations in 1992 allow
promising therapies for serious or life-threatening diseases to become available with
considerably fewer data than required for approval. In the same year, the FDA published the
regulations for the Accelerated Approval based only on surrogate endpoints to accelerate the
approval process for promising drugs or therapies indicated for life-threatening diseases.
The size of trials conducted by the pharmaceutical industry can be as small as a dozen
subjects for the phase I trial in human, or it can be as large as a few thousands for support
of approval of ticlopidine for stroke prevention (Temple, 1993). The design of the trial can
be very simple as the single-arm trial with no control group, or it can be very complicated
as a 12-group factorial design for the evaluation of the dose responses of combination
drugs. Temple (1993) points out that information accumulated from previous experience in
the database of preapproval New Drug Application (NDA) or Product License Application
(PLA) can range from a few hundred subjects (e.g., contrast imaging agents) to four or five
thousand subjects (antidepressants or antihypertensives, antibiotics, etc.).
When the safety profile and mechanism of action for the efficacy of a new drug or ther-
apy are well established, probably after its approval, a simple but large confirmatory trial is
usually conducted to validate the safety and effectiveness of the new drug or therapy. This

Table 1.2.3 Summary of Median Review Time at CDER of the U.S. FDA in 2001
Number of Approved Drugs Median Review Time in Months
66 14
NME (24) 19
Priority status (10) 6
Standard status (56) 12
Source: FDA talk paper on January 25, 2002 at www.fda.gov.
NME ⫽ New Molecular Entities.
 REGULATORY PROCESS AND REQUIREMENTS 7

kind of trial is large in the sense that there are relaxed the entrance criteria to enroll a large
number of subjects (e.g., tens of thousands) with various characteristics and care settings.
The purpose of this kind of trial is to increase the exposure of a new drug or therapy to
more subjects with the indicated diseases. For example, the first Global Utilization of
Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries Trial
(GUSTO I, 1993) enrolled over 41,000 subjects in 1,081 hospitals from 15 countries while
in the Physician’s Health Study funded by the NIH over 22,000 physicians were random-
ized to one of four arms in the trial. In addition, these trials usually follow subjects for
a much longer period of time than most trials for marketing approval. For example,
Helsinki Heart Study followed a cohort over 4,000 middle-aged men with dyslipidemia for
five years (Frick et al., 1987). The recent Prostate Cancer Prevention Trial (PCPT) plans
to follow 18,000 healthy men over age 55 for 7 years (Feigl et al., 1995). Such trials are
simple in the sense that only few important data are collected from each subject. Because
the sizes of these trials are considerably large, they can detect a relatively small yet impor-
tant and valuable treatment effects that previous smaller studies failed to detect. Some-
times, public funded clinical trials can also be used as a basis for approval of certain
indications. An example is the combined therapy of leuprolide with flutamide for patients
with disseminated, previously untreated D2 stage prostate cancer. Approval of flutamide
was based on a study funded by NCI.
On the other hand, health care providers such as HMO or insurance companies will be
more interested in providing funding for rigorous clinical trials to evaluate not only efficacy
and safety of therapies but also quality of life, pharmacoeconomics, and outcomes. The pur-
pose of this kind of clinical trial is to study the cost associated with the health care provided.
The concept is to minimize the cost with the optimal therapeutic effect under the same qual-
ity of health care. Temple (1993) points out that from the results of the study of Systolic
Hypertension in the Elderly (SHEP), a potential savings of six billion dollars per year can be
provided by the treatment regimen of chlorthalidone with a beta blocker backup such a atenol
as compared to the combined treatment of an angiotensin converting enzyme (ACE) inhibitor
with a calcium channel blocker backup. Temple (1993) also indicates that a multicooperative
group study supported by health care providers is already under way to evaluate the effects of
bone marrow transplant with aggressive chemotherapy for breast cancer.

1.3 REGULATORY PROCESS AND REQUIREMENTS

Chow and Liu (1995a) indicated that the development of a pharmaceutical entity is a lengthy
process involving drug discovery, laboratory development, animal studies, clinical trials,
and regulatory registration. The drug development can be classified into nonclinical, pre-
clinical, and clinical development phases. As indicated by the USA Today (Feb. 3, 1993),
approximately 75% of drug development is devoted to clinical development and regulatory
registration. In this section we will focus on regulatory process and requirements for clini-
cal development of a pharmaceutical entity.
For marketing approval of pharmaceutical entities, the regulatory process and require-
ments may vary from country (or region) to country (or region). For example, the European
Community (EC), Japan, and the United States have similar but different requirements as
to the conduct of clinical trials and the submission, review, and approval of clinical results
for pharmaceutical entities. In this section, for simplicity, we will focus on the regulatory
process and requirements for the conduct, submission, review, and approval of clinical
8 INTRODUCTION

trials currently adopted in the United States. As was indicated earlier, the FDA was formed
in 1931 to enforce the FD&C Act for marketing approval of drugs, biological products, and
medical devices. With very few exceptions, since the enactment of the FD&C Act, treat-
ment interventions such as drugs, biological products, and medical devices either currently
on the market or still under investigation are the results of a joint effort between the phar-
maceutical industry and the FDA. To introduce regulatory process and requirements for
marketing approval of drugs, biological products, and medical devices, it is helpful to be
familiar with the functional structure of the FDA.

The Food and Drug Administration

The FDA is a subcabinet organization within the Department of Health and Human Ser-
vices (HHS) which is one of the major cabinets in the United States government. The FDA
is headed by a commissioner with several deputy or associate commissioners to assist him
or her in various issues such as regulatory affairs, management and operations, health
affairs, science, legislative affairs, public affairs, planning and evaluation, and consumer
affairs. Under the office of commissioner, there are currently six different centers of vari-
ous functions for evaluation of food, drugs, and cosmetics. They are Center for Drug Eval-
uation and Research (CDER), Center for Biologics Evaluation and Research (CBER),
Center for Devices and Radiological Health (CDRH), National Center for Toxicological
Research (NCTR), Center for Veterinary Medicine (CVM), and Center for Food Safety
and Applied Nutrition (CFSAN).
Recently, in the interest of shortening the review process, the sponsors are required to
provide the so-called user’s fee for review of submission of applications to the FDA. In
October 1995 CDER was reorganized to reflect the challenge of improving efficiency and
shortening the review and approval process as demanded by the United States Congress and
the pharmaceutical industry. Figure 1.3.1 provides the current structure of CDER at the
FDA, which is composed of 10 major offices. These offices include Office of Management,
Office of Training and Communications, Office of Compliance, Office of Information Tech-
nology, Office of Regulatory Policy, Office of Executive Program, Office of Medical Policy,
Office of New Drugs, Office of Pharmaceutical Science, and Office of Pharmacoepidemiol-
ogy and Statistical Science. The Office of New Drugs is responsible for drug evaluation,
which consists of six offices, including Offices of Drug Evaluation I-V and Office of Pedi-
atric Drug Development and Program Initiatives. On the other hand, Office of Pharmaceuti-
cal Science consists of four offices, including Office of New Drug Chemistry, Office of
Generic Drugs, Office of Clinical Pharmacology and Biopharmaceutics, and Office of Test-
ing and Research. Furthermore, CDER recently establishes the Office of Pharmacoepidemi-
ology and Statistical Science in recognition of the importance of epidemiology and statistics
in drug evaluation. Office of Pharmacoepidemiology and Statistical Science includes Office
of Drug Safety and Office of Biostatistics. Note that each of these offices consists of several
divisions. Figures 1.3.2, 1.3.3, and 1.3.4 provide respective organizations of Offices of New
Drugs, Pharmaceutical Science and Pharmacoepidemiology and Statistical Science. Note
that CBER has a similar functional structure though it has fewer offices than CDER.

FDA Regulations for Clinical Trials

For evaluation and marketing approval of drugs, biological products, and medial devices, the
sponsors are required to submit substantial evidence of effectiveness and safety accumulated
 Office of Counter
Terrorism & Pediatric
Drug Dev. (HFD-950)
Office of the Center Director Dianne Murphy, M.D.
Janet Woodcock, M.D. (Director, Center for Drug Evaluation and Research) (HFD-001) 301-827-7777
FAX 301-827-7738
Steven Galson, M.D. (Deputy Director, CDER)
Controlled Substance Staff (HFD-009) Deborah Leiderman, M.D., 301-827-1999, FAX 301-443-9222
Division of Pediatric Division of Counter-
Jane Axelrad (Associate Director for Policy) (HFD-005), 301-594-5400, FAX 301-594 6197 Drug Dev. (HFD-960)
Terrorism (HFD-970)
Warren Rumble (Actg) (Ombudsman) (HFD-001), 301-594-5443, FAX 301-594-6197 Shirley Murphy, M.D. Mary Purucker, M.D.
301-594-7337 301-827-7711
EEO/Recruitment Staff (HFD-008) Lena Clark , 301-594-6645, FAX 301-594-5491 FAX 301-827-7738 FAX 301-827-7722

Office of Executive Office of Compliance Office of Information Office of Training and

Programs Office of Medical Policy Office of Regulatory Office of Management Technology (HFD-070) Communications
(HFD-040) Policy (HFD-005) (HFD-300) (HFD-010)
(HFD-006) (HFD-200)
Deborah Henderson Robert Temple, M.D. Jane Axelrad David J. Horowitz Russell Abbott Linda Burek (Actg.) Nancy Smith, Ph.D.
301-594-6779 301-594-6758 301-594-5400 301-827-8910 301-594-6741 301-827-6240 301-827-1651
FAX 301-594-5493 FAX 301-594-5298 FAX 301-594-6197 FAX 301-827-8901 FAX 301-827-5491 FAX 301-443-0876 FAX 301-827-3056

International Program Div. of Management and Technology Support Division of Public

(HFD-001) Div. of Drug Marketing, Div. of Regulatory Policy I Div. of New Drugs and Services Staff (HFD-073)
Advertising, and Comm. (HFD-007) Labeling Compliance Budget (HFD-050) Affairs (HFD-210)
(HFD-042) (HFD-310)
Justina Molzon David Moss
David Read William Nychis (Actg.) Robert Linkous Ellen Shapiro
301-594-5580 Thomas W. Abrams 301-827-3276
301-594-2041 301-827-8930 301-827-7810 301-827-1243
FAX 301-827-3698 301-827-2828 FAX 301-594-6183
FAX 301-827-5562 FAX 301-827-8904 FAX 301-827-7828 FAX 301-827-3055
FAX 301-594-6771

Information Management Quality Assurance Division of Training

Program (HFD-001) Division of Scientific Div. of Manufacturing Division of and Development
Div. of Regulatory Policy II Management Services Staff
Investigations (HFD-045) (HFD-007) and Product Quality (HFD-074) (HFD-220)
(HFD-320) (HFD-060)
Randy Levin Rita Thompson Paul McCarthy
Joanne Rhoads, M.D. Virginia Beakes Joseph Famulare Janice Newcomb
301-594-5411 301-827-5589 301-827-3276
301-594-0020 301-594-2041 301-827-8940 301-827-4580
FAX 301-827-5410 FAX 301-827-8907 FAX 301-827-0901 FAX 301-827-3686
FAX 301-594-1204 FAX 301-827-5562 FAX 301-827-4575

Executive Operations Division of Applications Division of Library

Staff (HFD-006) Div. of Compliance Risk Development Services and Information
Div. of Information (HFD-075) Services (HFD-230)
Disclosure Policy (HFD-013) Mgmt. and Surveillance
Khyati Roberts (HFD-330) Mary Forbes (Actg.) Carol Cavanaugh
301-594-6740 Andrea Masciale 301-827-3277 301-827-5701
Kathy Miracco (Actg.)
FAX 301-594-5493 301-827-4565 FAX 301-827-3699 FAX 301-827-5540
301-827-8920
FAX 301-827-4576
FAX 301-827-8902

Review Standards Staff Division of Infrastructure

(HFD-001)
Management and Services Division of Drug
(HFD-080) Information (HFD-240)
Lana Pauls (Actg.) Fred Goetze (Actg.)
301-594-5612 Barry Poole
301-827-3278 301-827-4570
FAX 301-594-6197 FAX 301-827-0554 FAX 301-827-4577

Division of Data
Advisors and Consultants Management and Services
Staff (HFD-021) (HFD-090)

John Treacy Cathie Schumaker (Actg.)

301-827-7001 301-827-5467
FAX 301-827-6776 FAX 301-594-6463

9
Figure 1.3.1 Center for Drug Evaluation and Research.
10
Pregnancy Labeling Program Management Reports and Data Mgmt. Pharmacology/Toxicology
Team (HFD-020) Team (HFD-022) Team (HFD-023) Staff (HFD-024)
Office of New Drugs (HFD-020)
Sandra Kweder William Oswald Robert Osterberg, Ph.D.
John Jenkins, M.D. Ann Myers (Actg.)
301-594-5476 301-594-5665 301-594-2109
301-594-3937 301-594-5476
FAX 301-827-0486 FAX 301-827-6707
FAX 301-827-0486 FAX 301-827-1540 FAX 301-594-5147

Office of Drug Office of Drug Office of Drug Office of Drug

Evaluation II (HFD-102) Evaluation III Office of Drug
Evaluation I (HFD-101) Evaluation IV Evaluation V (HFD-105)
(HFD-103) (HFD-104)
Robert Temple, M.D. Robert Meyer, M.D. Florence Houn, M.D. Mark Goldberger, M.D.
(Actg.) Jonca Bull, M.D.
301-827-5920 301-827-3144 301-827-2350
301-594-6758 301-827-2250
FAX 301-480-6644 FAX 301-480-3761 FAX 301-827-2520
FAX 301-594-5298 FAX 301-827-2317

Drug Shortages Program

Div. of Div. of Metabolic and Div. of GastroIntestinal
Neuropharmacological Endocrine Drug and Coagulation Drug Div. of Anti-Inflammatory,
Antimicrobial Resistance Analgesic, and
Drug Products (HFD-120) Products (HFD-510) Products (HFD-180) Initiative
Ophthalmologic Drug
Russell Katz, M.D. David Orloff, M.D. Robert Justice, M.D. Products (HFD-550)
301-827-6430 301-827-7310 Division of Anti- Lee Simon, M.D.
301-594-2850 Infective Drug
FAX 301-594-2859 FAX 301-443-9282 FAX 301-443-9285 Products (HFD-520) 301-827-2040
Janice Soreth, M.D. FAX 301-827-2531
301-827-2120
Division of Oncology Division of Pulmonar Drug Div. of Reproductive and
Products FAX 301-827-2325 Div. of Dermatologic
Drug Products Urologic Drug Products
(HFD-570) (HFD-580) and Dental Drug
(HFD-150)
Products (HFD-540)
Richard Pazdur, M.D. Badrul Chowdhury, M.D. Daniel Shames, M.D.
(Actg.) Division of AntiViral Jonathan Wilkin, M.D.
301-594-2473 301-827-4260
301-827-1050 Drug Products 301-827-2021
FAX 301-594-0498 FAX 301-827-4267 (HFD-530)
FAX 301-827-1271 FAX 301-827-2075
Debra B. Birnkrant, M.D.
Div. of Anesthetic, Critical 301-827-2330
Division of Cardio- Div. of Medical Imaging FAX 301-827-2523
Care, and Addiction Drug and Radiopharmaceutical Division of Over-The-
Renal Drug Products Products (HFD-170) Counter Drug
(HFD-110) Drug Products (HFD-160)
Products (HFD-560)
Douglas Throckmorton, M.D. Bob Rappaport, M.D. Patricia Y. Love, M.D.
(Actg.) Charles Ganley, M.D.
301-827-7510 Div. of Special Pathogen
301-594-5300 301-827-7419 and Immunologic Drug 301-827-2222
FAX 301-594-5495 FAX 301-443-7068 FAX 301-443-9281 Products (HFD-590) FAX 301-827-2315
Renata Albrect, M.D.
301-827-2336
FAX 301-827-2510

Figure 1.3.2 Office of New Drugs.

 REGULATORY PROCESS AND REQUIREMENTS 11

Office of Pharmaceutical Science (HFD-003)

Helen N. Winkle (Actg.)
301-594-2847
FAX 301-827-3698

Informatic Computation
Safety Analysis Staff Operations Staff
(HFD-901)
Joseph Contrera, Ph.D
301-827-5188 Vacant
FAX 301-827-3787

Quality Implementation Microbiology Team

Staff (HFD-357) (HFD-805)
Nancy Sager Peter Cooney, Ph.D.
301-594-5633 301-827-7340
FAX 301-827-2772 FAX 301-443-9281

Office of New Drug Chemistry Office of Generic Drugs Office of Clinical Office of Testing and
(HFD-800) (HFD-600) Pharmacology and Research (HFD-900)
Biopharmaceutics (HFD-850)
Yuan-yuan Chiu, Ph.D. Gary Buehler Lawrence J. Lesko, Ph.D. Frank Sistare, Ph.D. (Actg.)
301-827-5918 301-827-5845 301-594-5690 301-827-5917
FAX 301-594-0746 FAX 301-594-0183 FAX 301-827-7705 FAX 301-827-3787

Division of New Drug Division of Chemistry I Division of

Chemistry I (HFD-810) (HFD-620) Pharmaceutical Laboratory of Clinical
Evaluation I (HFD-860) Pharmacology (HFD-902)
John Simmons, Ph.D. Rashmikant Patel, Ph.D. Mehul Mehta, Ph.D. Jerry Collins, Ph.D.
301-594-2570 301-827-5848 301-594-2568 301-827-5471
FAX 301-827-4590 FAX 301-594-0180 FAX 301-480-3212 FAX 301-594-6306

Division of Chemistry II Division of Division of Applied

Division of New Drug Pharmaceutical
Chemistry II (HFD-820) (HFD-640) Pharmacology Research
Evaluation II (HFD-870) (HFD-910)
Eric Duffy, Ph.D. Florence Fang Henry Malinowski, Ph.D.
(Actg.) Joseph Hanig, Ph.D. (Actg.)
301-827-6420 301-827-5849
301-827-5919 301-594-0510
FAX 301-594-6071 FAX 301-443-3839
FAX 301-480-6645 FAX 301-594-3037

Division of Pharmaceutical
Division of New Drug Division of Bioequivalence Evaluation III (HFD-880) Division of
(HFD-650) Pharmaceutical Analysis
Chemistry III (HFD-830) (HFD-920)
John Lazor, Pharm.D.
Chi-Wan Chen, Ph.D. Dale P. Conner, Pharm.D.
301-827-2010 Moheb Nasr, Ph.D.
301-827-2001 301-827-5847
FAX 301-827-2579 314-539-2136
FAX 301-827-2103 FAX 301-594-0181 FAX 314-539-2113

Division of Labeling and Division of Product Quality

Program Support (HFD-610) Research (HFD-940)

Peter Rickman Robbe Lyon, Ph.D. (Actg.)

301-827-5846 301-827-5246
FAX 301-594-0183 FAX 301-594-6289

Figure 1.3.3 Office of Pharmaceutical Science.

from adequate and well-controlled clinical trials to CDER, CBER, or CDRH of the FDA,
respectively. The current regulations for conducting clinical trials and the submission,
review and approval of clinical results for pharmaceutical entities in the United States can
be found in CFR (e.g., see 21 CFR Parts 50, 56, 312, and 314). These regulations are devel-
oped based on the FD&C Act passed in 1938. Table 1.3.1 summarizes the most relevant
regulations with respect to clinical trials. These regulations cover not only pharmaceutical
entities such as drugs, biological products, and medical devices under investigation but
also the welfare of participating subjects and the labeling and advertising of pharmaceuti-
cal products. It can be seen from Table 1.3.1 that pharmaceutical entities can be roughly
divided into three categories based on the FD&C Act and hence the CFR. These categories
include drug products, biological products, and medical devices. For the first category,
a drug is as defined in the FD&C Act (21 U.S.C. 321) as an article that is (1) recognized in
the U.S. Pharmacopeia, official Homeopathic Pharmacopeia of the United States, or offi-
cial National Formulary, or a supplement to any of them; (2) intended for use in the diag-
nosis, cure, mitigation, treatment, or prevention of disease in humans or other animals,
12 INTRODUCTION

Office of Pharmacoepidemiology & Statistical Science (HFD-030)

Paul Seligman, M.D.

301-827-6276
FAX 301-594-6197

Office of Drug Safety Office of Biostatistics

(HFD-400) (HFD-700)

Victor Raczkowski, M.D. Robert O’Neill, Ph.D.

301-827-3219 301-827-3195
FAX 301-443-5161 FAX 301-480-2825

Div. of Surveillance, Re- Quantitative Methods &

search, & Comm. Support Research Staff (HFD-705)
(HFD-410)
Stella Machado, Ph.D.
Anne Trontell, M.D. 301-827-3218
301-827-3172 FAX 301-480-2825
FAX 301-480-0628

Div. of Medication Errors Division of Biometrics I

& Tech. Support (HFD-420) (HFD-710)

Thomas Phillips (Actg.) George Chi, Ph.D.

301-827-3242 301-594-2627
FAX 301-443-9664 FAX 301-594-6593

Division of Drug Risk Division of Biometrics II

Evaluation (HFD-430) (HFD-715)

Julie Beitz, M.D. S. Edward Nevius, Ph.D.

301-827-3159 301-827-5873
FAX 301-827-5190 FAX 301-827-5875

Division of Biometrics III

(HFD-725)

Mohammad Huque , Ph.D.

301-827-2110
FAX 301-827-2577

Figure 1.3.4 Office of Pharmacoepidemiology and Statistical Science.

or (3) intended to affect the structure or function of the body of humans or other animals.
For the second category, a biological product is defined in the 1944 Biologics Act (46
U.S.C. 262) as a virus, therapeutic serum, toxin, antitoxin, bacterial or viral vaccine, blood,
blood component or derivative, allergenic product, or analogous product, applicable to the
prevention, treatment, or cure of disease or injuries in humans. Finally, a medical device is
defined as an instrument, apparatus, implement, machine contrivance, implant, in vitro
reagent, or other similar or related article, including any component, part, or accessory
that—similar to a drug—is (1) recognized in the official National Formulary or the U.S.
Pharmacopeia or any supplement in them; (2) intended for use in the diagnosis in humans
or other animals; or (3) intended to affect the structure or function of the body of humans
or other animals.
 REGULATORY PROCESS AND REQUIREMENTS 13

Table 1.3.1 U.S. Codes of Federal Regulation (CFR) for Clinical Trials Used to
Approve Pharmaceutical Entities
CFR Number Regulations
21 CFR 50 Protection of human subjects
21 CFR 56 Institutional review boards (IRB)
21 CFR 312 Investigational new drug application (IND)
Subpart E Treatment IND
21 CFR 314 New drug application (NDA)
Subpart C Abbreviated applications
Subpart H Accelerated approval
21 CFR 601 Establishment license and product license applications
(ELA and PLA)
Subpart E Accelerated approval
21 CFR 316 Orphan drugs
21 CFR 320 Bioavailability and bioequivalence requirements
21 CFR 330 Over-the-counter (OTC) human drugs
21 CFR 812 Investigational device exemptions (IDE)
21 CFR 814 Premarket approval of medical devices (PMA)
21 CFR 60 Patent term restoration
21 CFR 201 Labeling
21 CFR 202 Prescription drug advertising

The CDER of the FDA has jurisdiction over administration of regulation and approval
of pharmaceutical products classified as drug. These regulations include Investigational
New Drug Application (IND) and New Drug Application (NDA) for new drugs, orphan
drugs, and over-the-counter (OTC) human drugs and Abbreviated New Drug Application
(ANDA) for generic drugs. On the other hand, the CBER is responsible for enforcing the
regulations of biological products through processes such an Establishment License
Application (ELA) or Product License Application (PLA). Administration of the regula-
tions for medical devices belongs to the jurisdiction of the CDRH through Investigational
Device Exemptions (IDE) and Premarket Approval of Medical Devices (PMA) and other
means.
A treatment for a single illness might consist of a combination of drugs, biological
products, and/or medical devices. If a treatment consists of a number of drugs, then it is
called a combined therapy. For example, leuprolide and flutamide are for treatment of dis-
seminated, previously untreated D2 stage prostate cancer. However, if a treatment consists
of a combination of drugs, biologics, and/or devices such as drug with device, biologic
with device, drug with biologic, drug with biologic in conjunction with device, then it is
defined as a combined product. For a combined product consisting of different pharma-
ceutical entities, FDA requires that each of entities should be reviewed separately by
appropriate centers at the FDA. In order to avoid confusion of jurisdiction over a combina-
tion product and to improve efficiency of approval process, the principle of primary mode of
action of a combination product was established in the Safe Medical Devices Act (SMDA) in
1990 (21 U.S.C. 353). In 1992, based on this principle, three intercenter agreements were
signed between CDER and CBER, between CDER and CDRH, and between CBER and
14 INTRODUCTION

CDRH to establish the ground rules for assignment of a combined product and intercenter
consultation (Margolies, 1994).

Phases of Clinical Development

In a set of new regulations promulgated in 1987 and known as the IND Rewrite, the phases
of clinical investigation adopted by the FDA since the late 1970s is generally divided into
three phases (21 CFR 312.21). These phases of clinical investigation are usually conducted
sequentially but may overlap.
Phase I clinical investigation provides an initial introduction of an investigational new
drug to humans. The primary objectives of phase I clinical investigation are twofold. First,
it is to determine the metabolism and pharmacologic activities of the drug in humans, the
side effects associated with increasing doses, and early evidence on effectiveness. In addi-
tion it is to obtain sufficient information about the drug’s pharmacokinetics and pharmaco-
logical effects to permit the design of well-controlled and scientifically valid phase II
clinical studies. Thus phase I clinical investigation includes studies of drug metabolism,
bioavailability, dose ranging, and multiple doses. Phase I clinical investigation usually
involves 20 to 80 normal volunteer subjects or patients. In general, protocols for phase I
studies are less detailed and more flexible than for subsequent phases, but they must pro-
vide an outline of the investigation and also specify in detail those elements that are criti-
cal to safety. For phase I investigation, FDA’s review will focus on the assessment of
safety. Therefore extensive safety information such as detailed laboratory evaluations are
usually collected at very intensive schedules.
Phase II studies are the first controlled clinical studies of the drug, and they involve no
more than several hundred patients. The primary objectives of phase II studies are not only
to initially evaluate the effectiveness of a drug based on clinical endpoints for a particular
indication or indications in patients with the disease or condition under study but also to
determine the dosing ranges and doses for phase III studies and the common short-term
side effects and risks associated with the drug. Although the clinical investigation usually
involves no more than several hundred patients, expanded phase II clinical studies may
involve up to several thousand patients. Note that some pharmaceutical companies further
differentiate this phase into phases IIA and IIB. Clinical studies designed to evaluate dos-
ing are referred to as phase IIA studies, and studies designed to determine the effectiveness
of the drug are called phase IIB.
Phase III studies are expanded controlled and uncontrolled trials. The primary objec-
tives of phase III studies are not only to gather the additional information about effective-
ness and safety needed to evaluate the overall benefit-risk relationship of the drug but also
to provide an adequate basis for physician labeling. Phase III studies, which can involve
from several hundred to several thousand patients, are performed after preliminary evi-
dence regarding the effectiveness of the drug has been demonstrated. Note that studies per-
formed after submission before approval are generally referred to as phase IIIB studies.
In drug development, phase I studies refer to an early stage of clinical pharmacology,
and phase II and III studies correspond to a later stage of clinical development. For differ-
ent phases of clinical studies, the investigational processes are regulated differently, for
example, the FDA review of submissions in phase I ensures that subjects are not exposed
to unreasonable risks, while the review of submissions in phases II and III also ensures that
the scientific design of the study is likely to produce data capable of meeting statutory
standards for marketing approval.
 INVESTIGATIONAL NEW DRUG APPLICATION 15

Phase IV trials generally refer to studies performed after a drug is approved for market-
ing. The purpose for conducting phase IV studies is to elucidate further the incidence of
adverse reactions and determine the effect of a drug on morbidity of mortality. In addition
a phase IV trial is also conducted to study a patient population not previously studied such
as children. In practice, phase IV studies are usually considered useful market-oriented
comparison studies against competitor products.
Note that there is considerable variation within the pharmaceutical industry in categoriz-
ing clinical studies into phases. For example, in addition to phases I through IV described
above, some pharmaceutical companies consider clinical studies conducted for new indica-
tions and/or new formulations (or dosage forms) as phase V studies.

1.4 INVESTIGATIONAL NEW DRUG APPLICATION

As indicated in the previous section, different regulations exist for different products, such
as IND and NDA for drug products, ELA and PLA for biological products, IDE and PMA
for medical devices. However, the spirit and principles for the conduct, submission, review,
and approval of clinical trials are the same. Therefore, for the purpose of illustration, we
will only give a detailed discussion on IND and NDA for drug products.
Before a drug can be studied in humans, its sponsor must submit an IND to the FDA.
Unless notified otherwise, the sponsor may begin to investigate the drug 30 days after the
FDA has received the application. The IND requirements extend throughout the period
during which a drug is under study. As mentioned in Sections 312.1 and 312.3 of 21 CFR,
an IND is synonymous with Notice of Claimed Investigational Exemption for a New Drug.
Therefore an IND is, legally speaking, an exemption to the law that prevents the shipment
of a new drug for interstate commerce. Consequently the drug companies that file an IND
have flexibility of conducting clinical investigations of products across the United States.
However, it should be noted that different states might have different laws that may require
the sponsors to file separate IND to the state governments. As indicated by Kessler (1989),
there are two types of INDs, commercial and noncommercial. A commercial IND permits
the sponsor to gather the data on the clinical safety and effectiveness needed for an NDA.
If the drug is approved by the FDA, the sponsor is allowed to market the drug for specific
uses. A noncommercial IND allows the sponsor to use the drug in research or early clinical
investigation to obtain advanced scientific knowledge of the drug. Note that the FDA itself
does not investigate new drugs or conduct clinical trials. Pharmaceutical manufacturers,
physicians, and other research organizations such as NIH may sponsor INDs. If a commer-
cial IND proves successful, the sponsor ordinarily submits an NDA. During this period the
sponsor and the FDA usually negotiate over the adequacy of the clinical data and the word-
ing proposed for the label accompanying the drug, which sets out description, clinical
pharmacology, indications and usage, contraindications, warnings, precautions, adverse
reactions, and dosage and administration.
By the time an IND is filed, the sponsor should have enough information about the chem-
istry, manufacturing, and controls of the drug substance and drug product to ensure the iden-
tity, strength, quality, and purity of the investigational drug covered by the IND. In addition the
sponsor should provide adequate information about pharmacological studies for absorption,
distribution, metabolism, and excretion (ADME) and acute, subacute, and chronic toxicologi-
cal studies and reproductive tests in various animal species to support that the investigational
drug is reasonably safe to be evaluated in clinical trials of various durations in humans.
16 INTRODUCTION

A very important component of an IND is the general investigational plan, which is in

fact an abbreviated version of the clinical development plan for the particular pharmaceu-
tical entity covered by the IND. However, the investigational plan should identify the
phases of clinical investigation to be conducted that depend on the previous human experi-
ence with the investigational drug. Usually if a new investigational drug is developed in the
United States, it is very likely that at the time of filing the IND no clinical trial on human has
ever been conducted. Consequently the investigational plan might consist of all clinical tri-
als planned for each stage of phases I, II, and III during the entire development period. On
the other hand, some investigational pharmaceutical entities may be developed outside the
United States. In this case sufficient human experiences may have already been accumu-
lated. For example, for an investigational drug, suppose that the clinical development plan
outside the United States has already completed phase II stage. Then the initial safety and
pharmacological ADME information can be obtained from phase I clinical trials. In addi-
tion phase II dose response (ranging) studies may provide adequate dose information for
the doses to be employed in the planned phase III studies. Consequently the investigational
plan may only include the plan for phase III trials and some trials for specific subject pop-
ulation such as renal or hepatic impaired subjects. However, all information and results
from phases I and II studies should be adequately documented in the section of previous
human experience with the investigational drug in the IND. A general investigational plan
may consist of more than one protocol depending on the stage of the clinical investiga-
tional plan to be conducted.
An IND plays an important role in the clinical development of a pharmaceutical entity.
An IND should include all information about the drug product available to the company up
to the time point of filing. Table 1.4.1 lists the contents of an IND provided in Section 312.23
(a) (6) of 21 CFR that a sponsor must follow and submit. A cover sheet usually refers to the
form of FDA-1571. The form reinforces the sponsor’s commitment to conduct the investiga-
tion in accordance with applicable regulatory requirements. A table of contents should also
be included to indicate the information attached in the IND submission. The investigational
plan should clearly state the rationale for the study of the drug, the indication(s) to be stud-
ied, the approach for the evaluation of the drug, the kinds of clinical trials to be conducted,
the estimated number of patients, and any risks of particular severity or seriousness antici-
pated. For completeness, an investigator’s brochure should also be provided. As mentioned
earlier, the central focus of the initial IND submission should be on the general investiga-
tional plan and protocols for specific human studies. Therefore a copy of protocol(s) which
includes study objectives, investigators, criteria for inclusion and exclusion, study design,

Table 1.4.1 Documents to Accompany an IND Submission

A cover sheet
A table of contents
The investigational plan
The investigator’s brochure
Protocol
Chemistry, manufacturing, and controls information
Pharmacology and toxicology information
Previous human experiences with the investigational drug
Additional information
Relevant information
 INVESTIGATIONAL NEW DRUG APPLICATION 17

dosing schedule, endpoint measurements, and clinical procedure should be submitted along
with the investigational plan and other information such as chemistry, manufacturing, and
controls, pharmacology and toxicology, previous human experiences with the investiga-
tional drug, and any additional information relevant to the investigational drug. Note that the
FDA requires that all sponsors should submit an original and two copies of all submissions
to the IND file, including the original submission and all amendments and reports.

Clinical Trial Protocol

To ensure the success of an IND, a well-designed protocol is essential when conducting
a clinical trial. A protocol is a plan that details how a clinical trial is to be carried out and
how the data are to be collected and analyzed. It is an extremely critical and the most
important document, since it ensures the quality and integrity of the clinical investigation
in terms of its planning, execution, and conduct of the trial as well as the analysis of the
data. Section 312.23 of 21 CFR provides minimum requirements for the protocol of a clin-
ical trial. In addition the Guideline for the Format and Content of the Clinical and Statisti-
cal Sections of an Application was issued by CDER of the FDA in October 1988.
Appendix C of this guideline describes key elements for a well-designed protocol. All of
these requirements and elements are centered around experimental units, treatments, and
evaluations of the treatments as discussed previously in Section 1.1.
Table 1.4.2 gives an example for format and contents of a well-controlled protocol for a
majority of clinical trials. A well-designed protocol should always have a protocol cover
sheet to provide a synopsis of the protocol. A proposed protocol cover sheet can be found
in Appendix C of the FDA guideline. The objective of the study should be clearly stated at
the beginning of any protocols. The study objectives are concise and precise statements of
prespecified hypotheses based on clinical responses for evaluation of the drug product
under study. The objectives usually consist of the primary objective, secondary objectives,
and sometimes the subgroup analyses. In addition these objectives should be such that can
be translated into statistical hypotheses. The subject inclusion and exclusion criteria should
also be stated unambiguously in the protocol to define the targeted population to which the
study results are inferred. The experimental design then employed should be able to
address the study objectives with certain statistical inference. A valid experimental design
should include any initial baseline or run-in periods, the treatments to be compared, the
study configuration such as parallel, crossover, or forced titration, and duration of the treat-
ment. It is extremely important to provide a description of the control groups with the
rationale as to why the particular control groups are chosen for comparison.
The methods of blinding used in the study to minimize any potential known biases
should be described in detail in the protocol. Likewise the protocol should provide the
methods of assignments for subjects to the treatment groups. The methods of assignment
are usually different randomization procedures to prevent any systematic selection bias
and to ensure comparability of the treatment groups with respect to pertinent variables.
Only the randomization of subjects can provide the foundation of a valid statistical infer-
ence. A well-designed protocol should describe the efficacy and safety variables to be
recorded, the time that they will be evaluated, and the methods to measure them. In addi-
tion the methods for measuring the efficacy endpoints such as symptom scores for benign
prostatic hyperplasis or some safety endpoints such as some important laboratory assay
should be validated and results of validation need to be adequately documented in the pro-
tocol. The FDA guideline also calls for designation of primary efficacy endpoints. From
18 INTRODUCTION

Table 1.4.2 Format and Contents of a Protocol

1. Protocol cover sheet
2. Background
3. Objectives
Primary
Secondary
4. Study plan
Study design
Subject inclusion criteria
Subject exclusion criteria
Treatment plan
5. Study drugs
Dose and route
Method of dispensing
Method and time of administration
Description of controls
Methods of randomization and blinding
Package and labeling
Duration of treatment
Concomitant medications
Concomitant procedures
5. Measurements and observations
Efficacy endpoints
Safety endpoints
Validity of measurements
Time and events schedules
Screening, baseline, treatment periods,
and post-treatment follow-up
6. Statistical methods
Database management procedures
Methods to minimize bias
Sample size determination
Statistical general considerations
Randomization and blinding
Dropouts, premature termination,
and missing data
Baseline, statistical parameters,
and covariates
Multicenter studies
Multiple testing
Subgroup analysis
Interim analysis
Statistical analysis of demography and
baseline characteristics
Statistical analysis of efficacy data
Statistical analysis of safety data
7. Adverse events
Serious adverse events
Adverse events attributions
Adverse event intensity
Adverse event reporting
Laboratory test abnormalities
 INVESTIGATIONAL NEW DRUG APPLICATION 19

Table 1.4.2 (Continued)

8. Warning and precautions
9. Subject withdrawal and discontinuation
Subject withdrawal
End of treatment
End of study
10. Protocol changes and protocol deviations
Protocol changes
Protocol deviation
Study termination
11. Institutional review and consent requirements
Institutional review board (IRB)
Informed consent
12. Obligations of investigators and
administrative aspects
Study drug accountability
Case report forms
Laboratory and other reports
Study monitoring
Study registry
Record retention
Form FDA 1572
Signatures of investigators
Confidentiality
Publication of results
13. Flow chart of studies activities
14. References
15. Appendixes

the primary objective based on the primary efficacy endpoint, the statistical hypothesis for
sample size determination can be formulated and stated in the protocol. The treatment
effects assumed in both null and alternative hypotheses with respect to the experimental
design employed in the protocol and the variability assumed for sample size determination
should be described in full detail in the protocol as should the procedures for accurate, con-
sistent, and reliable data. The statistical method section of any protocols should address
general statistical issues often encountered in the study. These issues include randomiza-
tion and blinding, handling of dropouts, premature termination of subjects, and missing
data, defining the baseline and calculation of statistical parameters such as percent change
from baseline and use of covariates such as age or gender in the analysis, the issues of mul-
ticenter studies, and multiple comparisons and subgroup analysis.
If interim analyses or administrative looks are expected, the protocol needs to describe
any planned interim analyses or administrative looks of the data and the composition, func-
tion, and responsibilities of a possible outside data-monitoring committee. The description
of interim analyses consists of monitoring procedures, the variables to be analyzed, the fre-
quency of the interim analyses, adjustment of nominal level of significance, and decision
rules for termination of the study. In addition the statistical methods for analyses of
demography and baseline characteristics together with the various efficacy and safety end-
points should be described fully in the protocol. The protocol must define adverse events,
serious adverse events, and attributions and intensity of adverse events and describe how
20 INTRODUCTION

the adverse events are reported. Other ethical and administration issues should also be
addressed in the protocol. They are warnings and precautions, subject withdrawal and dis-
continuation, protocol changes and deviations, institutional review board and consent
form, obligation of investigators, case report form, and others.
It should be noted that once an IND is in effect, the sponsor is required to submit a pro-
tocol amendment if there are any changes in protocol that significantly affect the subjects’
safety. Under 21 CFR 312.30(b) several examples of changes requiring an amendment are
given. These examples include (1) any increase in drug dosage, duration, and number of
subjects, (2) any significant change in the study design, (3) the addition of a new test or
procedure that is intended for monitoring side effects or an adverse event. In addition the
FDA also requires an amendment be submitted if the sponsor intends to conduct a study
that is not covered by the protocol. As stated in 21 CFR 312.30(a) the sponsor may begin
such study provided that a new protocol is submitted to the FDA for review and is
approved by the institutional review board. Furthermore, when a new investigator is added
to the study, the sponsor must submit a protocol amendment and notify FDA of the new
investigator within 30 days of the investigator being added. Note that modifications of the
design for phase I studies that do not affect critical safety assessment are required to be
reported to FDA only in the annual report.

Institutional Review Board

Since 1971 the FDA has required that all proposed clinical studies be reviewed both by the
FDA and an institutional review board (IRB). The responsibility of an IRB is not only to
evaluate the ethical acceptability of the proposed clinical research but also to examine the
scientific validity of the study to the extent needed to be confident that the study does not
expose its subjects to unreasonable risk (Petricciani, 1981). This IRB is formally desig-
nated by a public or private institution in which research is conducted to review, approve,
and monitor research involving human subjects. Each participating clinical investigator is
required to submit all protocols to an IRB. An IRB must formally grant approval before an
investigation may proceed, which is in contrast to the 30-day notification that the sponsors
must give the FDA. To ensure that the investigators are included in the review process, the
FDA requires that the clinical investigators communicate with the IRB. The IRB must
monitor activities within their institutions.
The composition and function of an IRB are subject to FDA requirements. Section 56.107
in Part 56 of 21 CFR states that each IRB should have at least five members with varying
backgrounds to promote a complete review of research activities commonly conducted by
the institution. In order to avoid conflict of interest and to provide an unbiased and objective
evaluation of scientific merits, ethical conduct of clinical trials, and protection of human
subjects, the CFR enforces a very strict requirement for the composition of members of an
IRB. The research institution should make every effort to ensure that no IRB is entirely
composed of one gender. In addition no IRB may consist entirely of members of one pro-
fession. In particular, each IRB should include at least one member whose primary con-
cerns are in the scientific area and at least one member whose primary concerns are in
nonscientific areas. On the other hand, each IRB should include at least one member who
is not affiliated with the institution and who is not part of the immediate family of a person
who is affiliated with the institution. Furthermore no IRB should have a member partici-
pate in the IRB’s initial or continuous review of any project in which the member has a
conflicting interest, except to provide information requested by the IRB.
 INVESTIGATIONAL NEW DRUG APPLICATION 21

Safety Report
The sponsor of an IND is required to notify FDA and all participating investigators in a writ-
ten IND safety report of any adverse experience associated with use of the drug. Adverse
experiences need to be reported include serious and unexpected adverse experiences. A seri-
ous adverse experience is defined as any experience that is fatal, life-threatening, requiring
inpatient hospitalization, prolongation of existing hospitalization, resulting in persistent or
significant disability/incapacity, or congenital anomaly/birth defect. An unexpected adverse
experience is referred to as any adverse experience that is not identified in nature, severity,
or frequency in the current investigator brochure or the general investigational plan or else-
where in the current application, as amended.
The FDA requires that any serious and unexpected adverse experience associated with
use of the drug in the clinical studies conducted under the IND be reported in writing to the
agency and all participating investigators within 10 working days. The sponsor is required
to fill out the FDA-1639 form to report an adverse experience. Fatal or immediately life-
threatening experience require a telephone report to the agency within three working days
after receipt of the information. A follow-up of the investigation of all safety information is
also expected.

Treatment IND
During the clinical investigation of the drug under an IND, it may be necessary and ethical
to make the drug available to those patients who are not in the clinical trials. Since 1987
the FDA permits an investigational drug to be used under a treatment protocol or treatment
IND if the drug is intended to treat a serious or immediately life-threatening disease, espe-
cially when there is no comparable or satisfactory alternative drug or other therapy avail-
able to treat that stage of the disease in the intended patient population. FDA, however,
may deny a request for treatment use of an investigational drug under a treatment protocol
or treatment IND if the sponsor fails to show that the drug may be effective for its intended
use in its intended patient population or that the drug may expose the patients to an unrea-
sonable and significant additional risk of illness or injury.

Withdraw and Termination of an IND

At any time a sponsor may withdraw an effective IND without prejudice. However, if an
IND is withdrawn, FDA must be notified and all clinical investigations conducted under
the IND shall be ended. If an IND is withdrawn because of a safety reason, the sponsor has
to promptly inform FDA, all investigators, and all reviewing IRBs with the reasons for
such withdrawal.
If there are any deficiencies in the IND or in the conduct of an investigation under an
IND, the FDA may terminate an IND. If an IND is terminated, the sponsor must end all
clinical investigations conducted under the IND and recall or dispose all unused supplies
of the drug. Some examples of deficiencies in an IND are discussed under 21 CFR 312.44.
For example, FDA may propose to terminate IND if it finds that human subjects would be
exposed to an unreasonable and significant risk of illness or injury. In such a case the FDA
will notify the sponsor in writing and invite correction or explanation within a period of
30 days. A terminated IND is subject to reinstatement based on additional submissions that
eliminate such risk. In this case a regulatory hearing on the question of whether the IND
should be reinstated will be held.
22 INTRODUCTION

Communication with the FDA

FDA encourages open communication regarding any scientific or medical question that
may be raised during the clinical investigation. Basically it is suggested that such commu-
nication be arranged at the end of the phase II study and prior to a marketing application.
The purpose of an end-of-phase II meeting is to review the safety of the drug proceeding to
phase III. This meeting is helpful not only in that it evaluates the phase III plan and proto-
cols but also in that it identifies any additional information necessary to support a market-
ing application for the uses under investigation. Note that a similar meeting may be held at
the end of phase I in order to review results of tolerance/safety studies and the adequacy of
the remaining development program. At the end of phase I, a meeting would be requested
by a sponsor when the drug or biologic product is being developed for a life-threatening
disease and the sponsor wishes to file under the expedited registration regulations. The
purpose of pre-NDA meetings is not only to uncover any major unresolved problems but
also to identify those studies that are needed for establishment of drug effectiveness. In
addition the communication enables the sponsor to acquaint FDA reviewers with the gen-
eral information to be submitted in the marketing application. More important, the com-
munication provides the opportunity to discuss (1) appropriate methods for statistical
analysis of the data and (2) the best approach to the presentation and formatting of the data.

1.5 NEW DRUG APPLICATION

For approval of a new drug, the FDA requires at least two adequate well-controlled clinical
studies be conducted in humans to demonstrate substantial evidence of the effectiveness
and safety of the drug. The substantial evidence as required in the Kefaurer-Harris amend-
ments to the FD&C Act in 1962 is defined as the evidence consisting of adequate and well-
controlled investigations, including clinical investigations, by experts qualified by scientific
training and experience to evaluate the effectiveness of the drug involved, on the basis of
which it could fairly and responsibly be concluded by such experts that the drug will have
the effect it purports to is represented to have under the conditions of use prescribed, rec-
ommended, or suggested in the labeling or proposed labeling thereof. Based on this
amendment, the FDA requests that reports of adequate and well-controlled investigations
provide the primary basis for determining whether there is substantial evidence to support
the claims of new drugs and antibiotics. Section 314.126 of 21 CFR provides the definition
of an adequate and well-controlled study, which is summarized in Table 1.5.1. It can be
seen from Table 1.5.1 that an adequate and well-controlled study is judged by eight criteria
specified in the CFR. These criteria are objectives, method of analysis, design of studies,
selection of subjects, assignment of subjects, participants of studies, assessment of
responses, and effect. First, each study should have a very clear statement of objectives for
clinical investigation such that they can be reformulated into statistical hypotheses and
estimation procedures. In addition proposed methods of analyses should be described in
the protocol and actual statistical methods used for analyses of data should be described in
detail in the report. Second, each clinical study should employ a design that allows a valid
comparison with a control for an unbiased assessment of drug effect. Therefore selection
of a suitable control is one of keys to integrity and quality of an adequate and well-
controlled study. The CFR recognizes the following controls: placebo concurrent control,
dose-comparison concurrent control, no treatment control, active concurrent control, and
historical control. Next, the subjects in the study should have the disease or condition
 NEW DRUG APPLICATION 23

Table 1.5.1 Characteristics of an Adequate and Well-Controlled Study

Criteria Characteristics
Objectives Clear statement of investigation’s purpose
Methods of analysis Summary of proposed or actual methods of analysis
Design Valid comparison with a control to provide a quantitative
assessment of drug effect
Selection of subjects Adequate assurance of the disease or conditions under study
Assignment of subjects Minimization of bias and assurance of comparability of groups
Participants of studies Minimization of bias on the part of subjects, observers, and
analysts
Assessment of responses Well-defined and reliable
Assessment of the effect Requirements of appropriate statistical methods

under study. Furthermore subjects should be randomly assigned to different groups in the
study to minimize potential bias and ensure comparability of the groups with respect to
pertinent variables such as age, gender, race, and other important prognostic factors. All
statistical inferences are based on such randomization and possibly stratification to achieve
these goals. However, bias will still occur if no adequate measures are taken on the part of
subjects, investigator, and analysts of the study. Therefore blinding is extremely crucial to
eliminate the potential bias from this source. Usually an adequate and well-controlled
study is at least double blinded whereby investigators and subjects are blinded to the treat-
ments during the study. However, currently a triple-blind study in which the sponsor (i.e.,
clinical monitor) of the study is also blinded to the treatment is not uncommon. Another
critical criterion is the validity and reliability of assessment of responses. For example, the
methods for measurement of responses such as symptom scores for benign prostate hyper-
plasia should be validated before their usage in the study (Barry et al., 1992). Finally,
appropriate statistical methods should be used for assessment of comparability among
treatment groups with respect to pertinent variables mentioned above and for unbiased
evaluation of drug effects.
Section 314.50 of 21 CFR specifies the format and content of an NDA, which is sum-
marized in Table 1.5.2. The FDA requests that the applicant should submit a complete
archival copy of the new drug application form (A) to (F) with a cover letter. In addition,
the sponsor needs to submit a review copy for each of the six technical sections with the
cover letter, application form (356H) of (A), index of (B), and summary of (C) as given in
Table 1.5.2 to each of six reviewing disciplines. The reviewing disciplines include chem-
istry reviewers for the chemistry, manufacturing, and controls; pharmacology reviewers
for nonclinical pharmacology and toxicology; medical reviewers for clinical data section;
and statisticians for statistical technical section. The outline of review copies for clinical
reviewing divisions include (1) cover letter, (2) application form (356H), (3) index, (4) sum-
mary, and (5) clinical section. The outline of review copies for statistical reviewing divi-
sion consists of (1) cover letter, (2) application form (356H), (3) index, (4) summary, and
(5) statistical section.
Table 1.5.3 provides a summary of the format and content of a registration dossier for
the European Economic Community (EEC). A comparison of Table 1.5.2 and Table 1.5.3
reveals that the information required by the FDA and ECC for marketing approval of a drug
is essentially the same. However, no statistical technical section is required in the ECC
24 INTRODUCTION

Table 1.5.2 A Summary of Contents and Format of a New

Drug Application (NDA)
Cover letter
A. Application form (365H)
B. Index
C. Summary
D. Technical sections
1. Chemistry, manufacturing, and controls
2. Nonclinical pharmacology and toxicology
3. Human pharmacology and bioavailability
4. Microbiology (for anti-infective drugs)
5. Clinical data
6. Statistical
E. Samples and labeling
F. Case report forms and tabulations
1. Case report tabulations
2. Case report forms
3. Additional data
Note: Based on Section 314.50 of Part 21 of Codes of Federal Regulation
(4-1-94 edition).

registration. In October 1988, to assist an applicant in presenting the clinical and statistical
data required as part of an NDA submission, the CDER of the FDA issued the Guideline
for the Format and Content of the Clinical and Statistical Sections of an Application under
21 CFR 314.50, which is summarized in Table 1.5.4. The guideline indicates the prefer-
ence of having one integrated clinical and statistical report rather than two separate reports.
A complete submission should include clinical section [21 CFR 314.50(d)(5)], statistical
section [21 CFR 314.50(d)(6)], and case report forms and tabulations [21 CFR 314.50(f)].
The same guideline also provides the content and format of the fully integrated clinical
and statistical report of a controlled clinical study in an NDA. A summary of it is given in
Table 1.5.5. Based on the content and format of the fully integrated and statistical report of
a controlled study required by the FDA, the Structure and Content of Clinical Study
Reports was also issued by the European Community in May 1993. A summary is given in
Table 1.5.6. In addition the European Community also published a guideline entitled Bio-
statistical Methodology in Clinical Trials in Applications for Marketing Authorizations for
Medicinal Products in March 1993.

Expanded Access
A standard clinical development program of phases I, II, and III clinical trials and tradi-
tional approval of a new pharmaceutical entity through IND and NDA processes by the
FDA will generally take between 8 to 12 years with an average cost around $500 million.
Kessler and Feiden (1995) indicated that on average, the FDA receives around 100 origi-
nal NDAs each year. For each NDA submission, FDA requires substantial evidence of
efficacy and safety be provided with fully matured and complete data generated from at
least two adequate and well-controlled studies before it can be considered for approval.
This requirement is necessary for drugs with marginal clinical advantages and for
 NEW DRUG APPLICATION 25

Table 1.5.3 Format and Contents of a Registration Dossier for the

European Economic Community (EEC)
Flyleaf
Annex I: General information
Annex II: Information and documents on physicochemical,
biological, or microbiological tests
Annex II.A: Complete qualitative and quantitative composition
Annex II.B: Method of preparation
Annex II.C: Controls of starting materials
Annex II.D: Control tests on intermediate products (if necessary)
Annex II.E: Control tests for the finished product
Annex II.F: Stability tests
Annex II.G: Conclusions
Annex III: Toxicological and pharmacological tests
Annex III.A: Acute toxicity
Annex III.B: Toxicity with repeated administration
Annex III.C: Fetal toxicity
Annex III.D: Fertility studies
Annex III.E: Carcinogenicity and mutagenicity
Annex III.F: Pharmacodynamics
Annex III.G: Pharmacokinetics
Annex IV: Clinical trials
Annex IV.A: Human pharmacology
Annex IV.B: Clinical data
Annex IV.C: Side effects and interactions
Annex V: Special particulars
Annex V.A: Dosage forms
Annex V.B: Samples
Annex V.C: Manufacturing authorization
Annex V.D: Marketing authorization

Table 1.5.4 Summary of the Clinical and Statistical

Section of an NDA
A. List of investigators; list of INDs and NDAs
B. Background/overview of clinical investigations
C. Clinical pharmacology
D. Control clinical studies
E. Uncontrolled clinical studies
F. Other studies and information
G. Integrated summary of effectiveness data
H. Integrated summary of safety data
I. Drug abuse and overdosage
J. Integrated summary of benefits and risks of the drug
Source: Based on Guideline for the Format and Content of the
Clinical and Statistical Sections of an Application (July, 1988,
Center for Drug Evaluation and Research, FDA).
26 INTRODUCTION

Table 1.5.5 Summary of Format and Contents of a Fully Integrated

Clinical and Statistical Report for a Controlled Study in an NDA
A. Introduction
B. Fully integrated clinical and statistical report of a controlled clinical study
1. Title page
2. Table of contents for the study
3. Identity of the test materials, lot numbers, etc.
4. Introduction
5. Study objectives
6. Investigational plan
7. Statistical methods planned in the protocol
8. Disposition of patients entered
9. Effectiveness results
10. Safety results
11. Summary and conclusion
12. References
13. Appendices
Source: Based on Guideline for the Format and Content of the Clinical and Statistical
Sections of an Application (July, 1988, Center for Drug Evaluation and Research, FDA).

treatment of conditions or diseases that are not life-threatening. However, if the diseases
are life-threatening or severely debilitating, then the traditional clinical development and
approval process might not be soon enough for the subjects whose life may be saved by
the promising drugs. According to Section 312.81 in 21 CFR, life-threatening diseases
are defined as (1) the diseases or conditions where the likelihood of death is high unless
the course of the disease is interrupted and (2) diseases or conditions with potentially fatal
outcomes, where the endpoint of clinical trial analysis is survival. On the other hand,

Table 1.5.6 Summary of Format and Contents of Clinical Study

Reports for the European Economic Community (EEC)
1. Title page
2. Table of contents for the study
3. Synopsis
4. Investigators
5. Introduction
6. Study objectives
7. Investigational plan
8. Study subjects
9. Effectiveness evaluation
10. Safety evaluation
11. Discussion
12. Overall conclusions
13. Summary tables, figures, and graphs cited in text
14. Reference list
15. Appendices
Source: Based on Structure and Content of Clinical Study Reports Joint EFPIA/CPMP
Document—May 13, 1993.
 NEW DRUG APPLICATION 27

severely debilitating diseases are those that cause major irreversible morbidity. Since
1987 regulations have been established for early access to promising experimental drugs
and for accelerated approval of drugs for treatment of life-threatening or severely debili-
tating diseases.
Expanded access is devised through treatment IND (Section 312.34 of 21 CFR) and
parallel track regulations. For a serious or immediately life-threatening disease with no
satisfactory therapy available, as mentioned before, a treatment IND allows promising
new drugs to be widely distributed even when data and experience are not sufficient
enough for a full marketing approval. On the other hand, for example, for the patients
infected with human immunodeficiency virus (HIV) who are not qualified for clinical tri-
als and have no other alternative treatment, parallel track regulations issued in 1992 pro-
vide a means for these patients to obtain experimental therapy very early in the
development stage through their private physicians. In 1992 the FDA also established the
regulations for accelerated approval of the drug for serious or life-threatening diseases
based on a surrogate clinical endpoint other than survival or irreversible morbidity (Sub-
part H of Section 314 in 21 CFR). A new concept for approval called Telescoping Trials
has also emerged (Kessler and Feiden, 1995). Under this concept, phase III clinical trials
might be totally eliminated. For example, the FDA might consider approval of a drug for a
serious disease which, during phase II clinical trials, demonstrates a positive impact on
survival or irreversible morbidity. The time table for drug evaluation and approval is illus-
trated in Figure 1.5.1 which is adopted from Kessler and Feiden (1995). A successful
example of expanded access and accelerated approval provided by these regulations is the
review and approval of dideoxyinosine (ddI) of Bristol-Myers Squibb Company for
patients with HIV. An expanded access to ddI was initiated in September 1989. The new
drug application based on the data of phase I clinical trials with no control group was filed
in April 1991. The FDA granted conditional approval of the drug in October 1991 based
on a clinical surrogate end point called a CD4⫹ lymphocyte count. With the data from
phases II and III clinical trials submitted in April 1992, the approval of ddI was broadened
in September 1992. The history of ddI case is illustrated in Figure 1.5.2 (also adopted
from Kessler and Feiden, 1995). Another example for fast-track development and acceler-
ated approval is the case of fludarabine phosphate (fludara) for treatment of refractory
chronic lymphocytic leukemia (CLL) (Tessman, Gipson, and Levins, 1994). Fludara is the
first new drug approved for this common form of adult leukemia in the United States over
50 years. The NDA, filed in November 1989 and approved in April 1991, was in fact based
on retrospective analyses of phase II clinical trials conducted by NCI through cooperative
groups including Southwest Oncology Group (SWOG) and M.D. Anderson Cancer Center
in Houston, Texas. In addition an early excess to the drug was provided in 1989 through
NCI’s Group C protocol, which is equivalent to NCI’s version of treatment IND. The last
example is the approval of Gleevec (omatinib mesylate) for oral treatment for patients
with chronic myeloid leukemia (CML) by the U.S. FDA in 2001. Gleevec is a specific
inhibitor of tyrosine kinase enzymes that plays an important role in CML. Under acceler-
ated approval regulation and orphan drug status, the U.S. FDA reviewed and approved the
marketing application in less than 3 months. This approval for three phases of CML was
based on separate single-arm studies using surrogate endpoints such as major cytogenetic
response. One of these studies was recently published (Kantarjian et al., 2002). However,
the then-U.S. FDA acting commissioner, B. A. Schwetz, D.V.M., Ph.D., indicated that fur-
ther studies are needed to evaluate whether Gleevec provides an actual clinical benefit,
such as improved survival.
28
Figure 1.5.1 Time table for drug evaluation and approval. Drug development can take many years of successively larger clinical studies (top).
The FDA’s expanded-access rules now make available to patients serious illness drugs that are still under investigation (middle). The agency has
also reduced the time it takes to approve new drugs for sale, and it may issue provisional approval for widespread marketing of a compound on
the basis of significantly fewer data than it once required (bottom). A drug may then be removed from the market if later evaluations show that
it is not beneficial. (Source: Kessler and Faiden, 1995.)
Random documents with unrelated
content Scribd suggests to you:
 “One thing I wanted to tell you, ranger man, is that Peterson and
his bunch are going to ‘get’ you, on account of that fight. I heard
Little Bill telling the boys so. He wanted them to go in on the
scheme, but they wouldn’t do it: or, at least, that’s what I
understood from what I overheard.”
“I take it your father would not object to the plan, at any rate.”
Patrick O’Neill was not smiling now.
“Father? He never would have anything to do with it! I—I happen
to know, ranger, that he has a scheme of his own for getting rid of
you.”
“Yes? And if I might ask——”
“I shouldn’t tell you, because it isn’t going to work, anyway. He
merely wrote to his brother-in-law—who is my uncle, of course—in
Washington, asking him to see that you are removed from this
district as your conduct is most obnoxious. But that doesn’t mean
anything at all, for I wrote in the very next mail to my uncle, and
told him that father is merely prejudiced against the forest service in
general, and that—that you are the most competent ranger we have
ever had here. I said he must not pay any attention to father. He
won’t, either. I lived with Uncle John and Aunt Martha while I was in
school, and they know just how cranky and unreasonable father can
be. So that’s all right. But Peterson is a different proposition. From
what Little Bill said——”
“I think,” said Ranger O’Neill, turning to his horse, “I had better
go and have a little talk with our friend Peterson.”
“You will not!” Isabelle caught him by the arm. “That’s exactly
what you must not do! I only told you so that you would be on your
guard and refuse to be drawn into any argument, as you were at
Bad Cañon the other day. Can’t you see? If you know how they feel,
you can avoid coming into contact with them until they forget about
it. It’s only because they were licked, and Peterson hates that worse
than anything else.”
“And would you have me stick close to my station, then?” O’Neill’s
eyes held a sparkle it was as well Isabelle did not see. “And what
then, if they come after me there?”
 “That,” cried Isabelle, “is beside the point! They would never dare
attack you at the station. What I think they will do is probably start
another quarrel with you, and when you are silly enough to fight,
they mean to—to shoot you, for all I know! Little Bill said: ‘We’re
goin’ to get him, next time, and get him good! And you’ve got to
keep out, I tell you. All this fighting is exactly what they want.’
“And they’ll get what they’re wantin’ or my name is not Patrick
O’Neill! Leave go my arm, Queen Isabelle, and let me carry the war
to the enemy’s camp—for that’s what they taught me at West Point,
and it’s one thing they taught that I thoroughly approve!”
“Oh,” wailed Isabelle, while tears of anger stood in her eyes,
“you’re such a blithering fool! All you Irish can think of is fighting!
You’re worse than Cushman or Waller or any of the other shoot-’em-
up rangers that had to leave or get killed. You promised me you’d
win them to you with kindness and courtesy, and if you break that
promise, I hope they break your head!”
“And thank you for that same, Miss Boyce,” said Patrick O’Neill,
with icy politeness, as he sprang to the saddle. “It’s a fine example
of kindness and courtesy you’re setting me now—as like your father
as one white bean is like another! So I’ll pass it along to Peterson
and Little Bill, and crack their heads as you so sweetly wish them to
do by me!”
He lifted his hat from his thick brown hair and gave her a courtly
bow that left her furiously stamping her foot and gritting her teeth at
him as he galloped away, headed north to the Box S Range that lay
along Bad Cañon Creek, between Lodgepole Basin and Trout Creek
where the sheep had entered. That the trail led homeward as well
never once occurred to Isabelle, who saw him going foolhardily to
place his head in the jaws of the lion that roared for his bones to
crunch; in other words, to fight on their own ground Peterson and
his crowd that had boasted how they would get him.
“She’ll do me the favor to be thinking of me now,” said Patrick
O’Neill to himself, though he never once looked back.
 CHAPTER V. PLOTTERS AT WORK.

As the valley of the Stillwater River—so named because of its

swiftness—approaches the high Rockies, it is divided into many
sections by the streams that go rushing down to join the larger river;
so that the valley resembles a giant hand with outstretched fingers
pointing toward the higher peaks to the westward.
Each branch bears a name which grew out of its most
conspicuous characteristic, and little timber grows in the valley but
crowds close to the base of the mountains. So the broad plateaus
that lie between the tributaries of the Stillwater make wonderful
grazing ground, while the creeks running down the cañons are
bordered with willows and quaking aspen groves that give shelter to
the cattle and horses that tread down the trails from higher ground
to water.
Before the national forest reserve brought this fine cattle country
under its supervision and allotted to each settler certain well-defined
grazing grounds for which he must pay an annual fee based upon
the number of animals which feed thereon, Stillwater Valley saw
many a range battle waged between rival ranchers. Now that the
national forest service held all the range—or at least the best of it
next the mountains—the fight went much the same, except that the
policing of the forest injected a new factor into the struggle. Isabelle
Boyce was right, and Ranger Cushman also summed up the situation
rather accurately. The stockmen were ready to fly at each other’s
throats for little cause, but they stood as one man against the forest
service.
“And it’s man by man that I must take them and make them see
sense, if I have to crowd it down the throats of them with my fist!”
mused Patrick O’Neill, as he reined his horse into the trail that led
with steep and devious turnings down into Bad Cañon, which he
must cross in order to reach Peterson’s home ranch.
 “I’ll talk to him fair,” Pat promised himself. “No man shall ever say
that Ranger O’Neill rushed into a fight for the pure love of the
scrimmage, without first giving the enemy a chance to eat his words
and go in peace. I’ll first reason with the big bully—should it so
happen that I have time enough for that. Then if he comes at me—
which he will!—I’ll use the fists God gave me for the purpose, and
drive my meaning home to the point of his jaw.
“For to teach a dog new tricks you must first convince him that
you’re the master of him—and faith, I shall point that out to Queen
Isabelle, should some rumors of what is to take place to-day reach
her before next Thursday. They’ll likely be out riding, since it’s the
round-up time, and he’ll have his friends about him, so that none
can say I took an unfair advantage of the man.”

So, thinking piously of his duty to Peterson, he rode splashing into

Bad Cañon Creek. A mountain trout the length of his forearm slid
from under the very feet of his horse and, with one flip of his tail,
darted into the shadow of a still pool sheltered by a mossy boulder,
and Ranger O’Neill forgot the duty which brought him there and
pulled back to the gravelly bank, dismounting in haste. For fishing
stood close to fighting in his Irish heart, and there were other trout
lying like slaty, living shadows in the depth of that pool.
To cut a short, pliable willow row and take a white miller from the
fine assortment of flies hooked into his hatband was the work of two
minutes, with another spent in unwinding trout line and leader from
a small card in his breast pocket, where he kept his book of cigarette
papers. Then O’Neill led his horse into the shade and tied him there
against wandering, pulled his hat low over his eyes to shield them
from whipping brush and sun glare alike, and stepped catwise to the
brink of the pool.
His tutelage of Peterson could wait, while the trout stream called
to the sporting blood of him. He got two trout from that small pool,
threaded their panting gills on a bit of line which he tied to his gun
belt—on the left side of him, since he was no fool after all—and
began fishing upstream, going stealthily from riffle to pool, oblivious
to all else for the time being, like all born anglers held entranced
with the whipping of a fly out over a mountain stream, skittering it
above the water to tempt the king of all wiliness from his dusky
retreat beneath a rock.
Any trout fisherman knows the lure of the next pool above, and
the next, and yet another. Patrick O’Neill crept warily upstream,
parting the bushes with care, landing each trout in silence and
putting back all but the largest of his catch. Just one more pool
would he whip before he turned back, he promised himself, and
stole up to a willow-bordered spot, where the slack water lay
enticingly under a high bank grown thick with bushes.

He stopped to reach forward, poised for the cast, then froze in his
tracks as some one beyond the bushes spoke his name. He turned
his head and stared upward, but could see nothing save the yellow-
leaved thicket.
“Aw, that damn ranger!” came Peterson’s drawling voice. “Forget
him! Plenty of time for gettin’ him outa the way. Now we’ll settle
about the cattle for Whiskers. When will he be through gatherin’
’em?”
“We’re through now with the bunch I told yuh about,” the voice of
Little Bill made reply. “All you can git away with safe. They was
throwed in on Castle Creek yesterday. That’s the reason the old
man’s been keepin’ cattle outa Castle Creek, so the feed’ll be good
to hold his beef steers on till he gits ready to trail ’em out.”
“Somebody’ll stay with ’em, perhaps. Will you be the one, Bill?”
“Aw, they don’t need herdin’, Gus. The drift fence holds ’em from
crossin’ to Drew’s range and they won’t work back up over the ridge
the other way—not with the feed like it is in there. That’s the way
old Boyce figures on savin’ men’s wages. He’ll throw all the beef in
there fast as we gather, and make one drive out. I’m s’posed to be
huntin’ strays over here, Gus.”
Peterson grunted, and another voice which O’Neill did not
recognize spoke up, offering a few choice remarks on the subject of
Boyce’s stinginess. He was answered by yet another, and when
Peterson spoke again, a third man’s voice was raised in protest.
“If you take ’em up around Lodgepole Basin and across Squaw
Gulch and that way—why, hell! You might just as well ride up to
Boyce and tell ’em you got his steers—and what’ll he do to yuh! He’s
goin’ to miss the bunch first time any one rides to Castle Creek, an’ a
blind man could foller their trail.
“Now, what yuh want to do is take ’em out on Drew’s range, on
Limestone. We can break the drift fence there and make it look like
the cattle done it, and take the bunch out that way, on Drew’s
range, and haze some of Drew’s cattle back through the fence onto
Castle Creek. That way, old Boyce won’t miss his cattle for a week,
maybe. Neither will Drew, because he ain’t half through with his
round-up yet. When they’re ready to make their drive out, it’ll look
like the cattle got mixed up, is all. And if Boyce don’t find his steers
over on Drew’s range, let ’em lock horns over it if they want to!
They’re always fighting, anyway, over the line or some darn thing.
“That way, there ain’t any mysterious tracks across Myers Creek
and up Squaw Gulch way, and it’s about as close to where you want
to hold ’em, Gus. Time the brands is healed and you get ’em down
outa that high basin, winter’ll be on and you’re dead safe. You’ll
make a late drive this year with your beef, that’s all, and you’ll have
all Box S brands—see? If that damn O’Neill don’t go prowling around
up there-”
“Aw, what’s goin’ to take him up there? That basin is hemmed in
on all sides with young lodgepole pines, and the chances are he
don’t even know it’s there. Yeah, that scheme oughta work fine,
Gus. We’ll see yuh as far as the hideout, for five dollars a head, and
from then on you’ll have to handle it alone.”
“You fellows should help change the brands, too, for five dollars,”
Peterson objected. “A five-spot just for drivin’ the cattle is too much.
I won’t pay five dollars for just to-night’s work.”

While they wrangled over the money, Patrick O’Neill went down
the creek to where his horse was tied, mounted and urged the
animal across the creek and up the farther side of the cañon, taking
a trail that led sharply away from his objective, which was the trail
up from Bad Cañon to the Box S Ranch. He wanted very much to
see the three men whose voices he failed to recognize.
Little Bill and Peterson, the ranger could swear to, if it came to a
court trial for cattle stealing, but he would feel much easier in his
mind if he had the added evidence of meeting the group riding up
the cañon where he had heard them planning the details of the
crime.
Morenci, the horse, was sweating to his ears when O’Neill finally
reached the trail he wanted and loped along it to Bad Cañon. The
detour had been made in record time, but even so he was too late,
as he was forced to admit when he rode down to the creek at the
point where he had heard the discussion, and found the men gone.
A windowless log hut set back from the creek bank beyond the
willow thicket had been their meeting place, he discovered. There
were signs enough of their presence—cigarette stubs on the dirt
floor, burned matches, boot tracks, while farther back from the creek
he found the place where they had tied their horses.
“They went down the creek, and I missed them entirely,” he
decided ruefully, at last. “Rode straight away from them as if the
devil was after me, when all I had to do was stop where I was, at
the creek with my fishing tackle, and they’d have been atop of me
before they knew I was there—and me with the best and most
peaceful excuse any man could want! Pat, me lad, you should be
well booted for that blunder!”
That night they would make the drive, they had said. They were
wise to hurry the job, since there was little time to spare before the
winter snows would send the stolen herd down from the high basin;
and the altered brands would take some time to heal so that the
theft would not be apparent. Furthermore, it was only a matter of
days until Boyce or Drew would discover the broken drift fence and
begin to search for strayed cattle.
Ranger O’Neill rode with a cigarette gone cold from neglect
between his lips while he pondered the best manner of protecting
Boyce. He could ride to the Bar B and warn them——
“But what if those strange men are Bar B riders?” he argued the
point with himself. “Or what if Boyce is not at home, or more likely
starts his tongue wagging at me and stirs the Irish before I get out
the news? I’d ride away and let Peterson put through the steal—if
Boyce makes me mad enough. And the time is short for a ride to the
Bar B and back again to Castle Creek soon enough to stop them.
“Morenci, you’ve the mark of a good cow pony in the way you
handle yourself on range inspection, and if you work fast enough,
I’m thinking we can handle this little matter alone; though it’s little
encouragement I’ve lately received for playing the patron saint to old
Boyce. Still, there’s a way to work it that appeals to my sense of
humor, and it’s that we’re going to do. So shake a leg, Morenci!
You’ve a lot of violent exercise between you and your feed box to-
night.”
And Patrick O’Neill, for the first time that day, whistled under his
breath, as he galloped, to show how content he was with his
mission.
 CHAPTER VI. A QUICK CHANGE.

Later Pat O’Neill did not whistle, though he still rode in haste. The
afternoon was older than he had suspected when he rode up out of
Bad Cañon and across the high grazing ground that lay between his
fishing place and Lodgepole Basin. He had a plan which he felt
would work beautifully, if only he had time for it; but now with the
sinking of the sun, he was not so sure. A great deal depended upon
his horse, and he had not spared the animal in his roundabout ride
to cut the homeward trail of Peterson and his men.
“First, I must be sure that Boyce’s steers are safe,” he decided,
and crossed Limestone Creek with a splash and a clatter of hoofs on
the stones. “It’s a new range the Bar B cattle are on, and if I can
read the mind of cow brutes, they have traveled as far down the
creek as they can go. They will not be satisfied to stay at the upper
end of the bottom where the grass is quite as good, but must range
farther in the vain hope of finding range that pleases them better. At
any rate, it’s worth the gamble.”
As he opened the wire gate in the drift fence which separated
Drew’s range from Boyce’s on Castle Creek just above its junction
with Limestone, the parklike basin was dusky with the coming of
night, but as he led his horse through, closed the gate and
remounted, a steer snorted dew from its nostrils not far away. O’Neill
turned and rode that way, peering down satisfiedly at the dark forms
of the Bar B beef steers bedded down on a rise of ground just back
from the creek and the mosquitoes and close to the fence.
“What did I tell you, Morenci? Now, rout them up and we’ll haze
them on down the fence toward Picket Pin. If it’s through a fence
they want to travel, they may try the other side of the fence on
Picket Pin and welcome—and the farther they drift, the safer they’ll
be, though it will make more work for the Bar B riders.”
 When he had finished that job and the Bar B steers were plodding
in the dark to find another bed ground on Picket Pin, Patrick O’Neill
cautiously lighted a match in the crown of his hat and looked at his
watch.
“Eight o’clock and our work only begun! Get away from here,
Morenci, and show the stuff that’s in you!” And striking into a cow
path that wound through thickets of aspen and across little open
glades, he pelted away up Castle Creek to the steep trail where the
rim rock broke down in a great slide of boulders on the divide
between Myers Creek and Castle.
When he reached Lodgepole Basin, his watch said ten o’clock and
Ranger O’Neill had a deep crease between his eyebrows, for Morenci
was wet to his ears—and that not from splashing through creeks,
though he had crossed two—and there were more cattle to be
moved.
But these were Peterson’s and Ranger O’Neill was not so gentle.
Across Lodgepole Basin, he galloped, to where a hundred head or
more of Box S cattle ranged happily enough and had for their bed
ground a knoll not far from Squaw Gulch, which was not very distant
from the Myers Creek divide. For the Stillwater Forest Reserve, you
must know, is a network of streams and their cañons, once you are
back in the hills.
So Ranger O’Neill made a hasty gathering of Peterson’s cattle and
hazed them along at a lumbering gallop to the fenced gap in the rim
rock and so down into the Castle Creek pasture which was leased to
Boyce. Just for good measure he rode after them and threw a hastily
gathered rock or two, and the cattle went down the creek as if a full
crew rode hard at their heels.
Ranger O’Neill pulled up and listened until the last sound of
whipping brush and the clicking of cloven feet against the rocks had
died to silence. The cattle were tired after that headlong drive up
Myers Creek to the rim. It had been steep in places and only the
manner in which he had rushed them along had held them to the
trail. Morenci was standing with his feet slightly braced—the mark of
a tired horse—and his flanks palpitating with exhaustion. O’Neill
listened while the horse caught his wind, then suddenly he leaned
forward and gave the reeking neck a grateful slap.
“Not a dozen horses in the district could have done it, and that’s
the truth, Morenci!” Then he fell silent, though his thoughts went on
quite as definitely as if he were actually speaking them.
“No sound of riders down below there, so the cattle will quiet
down before Peterson comes for them—he chooses late hours for his
stealing, thank the Lord! So now let him steal his own stock, though
what he’ll think or what he’ll say when he sees their brands in the
morning, I sure would like to know. I’d like to go and collect a bit of
gratitude from Queen Isabelle and the Honorable Standish Boyce for
this night’s work, but that will have to wait until Thursday, for I’m
due at Blind Bridger to-morrow. But when I do see her, she will
admit I’m doing much to promote peace and quiet along the
Stillwater, I’m thinking.”
Wherefore Ranger Patrick O’Neill was a contented young man
although a weary one as he rode home under the cool stars of
midnight. Morenci got an extra rubdown as well as his supper before
O’Neill went away to the cabin to fill his own empty stomach. The
fish he had caught were far past their fresh toothsomeness and he
threw them away and dined upon what happened to stand ready
cooked in the cupboard. But it was a good night’s work and he
grinned over it frequently.
“Murray would appreciate that!” O’Neill chuckled, as he pulled off
his boot. He was thinking of Peterson’s slack-jawed amazement
when he recognized the cattle he had stolen away from Castle Creek
that night.
The ranger’s last thought as he put his head on the pillow was of
the peppery Bar B owner and his probable mystification when he
found his beef herd over on the Picket Pin. Some one would catch a
tongue lashing, O’Neill suspected.
“But I’ll ride over and tell him about it before he has time to
discover the change of pasture,” he comforted himself. “Peterson
was counting on a week or so before the rustling would be
suspected, and I’ll see Boyce before then. And Isabelle,” he added
sleepily, and then began to dream of all that he would have to say.
 CHAPTER VII. FROM BAD TO WORSE.

“Sure and a most loyal subject bows before the queen this day!”
cried Patrick O’Neill, with his best brogue and a somewhat self-
satisfied grin on his face. “I was scarce hoping you’d ride out to
meet me, and that’s why I was taking the short cut to the Bar B this
morning. I’ve things to report that——”
“I should think you would have,” Isabelle Boyce told him sharply.
“With all this mix-up over the cattle, and the trouble it’s making, I
should think you would have something to say on the subject! Do
you know how Tod Drew’s cattle came to be on father’s best range,
and father’s beef herd over on that barren ground that wouldn’t
furnish grazing for a sheep? And the drift fence down——”
“Do I know? It’s a night’s sleep I lost in getting full knowledge of
the mystery, Queen Isabelle! I drove your father’s cattle to the Picket
Pin——”
“Indeed?” So much meaning may be crowded into one word with
a rising inflection that Patrick O’Neill felt a momentary panic. “I
hope, Mr. O’Neill, you will oblige me with your reasons for so
astounding a piece of trouble making. I am frankly curious to know
what possessed you to commit such a deed.”
“It was a good deed, of which I am proud to tell,” he informed
her, secretly pleased at the dramatic change he would presently
produce in her mood. “On last Friday afternoon I chanced to hear a
plan to steal your father’s gathering of beef steers which he was
holding on Castle Creek. Peterson was the leader, and they meant to
tear down the drift fence between your father’s range and Drew’s,
and drive out the steers that way. They would then drive as many of
Drew’s cattle as they could handily gather through the fence and
onto Castle Creek, so that it would look as though the cattle had
broken down the drift fence and were trespassing of their own
accord, and it would not be suspected at once that the beef herd
was stolen. Castle Creek Basin being brushy in the hollows, the plan
had a fair chance of success.
“I failed to see the men—and that was a bit of bad guessing, of
which I am not proud. But I recognized the voice of a Bar B rider,
among others. It was late, and though I could have waited at the
drift fence and held them up when they came, I could bring no
charge against them unless they had actually stolen the cattle. So I
thought I would play a trick on Peterson.
“I went to Castle Creek and moved the Bar B steers out of harm’s
way—regretting the poor pasturage but having little time to choose a
range for them. Then I rode back to Lodgepole, where a bunch of
Peterson’s cattle grazed, took them across Squaw Gulch to the head
of Myer’s Creek, and up over the divide and through the gap to
Castle Creek Basin. It was fast work and it was pretty work, Miss
Boyce, and I repeat that I am proud of it!”

With lips slightly parted and eyes wider than usual, Isabelle stared
at him and did not speak. So presently the grin smoothed itself from
his lips and the twinkle died in his eyes and left a puzzled look there,
which could easily turn hostile.
“Would you rather I had let them take your father’s whole beef
herd and run the fat off them getting them into some hidden place
in the mountains? Or perhaps you think I should have confronted
Peterson and fought the lot of them!”
“Of course I don’t think you should do anything so insane! But it
couldn’t be much worse. Why didn’t you come and tell father? Why
did you let days go by without saying a word? Is it possible you
don’t know that father and Tod Drew are always at sword’s points
over something, and jump at the least excuse for quarreling? You’ve
managed to stir up a pretty mess, Mr. O’Neill. You may have saved
father’s beef herd—but what is that when he and Drew have sent
each other warning that it will be shoot on sight from now on? I’ve
had all I could do to keep father from riding over and killing Drew
deliberately!”
 “It couldn’t be for what I did the other night,” O’Neill protested.
“What if the fence is down and Drew’s cattle were found on your
father’s range? That’s not a shooting matter, with sane men.”
Isabelle gave him a withering look. “Oh, how can you be so
dense! Do you suppose for one minute that father could ride to
Castle Creek and discover Tod Drew’s cattle there, and his own
driven over on Picket Pin—because there was no fence broken down
there to lay the blame on the cattle!—without doing something
about it? He drove Drew’s cattle off with his six-shooter. He killed
one and crippled another so Drew had to have it shot. If Tod Drew
had been at that drift fence, Mr. O’Neill, there would have been
murder! There will be yet, if something isn’t done to stop them, for
Tod Drew shot our cattle with a shotgun! For a man who was going
to do such great things in psychology,” she cried distractedly, “and
instill both liking and respect for the forest service into the hearts of
the Stillwater men, you have promoted as bloodthirsty a feud as
ever happened anywhere! The only difference is that it is confined to
two men, so far—though the cowboys are just as likely to take it up
as not, just for the excitement of it!”
“I have received no instructions, Miss Boyce, for guarding the
morals of other men,” Patrick O’Neill said somewhat stiffly. “But since
your respected parent has not yet committed a murder as well as a
felony against his neighbor’s property, I have time enough perhaps
to curb his homicidal tendencies. A bit of an explanation will clear
the air, I’m thinking.” And he reached for Morenci’s dragging bridle
reins.
“You’re never going to face them now and tell them you did it?”
Isabelle’s voice rose to a high note of protest. “They’ll kill you!”
But Ranger O’Neill was in the saddle and away, pelting along to
Drew’s place, since that was closer than the Bar B. Isabelle watched
him out of sight, then mounted and galloped up the road in the dust
cloud he left behind him, her heart beating queerly, away up in her
throat.
 It is strange how training oft will drop away from a man like a
garment of winter grown uncomfortable as summer approaches, yet
fall into place when the need of it arises again. So with Ranger
Patrick O’Neill when he pulled up his horse at Drew’s gate. In the
years since West Point he had put aside much of his military bearing
in everyday life, and he had gone rather irresponsibly out to meet
life, with his rollicky Irish manner to the front because it was easy to
wear.
Yet when he dismounted and walked up the path to the house, his
back was straight and his step was alert, his chest was out and his
belt was in and his eyes looked with keen discernment straight into
the leathery countenance of Tod Drew, who glanced cautiously out
of a near-by window before he opened the door to his insistent
knocking.
“Mr. Drew, I came to report what I know of the drift fence being
broken between your range and the Bar B lease on Castle Creek last
Friday night.” And Ranger O’Neill forthwith explained, with malice
toward none and naming no names, but making himself perfectly
clear for all that.
“I have no direct evidence upon which to convict these men, for I
failed to get a sight of them. There was little time to forestall them,
Mr. Drew, but I did what seemed to me best as a measure of
precaution. Since there has been a misunderstanding in the matter
of the cattle, I stand ready to make a fair adjustment of whatever
damages may have resulted from my removal of the Bar B herd
without due notice. I want you to go with me to call upon Mr. Boyce,
and I feel sure we can arrive at a friendly understanding.” Then, and
not until then, Drew had a glimpse of the grin that was so much a
part of Patrick O’Neill.
Drew gave O’Neill a peculiar, squinting look. “Say, me and that old
he-wolf has promised to swap lead however and wherever we meet
up with each other!” he stated emphatically, at last. “I’ll have to ride
up a-shootin’, or he’ll likely think I’m scared and plug me fer a
sheep!”
“Not if I ride with you,” urged Patrick O’Neill.
 “Dern that ole pelican! he shot two steers fer me——”
“And you killed one or two for him, but if necessary I can arrange
to pay for the damages. There’s nothing like going straight out
toward trouble, Mr. Drew. Nine times in ten it backs out of sight as
you ride toward it. If you’re willing to take a chance——”
“Oh, I was goin’ to ride over there and have it out with him,”
Drew told him, with dark meaning. “I’m willin’ to meet the old coot
halfway, whether it’s shootin’ or shakin’ hands!”
“I’ve had it in mind to get you two together and see what can be
done about clearing out this rustling. You may be the next to suffer,
you know. I’m here to do whatever you two think best——”
“Well, I got an idea we might set some kinda trap——”

Shortly thereafter, Isabelle Boyce reined her horse out of the trail
to let the two riders pass. Her heart was still beating heavily in her
throat, but she would not acknowledge the smiling salute she
received from Ranger O’Neill. They were headed for her father’s
ranch, but she refused to hurry after them; instead, she waited a
while before she turned her horse toward home. Of course, with Tod
Drew talking and gesticulating in his usual manner, she could not
think that he was going to do murder. Ranger O’Neill would put a
stop to all that. But her father would rave and threaten and she
doubted whether he would stop long enough to listen to the story
which Ranger O’Neill had to tell, or believe it when it was told.
But when she rode up to the house, there stood the two horses
tied to the fence, and there were no high voices to be heard. She
stood for a minute on the porch, looking and listening. A murmur of
conversational tones floated out from the living room, and she went
in and stood just outside the closed door, eavesdropping with no
compunction whatever.
“If one of my men is involved in this nefarious spoilation of the
range,” her father’s rasping voice was saying, “I see no way of
exculpating the others until such time as the thieves are
apprehended. Mr. O’Neill, I must concur in one statement which you
have made, and that is the statement that leasers of government
property are entitled to government protection. I shall write to my
relative, who stands very close to the head of the department of
forestry in Washington——”
Isabelle gave a relieved little laugh which caught in her throat like
a strangled sob, and ran upstairs to choose a dainty dress—just in
case Ranger O’Neill was invited to stay for supper.

Transcriber’s Note: This story appeared in the June 7, 1926 issue

of The Popular magazine.
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