Advances in Clinical Trial Biostatistics - N. Geller (Marcel Dekker, 2004) WW

278 Pages·2004·2.15 MB·English

ADVANCES IN
CLINICAL TRIAL
B IOSTATISTI CS

edited by
NANCY L. GELLER
National Heart, Lung, and Blood Institute
National Institutes of Health
Bethesda, Maryland, U.S.A.

M A R C E L
MARCEL
DEKKER,
INC.

D E K K E R

NEW YORK - BASEL

Copyright n 2004 by Marcel Dekker, Inc. All Rights Reserved.

This book was edited by Nancy L. Geller in her private capacity. The views expressed do not
necessarily represent the views of NIH, DHHS, or the United States.

Although great care has been taken to provide accurate and current information, neither the
author(s) nor the publisher, nor anyone else associated with this publication, shall be liable for
any loss, damage, or liability directly or indirectly caused or alleged to be caused by this book.
The material contained herein is not intended to provide specific advice or recommendations
for any specific situation.

Trademark notice: Product or corporate names may be trademarks or registered trademarks
and are used only for identification and explanation without intent to infringe.

Library of Congress Cataloging-in-Publication Data
A catalog record for this book is available from the Library of Congress.

ISBN: 0-8247-9032-4

This book is printed on acid-free paper.

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Biostatistics: A Series of References and Textbooks

Series Editor
Shein-Chung Chow

Vice President, Clinical Biostatistics and Data Management
Millennium Pharmaceuticals, Inc.
Cambridge, Massachusetts
Adjunct Professor
Temple University
Philadelphia, Pennsylvania

1. Design and Analysis of Animal Studies in Pharmaceutical Devel-
opment, edited by Shein-Chung Chow and Jen-pei Liu
2. Basic Statistics and Pharmaceutical Statistical Applications, James E.
De Muth
3. Design and Analysis of Bioavailability and Bioequivalence Studies,
Second Edition, Revised and Expanded, Shein-Chung Chow and
Jen-pei Liu
4. Meta-Analysis in Medicine and Health Policy, edited by Dalene K.
Stangl and Donald A. Berry
5. Generalized Linear Models: A Bayesian Perspective, edited by Dipak
K. Dey, Sujit K. Ghosh, and Bani K. Mallick
6. Difference Equations with Public Health Applications, Lemuel A. Moye
and Asha Seth Kapadia
7. Medical Biostatistics, Abhaya lndrayan and Sanjeev B. Sarrriukaddam
8. Statistical Methods for Clinical Trials, Mark X. Norleans
9. Causal Analysis in Biomedicine and Epidemiology: Based on Minimal
Sufficient Causation, Mike1 Aickin
10. Statistics in Drug Research: Methodologies and Recent Develop-
ments, Shein-Chung Chow and Jun Shao
11. Sample Size Calculations in Clinical Research, Shein-Chung Chow,
Jun Shao, and Hansheng Wang
12. Applied Statistical Designs for the Researcher, Daryl S. Paulson
13. Advances in Clinical Trial Biostatistics, Nancy L. Geller

ADDITIONAL VOLUMES IN PREPARATION

Copyright n 2004 by Marcel Dekker, Inc. All Rights Reserved.

Series Introduction

The primary objectives of the Biostatistics series are to provide useful ref-
erence books for researchers and scientists in academia, industry, and
government, and also to offer textbooks for undergraduate and/or grad-
uate courses in the area of biostatistics. The series provides comprehensive
and unified presentations of statistical designs and analyses of important
applications in biostatistics, such as those in biopharmaceuticals. A well-
balanced summary is given of current and recently developed statistical
methods and interpretations for both statisticians and researchers/scien-
tists with minimal statistical knowledge who are engaged in the field of
applied biostatistics. The series is committed to presenting easy-to-under-
stand, state-of-the-art references and textbooks. In each volume, statistical
concepts and methodologies are illustrated through real-world examples
whenever possible.
Clinical research is a lengthy and costly process that involves drug
discovery, formulation, laboratory development, animal studies, clinical
development, and regulatory submission. This lengthy process is necessary
not only for understanding the target disease but also for providing sub-
stantial evidence regarding efficacy and safety of the pharmaceutical com-
pound under investigation prior to regulatory approval. In addition, it
provides assurance that the drug products under investigation will possess
good characteristics such as identity, strength, quality, purity, and stability
after regulatory approval. For this purpose, biostatistics plays an impor-

Copyright n 2004 by Marcel Dekker, Inc. All Rights Reserved.

tant role in clinical research not only to provide a valid and fair assess-
ment of the drug product under investigation prior to regulatory approval
but also to ensure that the drug product possesses good characteristics with
the desired accuracy and reliability.
This volume provides a comprehensive summarization of recent
developments regarding methodologies in design and analysis of studies
conducted in clinical research. It covers important topics in early-phase
clinical development such as Bayesian methods for phase I cancer clinical
trials and late-phase clinical development such as design and analysis of
therapeutic equivalence trials, adaptive two-stage clinical trials, and cluster
randomization trials. The book also provides useful approaches to critical
statistical issues that are commonly encountered in clinical research such as
multiplicity, subgroup analysis, interaction, and analysis of longitudinal
data with missing values. It will be beneficial to biostatisticians, medical
researchers, and pharmaceutical scientists who are engaged in the areas of
clinical research and development.

Shein-Chung Chow

Series Introduction
iv

Copyright n 2004 by Marcel Dekker, Inc. All Rights Reserved.

Preface

As the medical sciences rapidly advance, clinical trials biostatisticians and
graduate students preparing for careers in clinical trials need to maintain
knowledge of current methodology. Because the literature is so vast and
journals are published so frequently, it is difficult to keep up with the rel-
evant literature. The goal of this book is to summarize recent methodology
for design and analysis of clinical trials arranged in standalone chapters.
The book surveys a number of aspects of contemporary clinical trials,
ranging from early trials to complex modeling problems. Each chapter
contains enough references to allow those interested to delve more deeply
into an area. A basic knowledge of clinical trials is assumed, along with a
good background in classical biostatistics. The chapters are at the level of
journal articles in Biometrics or Statistics in Medicine and are meant to be
read by second- or third-year biostatistics graduate students, as well as by
practicing biostatisticians.
The book is arranged in three parts. The first consists of two chapters
on the first trials undertaken in humans in the course of drug development
(Phase I and II trials). The second and largest part is on randomized clinical
trials, covering a variety of design and analysis topics. These include design
of equivalence trials, adaptive schemes to change sample size during the
course of a trial, design of clustered randomized trials, design and analysis
of trials with multiple primary endpoints, a new method for survival analy-
sis, and how to report a Bayesian randomized trial. The third section deals

Copyright n 2004 by Marcel Dekker, Inc. All Rights Reserved.

with more complex problems: including compliance in the assessment of
treatment effects, the analysis of longitudinal data with missingness, and
the particular problems that have arisen in AIDS clinical trials. Several of
the chapters incorporate Bayesian methods, reflecting the recognition that
these have become acceptable in what used to be a frequentist discipline.
The 20 authors of this volume represent five countries and 10 insti-
tutions. Many of the authors are well known internationally for their meth-
odological contributions and have extensive experience in clinical trials
practice as well as being methodologists. Each chapter gives real and rel-
evant examples from the authors’ personal experiences, making use of a
wide range of both treatment and prevention trials. The examples reflect
work in a variety of fields of medicine, such as cardiovascular diseases, neu-
rological diseases, cancer, and AIDS. While it was often the clinical trial
itself that gave rise to a question that required new methodology to answer,
it is likely that the methods will find applications in other medical fields. In
this sense, the contributions are examples of ‘‘ideal’’ biostatistics, tran-
scending the boundary between statistical theory and clinical trials prac-
tice.
I wish to express my deep appreciation to all the authors for their
patience and collegiality and for their fine contributions and outstanding
expositions. I also thank my husband for his constant encouragement
and Marcel Dekker, Inc., for their continuing interest in this project.

Nancy L. Geller

Preface
vi

Copyright n 2004 by Marcel Dekker, Inc. All Rights Reserved.

Contents

Series Introduction
Preface
Contributors

Part I
METHODS FOR EARLY TRIALS

1.
Bayesian Methods for Cancer Phase I Clinical Trials
James S. Babb and Andre´ Rogatko

2.
Design of Early Trials in Stem Cell Transplantation:
A Hybrid Frequentist-Bayesian Approach
Nancy L. Geller, Dean Follmann, Eric S. Leifer, and
Shelly L. Carter

Part II
METHODS FOR RANDOMIZED TRIALS

3.
Design and Analysis of Therapeutic Equivalence Trials
Richard M. Simon

4.
Adaptive Two-Stage Clinical Trials
Michael A. Proschan

5.
Design and Analysis of Cluster Randomization Trials
David M. Zucker

Copyright n 2004 by Marcel Dekker, Inc. All Rights Reserved.

6.
Design and Analysis of Clinical Trials with Multiple
Endpoints
Nancy L. Geller

7.
Subgroups and Interactions
Dean Follmann

8.
A Class of Permutation Tests for Some Two-Sample
Survival Data Problems
Joanna H. Shih and Michael P. Fay

9.
Bayesian Reporting of Clinical Trials
Simon Weeden, Laurence S. Freedman, and Mahesh
Parmar

Part III
MORE COMPLEX PROBLEMS

10.
Methods Incorporating Compliance in Treatment
Evaluation
Juni Palmgren and Els Goetghebeur

11.
Analysis of Longitudinal Data with Missingness
Paul S. Albert and Margaret C. Wu

12.
Statistical Issues Emerging from Clinical Trials in HIV
Infection
Abdel G. Babiker and Ann Sarah Walker

Index of Abbreviations
Index of Clinical Trials Used as Examples
Subject Index

Contents
viii

Copyright n 2004 by Marcel Dekker, Inc. All Rights Reserved.

Contributors

Paul S. Albert, Ph.D.
Mathematical Statistician, Biometrics Research
Branch, Division of Cancer Treatment and Diagnosis, National Cancer
Institute, National Institutes of Health, Bethesda, Maryland, U.S.A.

James S. Babb, Ph.D.
Department of Biostatistics, Fox Chase Cancer
Center, Philadelphia, Pennsylvania, U.S.A.

Abdel G. Babiker, Ph.D.
Head, Division of HIV and Infections, and
Professor of Medical Statistics and Epidemiology, Medical Research
Council Clinical Trials Unit, London, England

Shelly L. Carter, Sc.D.
Senior Biostatistician, The Emmes Corporation,
Rockville, Maryland, U.S.A.

Michael P. Fay, Ph.D.
Mathematical Statistician, Statistical Research
and Applications, National Cancer Institute, National Institutes of
Health, Bethesda, Maryland, U.S.A.

Dean Follmann, Ph.D.
Chief, Biostatistics Research Branch, National
Institute of Allergy and Infectious Diseases, National Institutes of Health,
Bethesda, Maryland, U.S.A.

Copyright n 2004 by Marcel Dekker, Inc. All Rights Reserved.