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									                             Textbook of Clinical Trials

Textbook of Clinical Trials. Edited by D. Machin, S. Day and S. Green
 2004 John Wiley & Sons, Ltd ISBN: 0-471-98787-5
   Textbook of Clinical Trials

                               Edited by

                          David Machin
         Division of Clinical Trials and Epidemiological Sciences,
National Cancer Centre, Singapore and UK Children’s Cancer Study Group,
                        University of Leicester, UK.

                            Simon Day
         Medicines and Healthcare products Regulatory Agency,
                             London, UK

                           Sylvan Green
              Arizona Cancer Centre, Tucson, Arizona, USA

                             Section Editors

                           Brian Everitt
                   Institute of Psychiatry, London, UK

                         Stephen George
              Department of Biostatistics and Informatics,
           Duke University Medical Centre, Durham, NC, USA
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Library of Congress Cataloging-in-Publication Data

Textbook of clinical trials / edited by David Machin ... [et al.].
     p. cm.
  Includes bibliographical references and index.
  ISBN 0-471-98787-5 (alk. paper)
   1. Clinical trials. I. Machin, David.

 R853.C55T49 2004
 610 .72 4–dc22

British Library Cataloguing in Publication Data

A catalogue record for this book is available from the British Library

ISBN 0-471-98787-5

Typeset in 10/12pt Times by Laserwords Private Limited, Chennai, India
Printed and bound in Great Britain by Antony Rowe Ltd, Chippenham, Wiltshire
This book is printed on acid-free paper responsibly manufactured from sustainable forestry
in which at least two trees are planted for each one used for paper production.

Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .      vii

Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .    xi

INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .                 1
 1 Brief History of Clinical Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .                   3
   S. Day and F. Ederer
 2 General Issues . . . . . . . . . . . . . . . . . . . .         ..............................                              11
   David Machin
 3 Clinical Trials in Paediatrics . . . . . . . . .               ..............................                              45
   Johan P.E. Karlberg
 4 Clinical Trials Involving Older People . .                     ..............................                              55
   Carol Jagger and Antony J. Arthur
 5 Complementary Medicine . . . . . . . . . . .                   ..............................                              63
   P.C. Leung

CANCER                                                                                                                        85
 6 Breast Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .          87
   Donald A. Berry, Terry L. Smith and Aman U. Buzdar
 7 Childhood Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .             101
   Sharon B. Murphy and Jonathan J. Shuster
 8 Gastrointestinal Cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .               117
   Dan Sargent, Rich Goldberg and Paul Limburg
 9 Haematologic Cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .               141
   Charles A. Schiffer and Stephen L. George
vi                                                       CONTENTS

10 Melanoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149
     P.-Y. Liu and Vernon K. Sondak
11 Respiratory Cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
     Kyungmann Kim

CARDIOVASCULAR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173
12 Cardiovascular . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175
     Lawrence Friedman and Eleanor Schron

DENTISTRY AND MAXILLO-FACIAL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191
13 Dentistry and Maxillo-facial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193
     May C.M. Wong, Colman McGrath and Edward C.M. Lo

DERMATOLOGY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209
14 Dermatology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211
     Luigi Naldi and Cosetta Minelli

PSYCHIATRY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233
15 Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235
     B.S. Everitt
16 Alzheimer’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243
     Leon J. Thal and Ronald G. Thomas
17 Anxiety Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255
   M. Katherine Shear and Philip W. Lavori
18 Cognitive Behaviour . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .          273
   Nicholas Tarrier and Til Wykes
19 Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   297
   Graham Dunn

REPRODUCTIVE HEALTH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313
20 Contraception . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315
     Gilda Piaggio
21 Gynaecology and Infertility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 337
     Siladitya Bhattacharya and Jill Mollison

RESPIRATORY                                                                                                               357
22 Respiratory                                                                                                            359
             a e
     Anders K¨ ll´ n

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 401

TONY ARTHUR        School of Nursing, Faculty of Medicine and Health Sciences,
                   University of Nottingham, Queens Medical Centre,
                   Nottingham NG7 2UH, UK, Email:

DONALD BERRY       Department of Biostatistics, UTMD Anderson Cancer Centre,
                   1400 Holcombe Blvd, Box 447, Houston, TX 77030, USA,
                   Email: dberry@odin.mdacc.tmc.edu

S. BHATTACHARYA    Department of Obstetrics and Gynaecology, Aberdeen
                   Maternity Hospital, Cronhill Road, Aberdeen AB25 2ZD, UK,
                   Email: s.bhattacharya@abdn.ac.uk

ARMAN BUZDAR       Department of Breast Medical Oncology, The University of
                   Texas, M.D. Anderson Cancer Centre, Texas, USA

SIMON DAY          Licensing Division, Medicines and Healthcare products
                   Regulatory Agency, Room 13-205 Market Towers, 1 Nine
                   Elms Lane, London SW8 5NQ, UK,
                   Email: simon.day@mhra.gsi.gov.uk

GRAHAM DUNN        Biostatistics Group, School of Epidemiology and Health
                   Sciences, Stopford Building, Oxford Road, Manchester M13
                   9PT, UK, Email: graham.dunn@man.ac.uk,

FRED EDERER        The EMMES Corporation, 401 North Washington Street, Suite
                   700, Rockville, MD 20850, USA, Email: federer@emmes.com
viii                CONTRIBUTORS

BRIAN EVERITT    Box 20, Biostatistics Department, Institute of Psychiatry,
                 Denmark Hill, London SE5 8AF, UK, Email:

LARRY FRIEDMAN   National Heart, Lung, and Blood Institute, Building 31, Room
                 5A03, Bethesda, MD 20892 2482, USA, Email:

STEPHEN GEORGE   Department of Biostatistics and Bioinformatics, Duke
                 University Medical Centre, Durham, NC 27710, USA, Email:

RICH GOLDBERG    Medical Oncology, Mayo Clinic, 200 1st Street SW,
                 Rochester, MN 55905, USA, Email:

SYLVAN GREEN     Arizona Cancer Centre, 1515 N Campbell Ave, PO Box
                 245024, Tucson, AZ 85724, USA, Email:

CAROL JAGGER     Trent Institute for HSR, Department of Epidemiology and
                 Public Health, University of Leicester, 22–28 Princess Road
                 West, Leicester LE1 6TP, UK, Email: cxj@leicester.ac.uk

        ¨  ´
ANDERS KALLEN    AstraZeneca R&D, Lund, Sweden, Email:

JOHAN KARLBERG   Clinical Trials Centre, Faculty of Medicine, The University of
                 Hong Kong, Hong Kong SAR, PR China, Email:

KYUNGMANN KIM    Department of Biostatistics & Medical Informatics, University
                 of Wisconsin, 600 Highland Avenue, Box 4675, Madison, WI
                 53792, USA, Email: kmkim@biostat.wisc.edu

PHILIP LAVORI    VACSPCC (151K), 795 Willow Road, Menlo Park, CA 94025
                 2539, USA, Email: Philip.Lavori@med.va.gov

P.C. LEUNG       Department of Orthopaedics & Traumatology, The Chinese
                 University of Hong Kong, Room 74026, 5th Floor, Clinical
                 Sciences Building, Prince of Wales Hospital, Shatin, Hong
                 Kong, Email: pingcleung@cuhk.edu.hk

PAUL LIMBURG     Gastroenterology and Hepatology, Mayo Clinic, 200 1st Street
                 SW, Rochester, MN 55905, USA, Email:
                      CONTRIBUTORS                                               ix

P.Y. LIU           SWOG Statistical Centre, MP 557, Fred Hutchinson Cancer
                   Research Centre, 1100 Fairview Avenue North, PO Box
                   19024, Seattle, WA 98109 1024, USA, Email:

EDWARD LO          Dental Public Health, Faculty of Dentistry, The University of
                   Hong Kong, 34 Hospital Road, Hong Kong, Email:

DAVID MACHIN       Division of Clinical Trials and Epidemiological Sciences,
                   National Cancer Centre Singapore, 11 Hospital Drive,
                   Singapore 169610, Singapore, Email: ctedav@nccs.com.sg,

COLAMN MCGRATH     Dental Public Health, Faculty of Dentistry, The University of
                   Hong Kong, 34 Hospital Road, Hong Kong, Email:

COSETTA MINELLI    Medical Statistics Group, Department of Epidemiology and
                   Public Health, University of Leicester, 22–28 Princess Road
                   West, Leicester LE1 6TP, UK, Email: cm109@le.ac.uk

JILL MOLLISON      Department of Public Health, University of Aberdeen,
                   Polwarth Building, Foresterhill, Aberdeen AB25 2ZD, UK,
                   Email: j.mollison@abdn.ac.uk

SHARON B. MURPHY   Children’s Cancer Research Institute, The University of Texas
                   Health Science Centre at San Antonio, 7703 Floyd Curl Drive,
                   MC 7784, San Antonio, TX 78229-3900, USA, Email:

LUIGI NALDI        Clinica Dermatologica, Ospedali Riuniti, L.go Barozzi 1,
                   24100 Bergamo, Italy, Email: luiginal@tin.it

GILDA PIAGGIO      Special Programme of Research, Development and Research
                   Training in Human Reproduction, Department of Reproductive
                   Health and Research, World Health Organisation, 1211
                   Geneva 27, Switzerland, Email: piaggiog@who.int

DANIEL SARGENT     Mayo Clinic, 200 First Street, SW, Kahler 1A, Rochester, MN
                   55905, USA, Email: sargent.daniel@mayo.edu

CHARLES SCHIFFER   Division of Oncology and Hematology/Oncology, Karmanos
                   Cancer Institute, Wayne State University School of Medicine,
                   Detroit, MI 48201, USA.

ELEANOR SCHRON     National Heart, Lung, and Blood Institute, Bethesda, MD
                   20892 2482, USA, Email: schrone@nhlbi.nih.edu
x                     CONTRIBUTORS

KATHERINE SHEAR    Panic Anxiety and Traumatic Grief Program, Western
                   Psychiatric Institute and Clinic, 3811 O’Hara Street,
                   Pittsburgh, PA 15213, USA, Email: shearmk@msx.upmc.edu,

JON SHUSTER        PO Box 100212, College of Medicine, University of Florida,
                   Gainesville, FL 32610 0212, USA, Email:

TERRY SMITH        UTMD Anderson Cancer Centre, 1400 Holcombe Blvd, Box
                   447, Houston, TX 77030, USA, Email:

VERNON K. SONDAK   University of Michigan Medical Centre, Division of Surgical
                   Oncology, 1500 E Medical Centre Drive, 3306
                   Cancer/Geriatrics Ctr Box 0932, Ann Arbor, MI 48109 0932,
                   USA, Email: vsondak@umich.edu

NICHOLAS TARRIER   University of Manchester, Academic Division of Clinical
                   Psychology Education & Research Building, Wythenshawe
                   Hospital, Southmoor Road, Manchester M23 9LT, UK, Email:

LEON THAL          Department of Neurosciences, University of California, San
                   Diego, 9500 Gilman Drive, San Diego, CA 92037, USA,
                   Email: lthal@ucsd.edu

RONALD THOMAS      Department of Family and Preventative Medicine, and
                   Neurosciences, UCSD 9500 Gilman Drive, La Jolla, CA
                   92039 0645, USA, Email: rgthomas@ucsd.edu

MAY C.M. WONG      Dental Public Health, Faculty of Dentistry, The University of
                   Hong Kong, 34 Hospital Road, Hong Kong, Email:

TIL WYKES          Department of Psychiatry, De Crespigny Park, London SE5
                   8AF, UK, Email: t.wykes@iop.kcl.ac.uk

This Textbook of Clinical Trials is not a textbook        needed from the concept stage, through design,
of clinical trials in the traditional sense. Rather, it   conduct, monitoring and reporting.
catalogues in part both the impact of clinical tri-          Some of the developments impacting on clini-
als – particularly the randomised controlled trial        cal trials have been truly statistical in nature, for
–on the practice of medicine and allied fields             example Cox’s proportional hazards model, while
and on the developments and practice of medical           others such as the intention-to-treat (ITT) princi-
statistics. The latter has evolved in many ways           ple are – in some sense – based more on expe-
through the direct needs of clinical trials and the       rience. Other important statistical developments
consequent interaction of statistical and clinical        have not depended on technical advancement,
disciplines. The impact of the results from clin-         but rather on conceptual advancement, such as
ical trials, particularly the randomised controlled       the now standard practice of reporting confidence
trial, on the practice of clinical medicine and           intervals rather then relying solely on p-values
                                                          at the interpretation stage. Of major importance
other areas of health care has been profound. In
                                                          over this same time period has been the expansion
particular, they have provided the essential under-
                                                          in data processing capabilities and the range of
pinning to evidence-based practice in many disci-
                                                          analytical possibilities only made possible by the
plines and are one of the key components for reg-
                                                          tremendous development in computing power.
ulatory approval of new therapeutic approaches            However, despite many advances, the majority
throughout the world.                                     of randomised controlled trials remain simple in
   Probably the single most important contribu-           design – most often a comparison between two
tion to the science of comparative clinical trials        randomised groups.
was the recognition, more than 50 years ago, that            On the medical side there have been many
patients should be allocated to the options under         changes including new diseases that raise
consideration at random. This was the founda-             new issues. Thus, as we write, SARS has
tion for the science of clinical trial research and       emerged: the final extent of the epidemic
placed the medical statistician at the centre of the      is unknown, diagnosis is problematical and
process. Although the medical statistician may be         no specific treatment is available. In more
at the centre, he or she is by no means alone.            established diseases there have been major
Indeed the very nature of clinical trial research is      advances in the types of treatment available, be
multidisciplinary so that a ‘team’ effort is always       they in surgical technique, cancer chemotherapy
xii                                             PREFACE

or psychotropic drugs. Advances in medical           the outcome cosmetic then a more conservative
and associated technologies are not confined          approach to treatment options would be justified.
to curative treatments but extend, for example,         In all this activity the choice of clinical trial
to diagnostic methods useful in screening for        design and its ultimate conduct are governed
disease, vaccines for disease prevention, drugs      by essential ethical constraints, the willingness
and devices for female and male contraception,       of subjects to consent to the trial in question
and pain relief and psychological support            and their right to withdraw from the trial should
strategies in palliative care.                       they wish.
   Clinical trials imply some intervention affect-      Thus the Textbook of Clinical Trials addresses
ing the subjects who are ultimately recruited into   some of these and many other issues as they
them. These subjects will range from the very        impact on patients with cancer, cardiovascular
healthy, perhaps women of a relatively young age     disease, dermatological, dental, mental and oph-
recruited to a contraceptive development trial,      thalmic health, gynaecology and respiratory dis-
to those (perhaps elderly) patients in terminal      eases. In addition, chapters deal with issues relat-
decline from a long-standing illness. Each group     ing to complementary medicine, contraception
studied in a clinical trial, from unborn child to    and special issues in children and special issues
aged adult, brings its own constraint on the ulti-   in older patients. A brief history of clinical tri-
mate design of the trial in mind. So too does the    als and a summary of some pertinent statistical
relative efficacy of the current standard. If the     issues are included.
outcome is death and the prognosis poor, then
bolder steps may be taken in the choice of treat-
ments to test. If the disease is self-limiting or         David Machin, Simon Day and Sylvan Green

Textbook of Clinical Trials. Edited by D. Machin, S. Day and S. Green
 2004 John Wiley & Sons, Ltd ISBN: 0-471-98787-5
                      Brief History of Clinical Trials
                                               S. DAY1 AND F. EDERER2
                  Licensing Division, Medicines and Healthcare products Regulatory Agency, London, UK
                                   The EMMES Corporation, Rockville, MD 20850, USA

The modern-day birth of clinical trials is usually                      Daniel lived around the period 800BC and although
considered to be the publication in 1948 by                             it may not be possible to confirm the accuracy
the UK Medical Research Council1 of a trial                             of the account, what is clear is that when this
for the treatment of pulmonary tuberculosis with                        passage was written–around 150BC –the ideas
streptomycin. However, earlier but less well                            certainly existed.
documented examples do exist. The comparative                              The passage from Daniel describes not just a
concept of assessing therapeutic efficacy has                            control group, but a concurrent control group.
been known from ancient times. Slotki2 cites a                          This fundamental element of clinical research did
description of a nutritional experiment involving                       not begin to be widely practised until the latter
a control group in the Book of Daniel from the                          half of the twentieth century.
Old Testament:                                                             Much later than the book of Daniel, but still
                                                                        very early, is an example from the fourteenth
   Then Daniel said to the guard whom the master                        century: it is a letter from Petrarch to Boccaceto
   of the eunuchs had put in charge of Hananiah,                        cited by Witkosky:3
   Mishael, Azariah and himself, ‘Submit to us this
   test for ten days. Give us only vegetables to eat                      I solemnly affirm and believe, if a hundred
   and water to drink; then compare our looks with                        or a thousand of men of the same age, same
   those of the young men who have lived on the                           temperament and habits, together with the same
   food assigned by the king, and be guided in your                       surroundings, were attacked at the same time by the
   treatment of us by what you see.’ The guard listened                   same disease, that if one followed the prescriptions
   to what they said and tested them for ten days. At                     of the doctors of the variety of those practicing at
   the end of ten days they looked healthier and were                     the present day, and that the other half took no
   better nourished than all the young men who had                        medicine but relied on Nature’s instincts, I have no
   lived on the food assigned them by the king. So                        doubt as to which half would escape.
   the guard took away the assignment of food and
   the wine they were to drink, and gave them only                      The Renaissance period (fourteenth to sixteenth
   the vegetables.                                                      centuries) provides other examples including an

Textbook of Clinical Trials. Edited by D. Machin, S. Day and S. Green
 2004 John Wiley & Sons, Ltd ISBN: 0-471-98787-5
4                                        TEXTBOOK OF CLINICAL TRIALS

unplanned experiment in the treatment of battle-             operated, by way of gentle physic. Two others had
field wounds. Packard4 describes how the surgeon              each two oranges and one lemon given them every
Ambroise Par´ was using the standard treatment
                e                                            day. These they eat with greediness, at different
of pouring boiled oil over soldiers’ wounds dur-             times, upon an empty stomach. They continued but
ing a battle to capture the castle of Villaine in 1537.      six days under this course, having consumed the
                                                             quantity that could be spared. The two remaining
When he ran out of oil, he resorted to a mixture of
                                                             patients, took the bigness of a nutmeg three times
egg yolks, oil of roses and turpentine. The supe-            a day of an electuary recommended by a hospital-
riority of the new ‘treatment’ became evident the            surgeon, made of garlic, mustard-feed, rad. raphan,
next day:                                                    balsam of Peru, and gum myrrh; using for common
                                                             drink barley-water well acidulated with tamarinds;
    I raised myself very early to visit them, when
                                                             by a decoction of which, with the addition of
    beyond my hope I found those to whom I applied
                                                             cremor tartar, they were greatly purged three or
    the digestive medicament feeling but little pain,
                                                             four times during the course.
    their wounds neither swollen nor inflamed, and
                                                                The consequence was, that the most sudden and
    having slept through the night. The others to whom
                                                             visible good effects were perceived from the use
    I had applied the boiling oil were feverish with
                                                             of the oranges and lemons; one of those who had
    much pain and swelling about their wounds. Then
                                                             taken them, being at the end of six days fit for
    I determined never again to burn thus so cruelly by
                                                             duty. The spots were not indeed at that time quite
                                                             off his body, or his gums sound; without any other
   Perhaps the most famous historical example of             medicine, than a gargle of elixir vitriol, he became
                                                             quite healthy before we came into Plymouth, which
a planned controlled, comparative, clinical trial
                                                             was on the 16th June. The other was the best
is from the eighteenth century: that where Lind5
                                                             recovered of any in his condition; and being now
found oranges and lemons to be the most effective            deemed pretty well, was appointed nurse, to the rest
of six dietary treatments for scurvy on board ships.         of the sick.
He wrote:
                                                           Pierre-Charles-Alexandre Louis, a nineteenth-
    On the 20th of May, 1747, I took twelve patients
    in the scurvy, on board the Salisbury at sea. Their
                                                           century clinician and pathologist, introduced the
    cases were as similar as I could have them. They all   numerical aspect to comparing treatments.6 His
    in general had putrid gums, the spots and lassitude,   idea was to compare the results of treatments on
    with weakness of their knees. They lay together        groups of patients with similar degrees of disease,
    in one place, being a proper apartment for the         i.e. to compare ‘like with like’:
    sick in the fore-hold; and had one diet common
    to all, viz. water-gruel sweetened with sugar in         I come now to therapeutics, and suppose that you
    the morning; fresh mutton-broth often times for          have some doubt as to the efficacy of a particular
    dinner; at other times puddings, boiled biscuit with     remedy: How are you to proceed?. . .You would
    sugar etc. And for supper, barley and raisins, rice      take as many cases as possible, of as similar a
    and currants, sago and wine, or the like. Two of         description as you could find, and would count
    these were ordered each a quart of cyder a day.          how many recovered under one mode of treatment,
    Two others took twenty-five gutts of elixir vitriol       and how many under another; in how short a time
    three times a day, upon an empty stomach; using a        they did so, and if the cases were in all respects
    gargle strongly acidulated with it for their mouths.     alike, except in the treatment, you would have some
    Two others took two spoonfuls of vinegar three           confidence in your conclusions; and if you were
    times a day, upon an empty stomach; having their         fortunate enough to have a sufficient number of
    gruels and their other food well acidulated with it,     facts from which to deduce any general law, it
    as also the gargle for their mouths. Two of the          would lead to your employment in practice of the
    worst patients, with the tendons in the ham rigid        method which you had seen oftenest successful.
    (a symptom none of the rest had) were put under
    a course of sea-water. Of this they drank half a       ‘Like with like’ was an important step forward
    pint every day, and sometimes more or less as it       from Lind’s treatment of scurvy. Note, although
                                         BRIEF HISTORY OF CLINICAL TRIALS                                             5

early in Lind’s passage he says that: ‘Their cases               At the beginning of each year. . . students were
were as similar as I could have them’, later                     assigned at random. . . to a control group or an
he acknowledges that the two worst cases both                    experimental group. The students in the control
received the same treatment: ‘Two of the worst                   groups. . . received placebos. . . All students thought
                                                                 they were receiving vaccines. . . Even the physi-
patients, with the tendons in the ham rigid (a
                                                                 cians who saw the students. . . had no information
symptom none of the rest had) were put under
                                                                 as to which group they represented.
a course of sea-water’. It remained for Bradford
Hill, more than a century later, to use a formal
method for creating groups of cases that were ‘in             However Gail14 points out that although this
all respects alike, except in the treatment’.                 appears to be a randomised clinical trial, a further
                                                              unpublished report by Diehl clarifies that this is
                                                              another instance of systematic assignment:
                                                                 At the beginning of the study, students who
The use of randomisation was a contribution by                   volunteered to take these treatments were assigned
the statistician R.A. Fisher in agriculture (see, for            alternately and without selection to control groups
example, Fisher,7 Fisher and McKenzie8 ). Fisher                 and experimental groups.
randomised plots of crops to receive different
treatments and in clinical trials there were early            Bradford Hill, in the study of streptomycin in
schemes to use ‘group randomisation’: patients                pulmonary tuberculosis,1 used random sampling
were divided into two groups and then the                     numbers in assigning treatments to subjects, so
treatment for each group was randomly selected.               that the subject was the unit of randomisation. This
The Belgian medicinal chemist van Helmont9                    study is now generally acknowledged to be the
described an early example of this:                           ‘first properly randomised clinical trial’.
                                                                 Later Bradford Hill and the British Medical
   Let us take out of the hospitals, out of the Camps,
                                                              Research Council continued with further ran-
   or from elsewhere, 200, or 500 poor People that
   have Fevers, Pleurisies, &c, Let us divide them into       domised trials: chemotherapy of pulmonary tuber-
   halfes, let us cast lots, that one half of them may        culosis in young adults,15 antihistaminic drugs
   fall to my share, and the others to yours,. . . we shall   in the prevention and treatment of the common
   see how many funerals both of us shall have: But           cold,16 cortisone and aspirin in the treatment
   let the reward of the contention or wager, be 300          of early cases of rheumatoid arthritis17,18 and
   florens, deposited on both sides.                           long-term anticoagulant therapy in cerebrovascu-
                                                              lar disease.19
Amberson and McMahon10 used group randomi-                       In America, the National Institutes of Health
sation in a trial of sanocrysin for the treatment             started its first randomised trial in 1951. It was
of pulmonary tuberculosis. Systematic assign-                 a National Heart Institute study of adrenocorti-
ment was used by Fibiger,11 who alternately                   cotropic hormone (ACTH), cortisone and aspirin
assigned diphtheria patients to serum treatment               in the treatment of rheumatic heart disease.20 This
or an untreated control group. Alternate assign-              was followed in 1954 by a randomised trial of
ment is frowned upon today because knowledge                  retrolental fibroplasia (now known as retinopathy
of the future treatment allocations may selectively           of prematurity), sponsored by the National Insti-
bias the admission of patients into the treatment             tute of Neurological Diseases and Blindness.21
group.12 Diehl et al.13 reported a common cold                During the four decades following the pioneer-
vaccine study with University of Minnesota stu-               ing trials of the 1940s and 1950s, there was a
dents as subjects where blinding and random                   large growth in the number of randomised trials
assignment of patients to treatments appears to               not only in Britain and the US, but also in Canada
have been used:                                               and mainland Europe.
6                                            TEXTBOOK OF CLINICAL TRIALS

                       BLINDING                                                        ETHICS

The common cold vaccine study published by                       Experimentation in medicine is as old as medicine
Diehl et al.,13 cited earlier, in which University               itself. Some experiments on humans have been
of Minnesota students were alternately assigned                  conducted without concern for the welfare of
to vaccine or placebo, was a masked (or blinded)                 the subjects, who have often been prisoners or
clinical trial:                                                  disadvantaged people. Katz23 provides examples
                                                                 of nineteenth-century studies in Russia and Ire-
                                                                 land of the consequences of infecting people with
    All students thought they were receiving vaccines. . .
                                                                 syphilis and gonorrhoea. McNeill24 describes
    Even the physicians who saw the students. . . had no
    information as to which group they represented.              how during the same period in the US, physicians
                                                                 put slaves into pit ovens to study heat stroke, and
                                                                 poured scalding water over them as an experi-
Blinding was used in the early Medical Research                  mental cure for typhoid fever. He even describes
Council trials in which Bradford Hill was involved.              how one slave had two fingers amputated in a
Thus, in the first of those trials, the study of strep-           ‘controlled trial’, one finger with anaesthesia and
tomycin in tuberculosis,1 the X-ray films were                    one without!
viewed by two radiologists and a clinician, each                    Unethical experiments on human beings have
reading the films independently and not knowing                   continued into the twentieth century and have
if the films were of C (control, bed-rest alone) or               been described by, for example, Beecher,25
S (streptomycin and bed-rest) cases.                             Freedman26 and McNeil.24 In 1932 the US Pub-
   Bradford Hill22 (Reproduced with permission)                  lic Health Service began a study in Tuskegee,
noted in respect of using such blinding and                      Alabama, of the natural progression of untreated
randomisation:                                                   syphilis in 400 black men. The study continued
                                                                 until 1972, when a newspaper reported that the
    If [the clinical assessment of the patient’s progress        subjects were uninformed or misinformed about
    and of the severity of the illness] is to be used            the purpose of the study.26 Shirer,27 amongst oth-
    effectively, without fear and without reproach, the          ers, describes how during the Nazi regime from
    judgements must be made without any possibility
                                                                 1933 to 1945, German doctors conducted exper-
    of bias, without any overcompensation for any
    possible bias, and without any possible accusation
                                                                 iments, mainly on Jews, but also on Gypsies,
    of bias.                                                     mentally disabled persons, Russian prisoners of
                                                                 war and Polish concentration camp inmates. The
                                                                 Nazi doctors were later tried for their atrocities in
Not simply overcoming bias, but overcoming
                                                                 1946–1947 at Nuremberg and this led to the writ-
any possible accusation of bias is an important
                                                                 ing, by three of the trial judges, of the Nuremberg
justification for blinding and randomisation.
                                                                 Code, the first international effort to lay down
   In the second MRC trial, the antihistamine
                                                                 ethical principles of clinical research.28 Principle
common cold study,16 placebos, indistinguishable
                                                                 1 of the Nuremberg Code states:
from the drug under test, were used. Here,
Bradford Hill noted:                                                The voluntary consent of the human subject is
                                                                    absolutely essential. This means that the person
    . . . in [this] trial. . . feelings may well run high. . .      involved should have legal capacity to give consent;
    either of the recipient of the drug or the clinical             should be so situated as to be able to exercise
    observer, or indeed of both. If either were allowed             free power of choice, without the intervention of
    to know the treatment that had been given, I believe            any element of force, fraud, deceit, duress, over-
    that few of us would without qualms accept that                 reaching, or other ulterior form of constraint or
    the drug was of value–if such a result came out of              coercion; and should have sufficient knowledge and
    the trial.                                                      comprehension of the elements of the subject matter
                                   BRIEF HISTORY OF CLINICAL TRIALS                                          7

  involved as to enable him to make an understanding   committee. In 1968 the first such committee was
  and enlightened decision.                            established, serving the Coronary Drug Project,
                                                       a large multicentre trial sponsored in the United
Other principles of the Code are that experiments      States by the National Heart Institute of the
should yield results for the good of society,          National Institutes of Health.35,36 In 1967, after a
that unnecessary suffering and injury should be        presentation of interim outcome data by the study
avoided, and that the subject should be free to        co-ordinators to all participating investigators of
withdraw from the experiment at any time and           the Coronary Drug Project, Thomas Chalmers
for any reason.                                        addressed a letter to the policy board chairman
   Other early advocates of informed consent           expressing concern:
were Charles Francis Withington and William
Osler. Withington29 realised, the ‘possible con-          that knowledge by the investigators of early nonsta-
flict between the interests of medical science and         tistically significant trends in mortality, morbidity,
those of the individual patient’, and concluded           or incidence of side effects might result in some
in favour of ‘the latter’s indefensible rights’.          investigators–desirous of treating their patients in
Osler30 insisted on informed consent in medi-             the best possible manner, i.e., with the drug that
                                                          is ahead–pulling out of the study or unblinding
cal experiments. Despite this early advocacy, and
                                                          the treatment groups prematurely. (Canner35 , repro-
the 1946–1947 Nuremberg Code, the application             duced with permission from Elsevier)
of informed consent to medical experiments did
not take hold until the 1960s. Hill,31 based on        Following this, a data and safety monitoring com-
his experience in a number of early randomised         mittee was established for the Coronary Drug
clinical trials sponsored by the Medical Research      Project. It consisted of scientists who were not con-
Council, believed that it was not feasible to draw     tributing data to the study, and thereafter the prac-
up a detailed code of ethics for clinical trials       tice of sharing accumulating outcome data with the
that would cover the variety of ethical issues that    study’s investigators was discontinued. The data
came up in these studies, and that the patient’s       safety and monitoring committee assumed respon-
consent was not warranted in all clinical tri-         sibility for deciding when the accumulating data
als. Gradually the medical community came to           warranted changing the study protocol or termi-
recognise the need to protect the reputation and       nating the study.
integrity of medical research and in 1955 a human         The first formal recognition of the need for
experimentation code was adopted by the Pub-           interim analyses, and the recognition that such
lic Health Council in the Netherlands.32 Later,        analyses affect the probability of the type I
in 1964, the World Medical Assembly issued the         error, came with the publication in the 1950s
Declaration of Helsinki33 essentially adopting the     of papers on sequential clinical trials by Bross37
ethical principles of the Nuremberg Code, with         and Armitage.38 The principal advantage of a
consent being ‘a central requirement of ethical        sequential trial over a fixed sample size trial, is
research’.34 The Declaration of Helsinki has been      that when the length of time needed to reach an
updated and amended several times: Tokyo, 1975;        endpoint is short, e.g. weeks or months, the sample
Venice, 1983; Hong Kong, 1989; Cape Town,              size required to detect a substantial benefit from
1996; and Edinburgh, 2000.                             one of the treatments is less.
                                                          In the 1970s and 1980s solutions to interim anal-
                                                       ysis problems came about in the form of group se-
             DATA MONITORING                           quential methods and stochastic curtailment.39 – 41
                                                       In the group sequential trial, the frequency of
In the modern randomised clinical trial, the accu-     interim analyses is usually limited to a small
mulating data are usually monitored for safety         number, say between three and six. The Pocock
and efficacy by an independent data monitoring          boundaries42 use constant nominal significance
8                                         TEXTBOOK OF CLINICAL TRIALS

levels; the Haybittle–Peto boundary43,44 uses               4. Packard FR. The Life and Times of Ambroise Par´ ,e
stringent significance levels for all except the final           2nd edn. New York: Paul B. Hoeber (1921)
test; in the O’Brien–Fleming method,45 stringency           5. Lind J. A Treatise of the Scurvy. Edinburgh: Sands
gradually decreases; in the method by Lan and                  Murray Cochran (1753) 191–3.
DeMets,46 the total type I error probability is grad-       6. Louis PCA. The applicability of statistics to the
ually spent in a manner that does not require the              practice of medicine. London Med Gazette (1837)
timing of analyses to be prespecified. More details             20: 488–91.
                                                            7. Fisher RA. The arrangement of field experiments.
of these newer methods in the development of clin-             J Min Agric (1926) 33: 503–13.
ical trials are given in the next chapter.                  8. Fisher RA, McKenzie WA. Studies in crop varia-
   Recent years have seen a huge increase in the               tion: II. The manurial response of different potato
numbers of trials carried out and published, and               varieties. J Agric Sci (1923) 13: 315.
in the advancement of methodological aspects                9. van Helmont JB. Oriatrike or Physik Refined
                                                               (translated by J. Chandler). London: Lodowick
relating to trials. Whilst many see the birth                  Loyd (1662).
of clinical trials (certainly in their modern-day          10. Amberson B, McMahon PM. A clinical trial of
guise) as being the Medical Research Council                   sanocrysin in pulmonary tuberculosis. Am Rev
streptomycin trial,1 there remains some contro-                Tuberc (1931) 24: 401.
versy (see, for example, D’Arcy Hart,47,48 Gill,49         11. Fibiger I. Om Serum Behandlung of Difteri.
                                                               Hospitalstidende (1898) 6: 309–25, 337–50.
and Clarke50 ). However, it is interesting to note         12. Altman DG, Bland JM. Treatment allocation in
that one of the most substantial reviews of histor-            controlled trials: why randomise? Br Med J (1999)
ical aspects of trials is based on work for a 1951             318: 1209.
M.D. thesis.51 Bull cites 135 historical examples          13. Diehl HS, Baker AB, Cowan DW. Cold vaccines:
and other supporting references–but no mention                 an evaluation based on a controlled study. J Am
                                                               Med Assoc (1938) 111: 1168–73.
of Bradford Hill and the Medical Research Coun-            14. Gail MH. Statistics in action. J Am Stat Assoc
cil. The modern-day story of clinical trials per-              (1996) 91: 1–13.
haps begins where Bull ended.                              15. Medical Research Council. Chemotherapy of pul-
                                                               monary tuberculosis in young adults. Br Med J
                                                               (1952) i: 1162–8.
               ACKNOWLEDGEMENTS                            16. Medical Research Council. Clinical trials of anti-
                                                               histaminic drugs in the prevention and treatment
This chapter is based heavily on work by                       of the common cold. Br Med J (1950) ii:
F. Ederer in: Armitage P, Colton T, eds, Ency-             17. Medical Research Council. A comparison of
clopedia of Biostatistics. Chichester: John Wiley              cortisone and aspirin in the treatment of early
& Sons (1998).                                                 cases of rheumatoid arthritis – I. Br Med J (1954)
                                                               i: 1223–7.
                                                           18. Medical Research Council. A comparison of
                     REFERENCES                                cortisone and aspirin in the treatment of early
                                                               cases of rheumatoid arthritis – II. Br Med J (1955)
                                                               ii: 695–700.
    1. Medical Research Council. Streptomycin treat-       19. Hill AB, Marshall J, Shaw DA. A controlled clin-
       ment of pulmonary tuberculosis. Br Med J (1948)         ical trial of long-term anticoagulant therapy in
       2: 769–82.                                              cerebrovascular disease. Q J Med (1960) 29(NS):
    2. Slotki JJ. Daniel, Ezra, Nehemiah, Hebrew Text          597–608.
       and English Translation with Introductions and      20. Rheumatic Fever Working Party. The evolution
       Commentary Soncino Press: London (1951) 1–6.            of rheumatic heart disease in children: five-year
    3. Witkosky SJ. The Evil That Has Been Said of             report of a co-operative clinical trial of ACTH,
       Doctors: Extracts From Early Writers (translated        cortisone, and aspirin. Circulation (1960) 22:
       with annotations by T.C. Minor). The Cincinnati         505–15.
       Lancet-Clinic, Vol. 41, New Series Vol. 22 (1889)   21. Kinsey VE. Retrolental fibroplasia. AMA Arch
       447–8.                                                  Ophthalmol (1956) 56: 481–543.
                                     BRIEF HISTORY OF CLINICAL TRIALS                                           9

22. Hill AB. Statistical Methods in Clinical and         36. Friedman L. The NHLBI model: a 25-year history.
    Preventative Medicine. Edinburgh: Livingstone            Stat Med (1993) 12: 425–31.
    (1962).                                              37. Bross I. Sequential medical plans. Biometrics
23. Katz J. The Nuremberg Code and the Nuremberg             (1952) 8: 188–295.
    Trial. A reappraisal. J Am Med Assoc (1996) 276:     38. Armitage P. Sequential tests in prophylactic and
    1662–6.                                                  therapeutic trials. Q J Med (1954) 23: 255–74.
24. McNeill PM. The Ethics and Politics of Human         39. Armitage P. Interim analysis in clinical trials. Stat
    Experimentation. Cambridge: Press Syndicate of           Med (1991) 10: 925–37.
    the University of Cambridge (1993).                  40. Friedman LM, Furberg CD, DeMets DL. Funda-
25. Beecher HK. Ethics and clinical research. New            mentals of Clinical Trials, 2nd edn. Boston: Wright
    Engl J Med (1966) 274: 1354–60.                          (1985).
26. Freedman B. Research, unethical. In: Reich WT,       41. Pocock SJ. Clinical Trials: A Practical Approach.
    ed., Encyclopedia of Bioethics. New York: Free           Chichester: John Wiley & Sons (1983).
    Press (1995) 2258–61.                                42. Pocock SJ. Group sequential methods in the
27. Shirer WL. The Rise and Fall of the Third Reich.         design and analysis of clinical trials. Biometrika
    New York: Simon and Schuster (1960).                     (1977) 64: 191–9.
28. US Government Printing Office. Trials of War          43. Haybittle JL. Repeated assessment of results of
    Criminals before the Nuremberg Military Tri-             cancer treatment. Br J Radiol (1971) 44: 793–7.
                                                         44. Peto R, Pike MC, Armitage P, Breslow NE, Cox
    bunals under Control Council Law No. 10, Vol. 2.
                                                             DR, Howard SV, Mantel N, McPherson K, Peto J,
    Washington: US Government Printing Office
                                                             Smith P. Design and analysis of randomized clin-
    (1949) 181–2.
                                                             ical trials requiring prolonged observation of each
29. Withington CF. Time Relation of Hospitals to
                                                             patient. 1. Introduction and design. Br J Cancer
    Medical Education. Boston: Cupples Uphman                (1976) 34: 585–612.
    (1886).                                              45. O’Brien PC, Fleming TR. A multiple testing pro-
30. Osler W. The evolution of the idea of experiment.        cedure for clinical trials. Biometrics (1979) 35:
    Trans Congr Am Phys Surg (1907) 7: 1–8.                  549–56.
31. Hill AB. Medical ethics and controlled trials. Br    46. Lan KKG, DeMets DL. Discrete sequential bound-
    Med J (1963) 1: 1043–9.                                  aries for clinical trials. Biometrika (1983) 70:
32. Netherlands Minister of Social Affairs and Health.       659–63.
    4 World Med J (1957) 299–300.                        47. D’Arcy Hart P. History of randomised controlled
33. World Medical Assembly. Declaration of Helsinki:         trials (letter to the Editor). The Lancet (1972) i:
    recommendations guiding physicians in biomed-            965.
    ical research involving human subjects. World        48. D’Arcy Hart P. Early controlled clinical trials
    Medical Assembly, Helsinki (1964).                       (letter to the Editor). Br Med J (1996) 312: 378–9.
34. Faden RR, Beauchamp T, King NMP. A History           49. Gill DBEC. Early controlled trials (letter to the
    of Informed Consent. New York: Oxford Univer-            Editor). Br Med J (1996) 312: 1298.
    sity Press (1986).                                   50. Clarke M. Early controlled trials (letter to the
35. Canner P. Monitoring of the data for adverse             Editor). Br Med J (1996) 312: 1298.
    or beneficial treatment effects. Contr Clin Trials    51. Bull JP. The historical development of clinical
    (1983) 4: 467–83.                                        therapeutic trials. J Chron Dis (1959) 10: 218–48.
                                               General Issues
                                                       DAVID MACHIN
              National Cancer Centre, Singapore and United Kingdom Children’s Cancer Study Group,
                                           University of Leicester, UK

                    INTRODUCTION                                        associated trial protocol should carefully describe
                                                                        (and in some detail) the elements essential for
Just as in any other field of scientific and                              its conduct. Thus the protocol will describe
medical research, the choice of an appropriate                          the rationale for the trial, the eligible group
design for a clinical trial is a vital element.                         of patients or subjects, the therapeutic options
In many circumstances, and for many of the                              and their modification should the need arise. It
trials described in this text, these designs may                        will also describe the method of patient allo-
not be overly complicated. For example, a                               cation to these options, the specific clinical
large majority will compare two therapeutic                             assessments to be made and their frequency,
or other options in a parallel group trial. In                          and the major endpoints to be used for eval-
which case the analytical methods used for                              uation. It will also include a justification of
description and analysis too may not be overly                          the sample size chosen, an indication of the
complicated. The vast majority of these are                             analytical techniques to be used for summary
described in basic medical statistics textbooks                         and comparisons, and the proforma for data
and implemented in standard software packages.                          collection.
Nevertheless there are circumstances in which                              Of major concern in all aspects of clinical trial
more complex designs, such as sequential trials,                        development and conduct is the ethical necessity
are utilised and for which specialist methods are                       which is written into the Declaration of Helsinki
required. There are also, often rather complex,                         of 19641 to ensure the well-being of the patients
statistical problems associated with monitoring                         or subjects under study. This in itself requires
the progress of clinical trials, their interim                          that clinical trials are well planned and conducted
analysis, stopping rules for early closure and the                      with due concern for the patient’s welfare and
possibility of extending recruitment beyond that                        safety. It also requires that the trial is addressing
initially envisaged.                                                    an important question, the answer to which will
   Although the clinical trial itself may not be                        bring eventual benefit to the patients themselves
of complex design in the statistical sense, the                         or at least to future patients.

Textbook of Clinical Trials. Edited by D. Machin, S. Day and S. Green
 2004 John Wiley & Sons, Ltd ISBN: 0-471-98787-5
12                                     TEXTBOOK OF CLINICAL TRIALS

         EVIDENCE-BASED MEDICINE                        Table 2.1. Objectives of the trials of different phases
                                                        in the development of drug (after Day3 )
In many circumstances trials have been con-             Phase                       Objective
ducted that are unrealistically small, some unnec-
essarily replicated while others have not been             I        The earliest types of studies that are
                                                                      carried out in humans. They are
published as their results have not been consid-                      typically done using small numbers of
ered of interest. It has now been recognised that                     healthy subjects and are to investigate
to obtain the best current evidence with respect                      pharmacodynamics, pharmacokinetics
to a particular therapy, all pertinent clinical trial                 and toxicity.
information needs to be obtained, and if circum-          II        Carried out in patients, usually to find
stances permit, the overview is completed by a                        the best dose of drug and to investigate
meta-analysis of the trial results. This recogni-                     safety.
tion has led to the Cochrane Collaboration and a          III       Generally major trials aimed at
worldwide network of overview groups address-                        conclusively demonstrating efficacy.
ing numerous therapeutic questions.2 In certain                      They are sometimes called
situations this has brought definitive statements                     confirmatory trials and, in the context
                                                                     of pharmaceuticals, typically are the
with respect to a particular therapy. For others                     studies on which registration of a new
it has led to the launch of large-scale confirma-                     product will be based.
tory trials.
                                                          IV        Studies carried out after registration of a
   Although it is not appropriate to review the                       product. They are often for marketing
methodology here, it is clear that the ‘overview’                     purposes as well as to gain broader
process has led to many changes to the way                            experience with using the new
in which clinical trial programmes have devel-                        product.
oped. They have provided the basic information
required in planning new trials, impacted on an
appropriate trial size, publication policy and very     be a Phase III study, as will a trial comparing
importantly raised reporting standards. They are        two surgical procedures for closing a cleft palate.
impacting directly on decisions that affect patient     In both these examples, any one of the Phase
care and questioning conventional wisdom in             I, II or IV trials would not necessarily be
many areas.                                             conducted. The objectives of each phase in a
                                                        typical development programme for a drug are
                                                        summarised in Table 2.1.
          TYPES OF CLINICAL TRIALS                         Without detracting from the importance of
                                                        Phase I, II and IV clinical trials, the main focus
In broad terms, the types of trials conducted in        of this text is on Phase III comparative trials.
human subjects may be divided into four phases.         In this context, reference will often be made to
These phases represent the stages in, for example,      the ‘gold standard’ randomised controlled trial
the development of a new drug which requires            (RCT). This does not imply that this is the only
early dose finding and toxicity data in man,             type of trial worthy of conduct, but rather that it
indications of potential activity, comparisons          provides a benchmark against which other trial
with a standard to determine efficacy and then           designs are measured.
(in certain circumstances) post-marketing trials.
The nomenclature of Phase I, II, III and IV has
been developed for drug development purposes                         PHASE I AND II TRIALS
and there may or may not be exact parallels in
other applications. For example, a trial to assess      The traditional outline of a series of clinical
the value of a health educational programme will        trials moving sequentially through Phases I to
                                              GENERAL ISSUES                                          13

IV is useful to consider in an idealistic set-            Although conducted in patients, Phase II trials
ting, although in practice the sequential manner       are typically still highly controlled and use
is not always followed (for reasons that will          highly defined (often narrow) patient groups so
become clear).                                         that extraneous variation is kept to a minimum.
   Pocock4 (pp. 2–3) also gives a convenient           These are very much exploratory trials aimed
summary of the four phases while Temple5 gives         at discovering if a compound can show useful
a discussion of them with emphasis from a              clinical results. Although it is not common,
regulatory perspective. Whether the sequential         some of these trials may have a randomised
nature of the four phases is adhered to or not, the    comparison group.
objectives of each phase are usually quite clearly
   As we have indicated in Table 2.1, Phase I stud-      NON-RANDOMISED EFFICACY STUDIES
ies aim to investigate the metabolism of a drug
and its pharmacodynamics and pharmacokinet-                       HISTORICAL CONTROLS
ics. Typical pharmacokinetic data would allow,
for example, investigation of peak drug concen-        In certain circumstances, when a new treatment
trations in the blood, the half-life and the time      has been proposed, investigators have recruited
to complete clearance. Such studies will assist in     patients in single-arm studies. The results from
defining what doses should be used and the dos-         these patients are then compared with information
ing frequency (once daily, twice daily, hourly)        on similar patients having (usually in the past)
for future studies. These Phase I studies (certainly   received a relevant standard therapy for the
the very first ones) are almost always undertaken       disease in question. However, such comparisons
in healthy volunteers and would naturally be the       may well be biased in many possible ways, such
very first studies undertaken in humans. However,       that it may not be reasonable to ascribe the
later in a drug development programme it may be        difference (if any) observed to the treatments
necessary to study its effects in patients with spe-   themselves. Nevertheless it has been argued that
cific diseases, in those taking other medications       using regression models to account for possible
or patients from special groups (infants, elderly,     confounding variables may correct such biases,6
ethnic groups, pregnant women).                        but this is at best a very uncertain procedure
   Most of the objectives of a Phase I study can       and is not often advocated. Similar problems
often be met with relatively few subjects – many       arise if all patients are recruited prospectively
studies have fewer than 20 subjects. In essence,       but allocation to treatment is not made at
they are much more like closely controlled             random. Of course, there will be situations
laboratory experiments than population-based           in which randomisation is not feasible and
clinical trials.                                       there is no alternative to the use of historical
   Broadly speaking, Phase II trials aim to set        controls or non-randomised prospective studies.
the scene for subsequent confirmatory Phase III         One clear example of this is the early evaluation
trials. Typically, although exceptions may occur,      of the Stanford Heart Transplant Program in
these will be the first ‘trials’ in patients. They      which patients could not be randomised to
are also the first to investigate the existence         receive or not a donor heart. Many careful
of possible clinical benefits to those patients.        analyses and reviews of this unique data set
However, although efficacy is important in Phase        have been undertaken and these have established
II it may often be in the form of surrogate, for       the value of the programme, but progress would
example, tumour response rather than survival          have been quicker (and less controversial) had
time in a patient with cancer. Along with efficacy,     randomisation been possible.
these studies will also be the first to give some          In the era of evidence-based medicine, infor-
detailed data on side effects.                         mation from non-randomised but comparative
14                                      TEXTBOOK OF CLINICAL TRIALS

studies is categorised as providing weaker evi-                 equipoise, as described by Freedman9 and Weijer
dence than randomised trials (see Altman,7                      et al.10 to justify random allocation to treatment
p. 3279).                                                       after due consent is given. Enkin,11 in a debate
                                                                with Weijer et al.,10 provides a counter view.
                                                                   There are at least two aspects of the eligibility
                                                                requirements that are important. The first is that
                                                                the patient indeed has the condition (here severe
       EQUIPOISE AND UNCERTAINTY                                burns) and satisfies all the other requirements.
As indicated, the randomised controlled trial is                There must be no specific reasons why the
the standard against which other trial designs may              patient should not be included. For example, in
be compared. One such trial, and there are many                 some circumstances pregnant or lactating women
other examples described in subsequent chapters,                (otherwise eligible) may be excluded for fear
compared conventional treatment, C, with a                      of impacting adversely either on the foetus or
complementary medicine alternative in patients                  the newborn child. The second is that all (here
with severe burns.8 The complementary medicine                  two) therapeutic options are equally appropriate
was termed Moist Exposed Burns Ointment                         for this particular patient. Only if both these
(MEBO). One essential difference between the                    aspects are satisfied should the patient be invited
two treatments was that C covered the wounds                    to consent to participate in the trial. There will be
(dressed) whilst MEBO left them exposed (not                    circumstances in which a patient may be eligible
dressed). See Figure 2.1.                                       for the trial but the attending physician feels (for
   In this trial patients with severe burns were                whatever reason) that one of the trial options is
emergency admissions requiring immediate treat-                 ‘best’ for the patient. In which case the patient
ment, so that once eligibility was confirmed,                    should receive that option, no consent for the trial
consent obtained, randomisation immediately fol-                is then required and the randomisation would not
lowed and treatment was then commenced. Such                    take place. In such circumstances, the clinician
a trial is termed a two-treatment parallel group                should not randomise the patient in the hope that
design. This is the most common design for com-                 the patient will receive the ‘best’ option. Then,
parative clinical trials. In these trials subjects are          if he or she did not, withdraw the patient from
independently allocated to receive one of several               the trial.
treatment options. No subject receives more than                   The consent procedure itself will vary from
one of these treatments.                                        trial to trial and will, at least to some extent,
   In addition there is genuine uncertainty as to               depend on local ethical regulations in the country
which of the options is best for the patient. It                in which the trial is being conducted. The ideal is
is this uncertainty which provides the necessary                fully informed and written consent by the patient

                     Patients          Eligible            Random                MEBO           s
                    presenting          and               allocation                            e
                    with partial     consenting               to                                s
                      degree          subjects            treatment                             m
                       burns                                                  Conventional
                                                                               Dressing         n
                  Source : Reproduced from Ang et al.,8

Figure 2.1. Randomised controlled trial to compare conventional treatment and Most Exposed Burns Ointment
(MEBO) for the treatment of patients with partial degree burns
                                               GENERAL ISSUES                                             15

him or herself. However, departures from this               STANDARD OR CONTROL THERAPY
may be appropriate. For example, such departures
may concern patients with severe burns who may          In the early stages of the development of a new
be unconscious at admission, very young children        therapy it is important to compare this with the
for whom a proxy must be used to obtain the             current standard for the disease in question. In
                                                        certain circumstances, the ‘new’ therapy may
consent for them, or patients with hand burns that
                                                        be compared against a ‘no treatment’ control.
are so severe that they affect their ability to write
                                                        For example, in patients receiving surgery for
their signature.
                                                        the primary treatment of head and neck cancer
   Clearly, during the period in which patients are
                                                        followed by best supportive care, the randomised
being assessed for eligibility and their consent
                                                        controlled trial may be assessing the value of
obtained, both the attending physician and the
                                                        adding post-operative chemotherapy. In this case
patient will be fully aware of the potential options
                                                        the ‘control’ group are those who receive no
being compared in the RCT. However, neither
                                                        adjuvant treatment, whilst the ‘test’ group receive
must be aware, at this stage, of the eventual
                                                        chemotherapy. In certain circumstances, patients
treatment allocation. It is important therefore
                                                        may receive a placebo control. For example,
that the randomisation list, for the current as         in the randomised controlled trial conducted
well as for future patients, is held by a neutral       by Chow et al.12 in those with advanced liver
third party. In most circumstances, this should         cancer, patients are randomised to receive either
be an appropriate trial office that is contacted         placebo or tamoxifen. In this trial both patients
by the responsible clinician once eligibility and       and the attending physicians are ‘blinded’ to
consent are obtained. This contact may be made          the actual treatment given to individual patients.
by telephone, fax, direct access by modem into          Such a ‘double-blind’ or ‘double-masked’ trial
a trial database, email or the web – whichever is       is a design that reduces any potential bias
convenient in the particular circumstance. It is        to a minimum. Such designs are not possible
then important that therapy is instituted as soon       however in many circumstances and neither are
as practicable after the randomisation is obtained.     those with a ‘no treatment’ control. In many
   In specific cases, the randomisation can be con-      situations, the ‘control’ will be the current best
cealed within opaque and sealed envelopes which         practice against which the new treatment will
are distributed to the centres in advance of patient    be compared. Should this turn out to be better
recruitment. Once a patient is deemed eligible,         than current practice then this, in its turn, may
the envelope is taken in the order specified in a        become standard practice against which future
prescribed list, opened and the treatment thereby       developments will be compared.
revealed. Intrinsically, there is nothing wrong            In general there will be both baseline and
with this process but, because of the potential         follow-up information collected on all patients.
for abuse, it is not regarded as entirely satisfac-     The baseline (pre-randomisation) information
tory. However, in some circumstances it will be         will be that required to determine eligibil-
unavoidable; perhaps a trial is being conducted         ity together with other information required to
in a remote area with poor communications. In           describe the patients recruited to the trial together
such cases, every precaution should be taken to         with those variables which are thought likely to
ensure that the process is not compromised.             influence prognosis. The key follow-up informa-
   The therapeutic options should be well des-          tion will be that which is necessary to determine
cribed within the trial protocol and details of         the major endpoint(s) of the randomised con-
what to do, if treatment requires modification           trolled trial. Thus in the example of the burns
or stopping for an individual patient should be         patients these may be when the unhealed body
given. Stopping may arise either when patients          surface area finally closes or the size and sever-
merely refuse to take further part in the trial or      ity of the resulting scars. To establish the first of
from safety concerns with a therapy under test.         these, the burns areas may have to be monitored
16                                   TEXTBOOK OF CLINICAL TRIALS

on a daily basis to determine exactly when the        terms enormous. Similar types of trials have
endpoint is achieved, whereas the latter may be a     been conducted in patients with breast cancer,
single assessment at the anniversary of the initial   one in particular compared the three adjuvant
burn accident. Pre-trial information on these end-    treatment possibilities: tamoxifen, anastrozole or
points, possibly from clinical experience or other    their combination.14
studies, will usually form the basis of the antic-
ipated difference between treatments (the effect
size), help determine the trial size and be the        INTERVENTION AND PREVENTION TRIALS
variables for the statistical comparisons.
                                                      The focus so far has been on randomised con-
                                                      trolled trials in patients with medical conditions
            LARGE SIMPLE TRIALS                       requiring treatment or a medical intervention
                                                      of some sort. Such designs do apply to situa-
It has become recognised over time, particularly      tions such as trials in normal healthy women
in the fields of cardiovascular disease and cancer,    in which alternative forms of contraception are
that there are circumstances where small ther-        being tested.15 However, there are quite different
apeutic advantages may be worthwhile demon-           situations in which the object of a trial is to eval-
strating. In terms of trial size, the smaller the     uate alternative strategies for preventing disease
potential benefit, essentially the effect size, then   or for detecting its presence earlier than is rou-
the larger the trial must be in order to be rea-      tine. For example, intervention trials to encourage
sonably certain that the small benefit envisaged       ‘safe sex’ to prevent the spread of AIDS or breast
really exists at all.                                 screening trials to assess the value of early detec-
   Trials of this size, often involving many          tion of the disease on subsequent treatment and
thousands of patients, are a major undertaking. To    prognosis. In such cases, it may be impossible to
be practical, they must be in common diseases in      randomise on an individual subject basis. Thus an
order to recruit the required numbers of patients     investigator may have to randomise communities
in a reasonable time frame. They must be testing      to test out different types of health promotion
a treatment that has wide applicability and can be    or different types of vaccines, when problems
easily administered by the clinicians responsible     of contamination or logistics, respectively, mean
or the patients themselves. The treatments must       that it is better to randomise a group rather than
be relatively non-toxic else the small benefit will    an individual. This is the approach adopted by
be outweighed by the side effects. The trials         Donner et al.16 in a trial to compare a reduced
must be simple in structure and restricted as         antenatal care model with a standard care model.
to the number of variables recorded, so that          For this trial, because of the clustered randomisa-
the recruiting clinicians are not overburdened by     tion of the alternatives on a clinic-to-clinic basis,
the workload attached to large numbers of trial       the Zelen17 single consent design was utilised.
patients going through the clinic. They also need
to be simple in this respect, for the responsible
trial centre to cope with the large amounts of            PHASE IV TRIALS – POST-MARKETING
patient data collected.                                             SURVEILLANCE
   One example of such a trial tests the value of
aspirin in patients with cardiovascular disease.13    Within a regulatory framework, Phase IV trials
This trial concerned a very common disease using      are generally considered as ‘post-registration’
a very simple and low-cost treatment taken as         trials: that is, trials of products that already have
tablets with very few side effects. The resulting     a marketing authorisation. However, within this
estimates of absolute survival gain were (as          post-registration period studies may be carried
expected) small but the benefits in public health      out for a variety of purposes, some within
                                              GENERAL ISSUES                                              17

their existing licence and others out-with that        how is the size of a trial comparing three treat-
licence. Studies may also be undertaken in             ments, A, B and C, determined, since there are
countries where a marketing authorisation has          now three possible anticipated effect sizes that
not been approved, in which case they are              one can use for planning purposes? These corre-
regulatory or Phase III-type studies, at least         spond to the treatment comparisons A–B, A–C
for that country. Studies may be undertaken to         and B –C. The number of patients required for
expand the indications listed on a marketing           each of these comparisons may give three very
authorisation either for a different disease or a      different sample sizes. It is then necessary to
different severity of the indicated condition. They    decide which of these will form the basis for the
may be undertaken to gain more safety data for         final trial recruitment target, N . The trial will then
newly registered products: this latter situation is    randomise the patients equally into the three treat-
more usually what is considered as a true Phase        ment groups. In many circumstances, a three-arm
IV study.                                              trial will tend to require some 50% more patients
   Historically, pharmaceutical companies used to      than a two-arm trial comparing two of the three
carry out studies that were solely for market-         treatments under consideration.
ing purposes and answered very few (if any)               Once the trial has been completed, the result-
research questions. These were termed ‘seeding         ing analysis (and reporting) is somewhat more
studies’ although with tighter ethical constraints     complex than for a simple two-group comparison.
such studies are now very rare, if indeed they         However, it is the importance of the questions
take place at all. Certainly the ‘hidden’ objective    posed, rather than the ease of analysis, which
of many Phase IV studies carried out by pharma-        should determine the design chosen. A good
ceutical companies may be to increase sales, but       example of the use of such a design is the previ-
if the means of doing so is via answering a useful     ously mentioned trial in post-menopausal patients
scientific or medical question then this should be      with breast cancer in which three options are
of benefit both to society and to the company.          compared.14
   Many trials organised by academic depart-              Nevertheless practical considerations may rule
ments should also be considered as Phase IV            out this choice of design. The design poses
studies. Classic examples such as the RISC             particular problems in data monitoring. For
Group trials13 looking at the cardiovascular ben-      example, if an early advantage appears to favour
efits of aspirin are studies of licensed products to    one particular treatment and this suggests the trial
expand their use.                                      might be stopped early as a consequence. Then
                                                       it may not be clear whether the randomisation
                                                       between the other treatment groups should or
            ALTERNATIVE DESIGNS                        should not continue. Were the trial to stop
                                                       early, then the questions relating to the other
For illustrative purposes we have used the two-        comparisons are unlikely to have been resolved
arm parallel group RCT but these designs can be        at this stage. Should the (reduced) trial continue
generalised to compare three or more groups as         then there may be very complex issues associated
appropriate. In addition, there are other designs      with its analysis and reporting.
in common use which include 2 × 2 factorial and           In addition, a potentially serious problem of
crossover designs.18                                   bias can arise. At the onset of the trial, the
                                                       clinician has to assess whether or not all the
         MORE THAN TWO GROUPS                          three options (A, B or C) available for treatment
                                                       are suitable for the particular patient under
Although not strictly a different design, a parallel   examination. If any one of these were not thought
group trial with more than two treatments to com-      to be appropriate (for whatever reason), then the
pare does pose some difficulties. For example,          patient’s consent would not be sought to enter
18                                    TEXTBOOK OF CLINICAL TRIALS

the trial and to be randomised. Suppose later in
                                                                                               I - Placebo
the trial, an interim analysis suggests recruitment
to A is no longer necessary and that arm is             Eligible and
closed. For future patients, the clinician now has      consenting        Random             II - Atorovastin
                                                       patients with     allocation                alone
to assess whether or not only the two options (B
                                                       dyslipidaemia         to
or C) are suitable for the particular patient under      in visceral     treatment
                                                                                           III - Fish oil alone
examination. As a consequence, the patients now           obsesity
going into the trial are no longer potentials for A
and hence may be somewhat different than those                                              IV - Atorovastin
                                                                                              and fish oil
entering at the earlier stages. Although this will
not bias the final comparison between B and C, it       Figure 2.2. Randomised 2 × 2 factorial trial to
does imply that there will be a bias if the patients   determine the value of atorovastin, fish oil or both
entering at this stage are compared with those         in patients with dyslipidaemia in visceral obesity.
receiving A.                                           Reproduced from Chan et al.19
   In the above, we have assumed that the
three treatments A, B and C are, in a sense,
unrelated albeit all suitable for the patients in         In addition, the factorial design allows the
mind. However, if they were related, for example,      comparison of groups (I and IV) with (II and
perhaps three doses of the same drug, then a           III) and this estimates the so-called fish oil by
note of this structure may change the approach         atorovastin interaction. For example, suppose both
to design from that outlined here.                     the main effect of fish oil alone and the main
                                                       effect of atorovastin alone prove to be beneficial in
             FACTORIAL DESIGNS                         this context, then an interaction would arise if the
                                                       combination treatment fish oil–atorovastin gives
In a trial conducted by Chan et al.19 patients         a benefit greater (or lesser) than the sum of these
with dyslipidaemia in visceral obesity were            constituent parts. As is the situation here, factorial
randomised to either atorovastin alone, fish oil        designs can be of a double placebo type, where
alone, both or neither (placebo) to investigate        subjects of Group I of Figure 2.2 receive double
their influence on lipid levels. This trial may take    placebo, one representing each treatment factor.
the form of no treatment (1), atorovastin alone           In principle, the 2 × 2 or 22 design can be
(a), fish oil alone ( f) or both atorovastin and fish    extended to the 2k (k > 2). Circumstances where
oil (af). These alternative options are summarised     this kind of design may be useful are if perhaps
in Figure 2.2.                                         the first two factors are major therapeutic or
   In contrast to the two-group parallel design of     curative options and the third is a factor for
Figure 2.1, where MEBO is contrasted with con-         a secondary question not associated directly
ventional treatment C, the factorial design poses      with efficacy but (say) to relieve pain in such
two questions simultaneously. Those patients           subjects. However, the presence of a third factor
assigned to groups I and II are compared with          of whatever type increases the complexity of
those receiving III and IV, to assess the value        the trial design (not itself a particularly difficult
of fish oil. This estimates the effect of fish oil       statistical problem) which may have implications
and is termed the ‘main effect’ of that treat-         on the patient consent procedures and the timing
ment. Those assigned to I and III are compared         of randomisation(s). Nevertheless, a 23 design
to those receiving II and IV to assess the main        in a trial of falls prevention in the elderly
effect of atorovastin. In most situations the final     has been successfully conducted by Day et al.20
trial size will require fewer patients than would      Piantadosi21 describes several examples of the use
be necessary if the two questions were posed in        of these designs.
two distinct parallel group trials of the format of       However, Green22 has issued a cautionary note
Figure 2.2.                                            that some of the assumptions behind the use of
                                                 GENERAL ISSUES                                                19

factorial designs may not be entirely justified and           ensures that the between-treatment comparison
so any proposals for the use of such designs                 (A v B) within the patient remains unaffected
should be considered carefully.                              by anything other than the change in treatment
                                                             itself and random variation. These considerations
                                                             tend to restrict the applicability of the design
              CROSSOVER TRIALS
                                                             to patients with chronic conditions such as, for
                                                             example, arthritis, asthma or migraine. Senn24
In contrast to the design of Figure 2.1, in the
                                                             describes in careful and comprehensive detail the
crossover trial each patient will receive both
                                                             role of crossover designs in clinical studies.
treatment options, one followed by the other in
                                                                A clear advantage of the design is that the
two periods of time. The two treatments will be
                                                             patient receives both options and so the analysis
given either in the order A followed by B (AB)
                                                             includes within-patient comparisons which are
or the reverse (BA). The essential features of a
                                                             more sensitive than between-patient comparisons,
crossover design are summarised in Figure 2.3
                                                             implying that such trials would require fewer
for the trial conducted by Hong et al.23 in patients
                                                             subjects than a parallel group design comparing
with erectile dysfunction.
                                                             the same treatment options.
   Typically, in the two-period, two-treatment
crossover trial, for eligible patients there is a run-
in stage in which the subject receives neither                             EQUIVALENCE TRIALS
treatment. At the end of this randomisation to
either AB or BA takes place. Following active                In certain situations, a new therapy may bring
treatment in Period I (in effect either A or                 certain advantages over the current standard,
B depending on the randomisation), there is a                possibly in a reduced side-effects profile, easier
wash-out interval in which again no treatment                administration or cost. Nevertheless, it may not
is given, after which Period II commences and                be anticipated to be better with respect to the
the (other) treatment of the sequence is given.              primary efficacy variable. Under such conditions,
The characteristics of this design, for example the          the new approach may be expected to be at
possible run-in and the wash-out period, imply               least ‘equivalent’ to the standard in relation to
that only certain types of patients in which active          efficacy.
treatment can be withheld in this way are suitable              Trials to show that two (or more) treatments are
to be recruited. Further, there is an implication            ‘equivalent’ to each other pose special problems
that the patient returns to essentially the same             in design, management and analysis.25 ‘Proving
state at the beginning of Period II as he or she             the null hypothesis’ in a significance testing
was in at the commencement of Period I. This                 scenario is never possible: the strict interpretation

                                     Random              Korean red        a         Korean red
                   Patients                               ginseng          s          ginseng
                     with                                                  h
                                  to sequence
                    erectile                                               -
                  dysfunction                             Placebo          o          Placebo

                Source : Reproduced from Hong et al.,23 with permission.

Figure 2.3. Randomised placebo controlled, two-period crossover trial of Korean red ginseng in patients with
erectile dysfunction
20                                             TEXTBOOK OF CLINICAL TRIALS

when a statistically significant difference has                      there is no difference between the treatments and
not been found is that ‘there is insufficient                        then look for evidence to refute that null hypoth-
evidence to demonstrate a difference’. Small                        esis. In the case of equivalence we specify the
trials typically fail to detect differences between                 range of equivalence,      (25 g per week in the
treatment groups but not necessarily because                        above example) and then test two null hypothe-
no difference exists. Indeed it is unlikely that                    ses. We test that the observed difference is statis-
two different treatments will ever exert truly                      tically significantly greater than − ; and that the
identical effects.                                                  observed difference is statistically significantly
   A level of ‘therapeutic equivalence’ should be                   less than + . In practice it is much easier to
defined and this is a medical question, not a                        consider a confidence interval for the difference
statistical one. For example in a study of weight                   between the treatment means and draw this on
gain in pre-term infants, if two treatments show                    a graph with the agreed limits of equivalence.
mean increases in weight to within 25 g per week                    Figure 2.4 shows various scenarios. Some cases
then they may be considered as therapeutically                      show equivalence, some fail to show equivalence;
equivalent. Note that in this example 25 g is                       some cases show a statistically significant differ-
not the mean weight gain that is expected per                       ence, others fail to show a difference. Note that
week – we would hope that would be much                             it is quite possible to show a statistically signif-
more. But if infants receiving one feeding                          icant difference between two treatments yet also
regimen had a mean increase of 150 g per week                       demonstrate therapeutic equivalence. These are
then we would consider an alternative treatment                     not contradictory statements but simply a real-
to be equivalent if the mean weight gain were                       isation that although there is evidence that one
between 125 and 175 g per week.                                     treatment works better than another, the size of
   Conventionally, to show a treatment difference,                  the benefit is so small that it has little or no
we would state the null hypothesis as being that                    practical advantage.

                                                                                                      Not equivalent
                         Not equivalent

                                          −∆                      O                           +∆
                                                           True difference
                  Examples of possible results of using the confidence interval approach: −∆ to +∆ is
                  the prespecified range of equivalence; the horizontal lines correspond to possible
                  trial outcomes expressed as confidence intervals, with the associated significance
                  test result shown on the left; above each line is the decision concerning equivalence.
        Source : Reproduced from Jones et al.,86 with permission from the BMJ Publishing Group.

                        Figure 2.4. Schematic diagram to illustrate the concept of equivalence
                                                GENERAL ISSUES                                            21

   The analysis and interpretation can be quite           fixed sample size approach might have been
straightforward but the design and management             curtailed earlier had a sequential design been
of equivalence trials is often much more complex.         utilised. Fayers et al.27 describe the issues faced
In general, careless or inaccurate measurement,           when designing a sequential trial using α-
poor follow-up of patients, poor compliance with          interferon in patients with renal carcinoma. The
study procedures and medication all tend to bias          accumulating patient data from this trial crossed
results towards no difference. Since we are trying        an early termination boundary which inferred an
to offer evidence of equivalence, poor study              advantage to α-interferon.28
design and procedures may therefore actually                 A fully sequential design will monitor the trial
help to hide treatment differences. In general,           patient-by-patient as the information on the trial
therefore, the quality of equivalence trials should       endpoint is observed from them. Alternatively,
be demonstrably high.                                     a ‘group’ sequential trial will utilise information
   One special subset of equivalence trials is            from successive groups of patients. Computer
termed ‘non-inferiority’ trials. Here we only wish        programs to assist in the implementation of these
to be sure that one treatment is ‘not worse than’         designs are available29 and a review of some of
or is ‘at least as good as’ another treatment: if it is   the issues is given by Whitehead.30
better, that is fine (even though superiority would           The solid lines of Figure 2.5 indicate stopping
not be required to bring it into common use).             boundaries for declaring a statistically significant
All we need is to get convincing evidence that            difference between treatments A and B. If the
the new treatment is not worse than the standard.         broken boundary is crossed, the trial stops,
We still have the same design and management              concluding that no significant difference was
considerations but here, looking at Figure 2.4, we        found between the treatments. Potentially, the
would only be concerned with whether or not the           number of preferences could continue indefinitely
lower limit of the confidence interval is greater          between the upper solid and broken lines or
than the non-inferiority margin (− ).                     between the lower solid and broken lines; in such
                                                          a case no conclusion would ever be reached.
              SEQUENTIAL TRIALS                              In contrast to the open sequential design,
There has been an implicit assumption in the              the closed design of Figure 2.6 will continue
trial designs discussed above, that the total (and        to recruit to a pre-stated maximum or until a
final) sample size is determined at the design             boundary is crossed. Thus this design has a finite
stage and before recruitment commences to the             size and a conclusion will always be drawn.
trial in question. This fixed sample size approach         Again the solid lines indicate stopping boundaries
essentially implies that the data collected during        for declaring a statistically significant difference
the conduct of the trial will only be examined            between treatments and if the broken line is
for efficacy once the trial has closed to patient          crossed, concluding that no significant difference
accrual. However, the vast majority of Phase III          was found between the treatments.
trials will tend to recruit patients over perhaps            For more complex designs implementing a
an extended interval of time and so information           sequential option remains possible. For example,
on efficacy will be accumulated over this period.          a factorial structure of the treatments does permit
A sequential trial is one designed to utilise this        a sequential approach to trial design as the two
accumulating knowledge to better effect. Perhaps          questions can be monitored separately. Neverthe-
to decrease the final trial size if the data are           less, if one of the factors, say the chemotherapy
indicating an advantage to one of the treatments          option in the example we discussed previously,
and this can be firmly established at an early stage       is stopped by crossing a boundary during the
or to extend the trial size in other circumstances.       sequential monitoring, then the recruiting clini-
   In fact, Donaldson et al.26 give examples              cian will only have to put two rather than four
where trials that had been conducted using a              choices to the patients. Again, the subsequent
22                                                             TEXTBOOK OF CLINICAL TRIALS


                                                          A significantly
                                                          better than B

                Excess preferences (A − B)

                                               0                                                        No significant


                                                          B significantly
                                                          better than A
                                                   0          10               20           30         40           50
                                                                            Number of preferences
                                              Open sequential design. The solid lines indicate stopping boundaries for
                                              declaring a statistically significant difference between treatments A and B.
                                              If the broken boundary is crossed, then the study stops, concluding that
                                              no significant difference was found between the treatments. Potentially the
                                              number of preferences could continue indefinitely between the upper solid
                                              and broken lines or between the lower solid and broken lines; in such a case
                                              no conclusion would ever be reached.
                                              Source : Reproduced from Day3 (Figure 24), with permission.

                                                              Figure 2.5. Open sequential design

patients recruited may then be somewhat dif-                                           terms the use of sequential designs is still some-
ferent from those at the first stage of the trial.                                      what limited.
This will then impact on the form of the subse-
quent analysis.                                                                                       ZELEN’S DESIGNS
   In contrast, the three-arm trial cannot be so
easily designed in a sequential manner although                                        Although not strictly an alternative ‘design’
both Whitehead31 and Jennison and Turnbull32                                           in the sense of those of this section, Zelen’s
address the problem. They do not however appear                                        randomised consent design combines aspects of
to give an actual clinical example of their use.                                       design with problems associated with obtaining
   There are however several problems associ-                                          consent from patients to participate in clinical
ated with the use of sequential designs. These                                         trials. They were motivated by the difficulties
range from difficulties of financing a trial of                                          expressed by clinicians in obtaining consent from
uncertain size, making sure the data is fully up-                                      women who they wished to recruit to trials
to-date as the trial progresses, to the more tech-                                     with breast cancer.17,33 Essentially subjects are
nical concerns associated with the calculation of                                      randomised to one of two treatment groups.
the appropriate confidence intervals. However,                                          Those who were randomised to the standard
Whitehead,31 see also Jennison and Turnbull,32                                         treatment (conventional dressing in Figure 2.1)
has argued very persuasively that all these objec-                                     are all treated with it. For these patients no
tions can be resolved. Nevertheless, in relative                                       consent to take part in the trial is sought. On
                                                                         GENERAL ISSUES                                                                    23


                                                          A significantly
                                                          better than B

                 Excess preferences (A − B)

                                               0                                                              No significant


                                                          B significantly
                                                          better than A
                                                    0             10                 20                30                   40
                                                                            Number of preferences
                                               Closed sequential design. The solid lines indicate stopping boundaries
                                               for declaring a statistically significant difference between treatments A
                                               and B. For example, if out of ten patients expressing a preference for
                                               one or other treatment, nine preferred treatment B and only one preferred
                                               A, then the study would stop, concluding that B is significantly better than A.
                                               If the broken boundary is crossed, then the study stops and the conclusion
                                               is drawn that no significant difference was found between the treatments.
                                               Source : Reproduced from Day3 (Figure 4), with permission.

                                                              Figure 2.6. Closed sequential design

the other hand, those who are randomised to                                                                      Eligible patients
the experimental treatment (MEBO dressing in
Figure 2.1) are asked for their consent; if they
agree they are treated with the experimental                                                                       Randomise
treatment; if they disagree they are treated with                                           Standard (G1)                              New   (G2)
the standard treatment. This is known as Zelen’s
                                                                                                Obtain consent                       Obtain consent
single consent design. An alternative is that those
randomised to the standard treatment may also                                             Yes                    No          Yes                      No
be asked if they accept that treatment; again,                                            Treat with     Treat with          Treat with       Treat with
they are actually given their treatment of choice.                                        standard          new                 new           standard

This latter double consent design is described
in Figure 2.7; in either case, the analysis must                                          Evaluate          Evaluate         Evaluate         Evaluate
be by intention-to-treat, that is based on the
treatment to which patients were randomised, not
the treatment they actually received.                                                                               Compare
   The properties of these designs have been                                             Source : After Altman et al.34 (Figure 3).
examined in some detail by Altman et al.34 who
concluded that: ‘There are serious statistical argu-                                   Figure 2.7. The sequence of events to follow in
ments against the use of randomised consent                                            Zelen’s double randomised consent design, seeking
designs, which should discourage their use’. In                                        consent in conjunction with randomisation
24                                     TEXTBOOK OF CLINICAL TRIALS

any event, they have rarely been used in prac-          may be of assistance in interpreting the results
tice although they continue to be advocated.35          of a trial. Despite some technical difficulties, it is
Nevertheless, in the large antenatal care trial         fairly certain that Bayesian methods will become
described by Donner et al.16 the Zelen single           more prominent in Phase II trial methodology.
consent design is utilised. However, this is a          For example, Tan et al.37 suggest how such ideas
cluster randomised trial and the issues are some-       may be useful in a Phase II programme.
what different.

             BAYESIAN METHODS                              RANDOMISATION AND ALLOCATION
                                                                   TO TREATMENT
The essence of Bayesian methodology in the con-
text of the design of clinical trials is to incorpo-    We have indicated above that randomisation of
rate relevant information into the design process.      patients to the treatment they receive is an
At a later stage, Bayesian methods may assist           important part of the ‘gold’ standard. In fact it is
in data monitoring (as trial data accumulate) and       the key element. The object of randomisation is to
with the final analysis and interpretation of the        help ensure that the final comparison of treatment
(now complete) trial data. In theory the informa-       options is as unbiased as possible, that is, that any
tion available and which is pertinent to the trial in   difference or lack of difference observed between
question can be summarised into a prior distribu-       treatments in efficacy is not due to the method by
tion. This may include (hard) information from          which patients are chosen for the options under
the published literature and/or elicited clinical       study. For example, if the attending clinician
opinion. The mean of such a distribution would          chose which of MEBO or C should be given to
correspond to the possible effect size which can        each patient, then any differences observed may
then be assessed by the design team as clinically       be due, at least in part, to the selection process
worthwhile in their context and hence used for          itself rather than to a true difference in efficacy.
sample size estimation purposes. The same prior,           Apart from the possible effect of the allocated
or that prior updated from new external evidence        treatments themselves, observed differences may
accumulated during the course of the trial, may         arise through the play of chance alone or possibly
be used by the trial Data Monitoring Committee          an imbalance of patients with differing prognoses
(DMC) to help form the basis of recommenda-             in the treatment groups or both. The object of
tions with respect to future conduct of the trial.      the statistical analysis will be to take account
Perhaps to close the trial as efficacy has been          of any imbalance and assess the role of chance.
clearly established or increase the planned size of     Some of the imbalance in the major prognostic
the trial as appropriate. Finally once the trial data   variables may be avoided by stratifying the
is complete, these can be combined with the prior       randomisation by prognostic group and ensuring
(or updated prior) to obtain the posterior distribu-    that an equal number of patients are allocated
tion, from which Bayesian estimates of treatment        within each stratum to each of the options. This
effect and corresponding credibility intervals can      may be achieved by arranging the randomisation
be calculated.                                          to be balanced within predetermined blocks of
   However, despite the feasibility of the above        patients within each of the strata. Blocks are
approach few trials to date have implemented            usually chosen as neither too small nor too large,
a full Bayesian approach. A review of articles          four or six are often used. Sometimes the block
in the British Medical Journal from 1996 to             size, perhaps between these options, is chosen
November 1999 found no examples.7 Never-                at random for successive sequences of patients
theless, Spiegelhalter et al.36 show convincingly       within a stratum of patient types.
how the concept of optimistic and sceptical prior          Alternatively, the balance of treatments bet-
distributions obtained from the clinical teams          ween therapeutic options can be made using a
                                             GENERAL ISSUES                                           25

dynamic allocation procedure. In such schemes,        so that they can be determined for each patient
during the randomisation procedure a patient is       recruited to the trial. It is good practice to
identified to belong to a predetermined category       define which endpoint is the major endpoint of
according to certain covariates. This category        the trial as this will be used to determine trial
may, for example, be defined as those of a par-        size and be the main focus for the efficacy
ticular age, gender and tumour stage group. Once      evaluation. In many situations, there may be
the category is determined, then randomisation to     several endpoints of interest, but in this case it
the treatment options may proceed as described        is important to order them in order of priority or
above. One option, however, is to allocate the        at least to identify those of primary or secondary
next patient to the treatment with the fewest         importance. If there are too many endpoints
patients already assigned within that category. In    defined, then the multiplicity of comparisons then
which case, the allocation at that stage is deter-    made at the analysis stage may result in spurious
ministic. A better option in such circumstances is    statistical significance. This is a major concern if
to weight the randomisation, perhaps in the ratio     endpoints for health-related quality of life and
of 3:2 in favour of the option with the fewest        health economic evaluations are added to the
patients. Clearly, if numbers are equal, the ran-     already established more clinical endpoints.
domisation would revert to 1:1.
   We have implicitly assumed that, for two treat-                  SINGLE MEASURES
ments, a 1:1 randomisation will take place. For
all practical purposes, this will be statistically    In some trials a single measure may be sufficient
the most efficient. However, the particular con-       to determine the endpoint in each patient. For
text may suggest other ratios. For example, if        example, the endpoint may be the diastolic
the patient pool is limited for whatever reason,      blood pressure measured at a particular time, say
then the clinical team may argue that they should     28 days post-randomisation in each patient. In
obtain more information within the trial from         this case the treatment groups will be summarised
the test treatment rather than the well-known         by the respective means. In some situations the
standard. Perhaps, there is a concern with the        endpoint may be patient response, for example,
toxicity profile rather than just the efficacy per      the patient becomes normo-tensive following a
se. In such circumstances, a randomisation ratio      period of treatment. Those who respond are
of say 2:3 or 1:2 in favour of the test therapy       termed successes and those that do not failures.
                                                      In this case, the treatment groups will be
may be decided. However, some loss of statistical
                                                      summarised by the proportion of responders. If,
power will ensue and this loss should be quan-
                                                      on the other hand, the patients are categorised
tified before a decision on the allocation ratio is
                                                      as: normo-tensive, still hypotensive but diastolic
finally made.
                                                      blood pressure (DBP) nevertheless reduced, or
                                                      still hypotensive and DBP not improved, then
                  ENDPOINTS                           this would correspond to an ordered categorical
                                                      variable. Alternatively, the endpoint may be
         DEFINING THE ENDPOINT(S)                     defined as the time from randomisation and
                                                      inception of treatment for the patient to become
The protocol for every clinical trial will detail     normo-tensive. In this situation repeated (say
the assessments to be made on the patients            daily) measures of DBP will be made until
recruited. Some of these assessments may focus        the value recorded is normo-tensive (as defined
on aspects of the day-to-day care of the patient      in the protocol). The interval between the date
whilst others may focus more on those measures        of randomisation and the date of recording the
which will be necessary in order to determine the     first occurrence of a normo-tensive recording is
trial endpoint(s) for each subject. It is important   the endpoint measure of interest. Such data are
that these endpoints are unambiguously defined         usually summarised using survival time methods.
26                                    TEXTBOOK OF CLINICAL TRIALS

   A particular feature of time-to-event studies                      QUALITY OF LIFE
occurs when the endpoint cannot be determined.
For example, in the trial monitoring the DBP           In many trials, endpoints such as the percent-
it may be that a patient never becomes normo-          age of patients responding to treatment, survival
tensive during the trial observation period. In        time or direct measures such as DBP have been
which case the time from randomisation until           used. In other situations, more psychosocial mea-
the end of the trial observation period represents     sures have been utilised such as pain scores, per-
the time a patient has been under observation          haps measured using a visual analogue scale, and
but has not yet become normo-tensive. Such a           emotional functioning scores, perhaps assessed
survival time is termed censored and is often          by patients completing a questionnaire them-
denoted by, say, 28+, which here means the             selves. Such self-completed questionnaires have
patient has been observed for 4 weeks but still        also been developed to measure aspects of qual-
remains hypotensive. In contrast, an observation       ity of life (QoL) in patients undergoing treatment
of 28 means the patient has been observed for          for their disease. One such instrument is the SF-
4 weeks and became normo-tensive on the last           36 of Ware and Sherbourne,41 part of which is
observation day.                                       reproduced in Figure 2.8.
                                                          The QoL domains measured by these instru-
             REPEATED MEASURES                         ments may then be used as the definitive end-
                                                       points for clinical trials in certain circumstances.
In the trial taking repeated DBP assessments,          For example, in patients with terminal cancer
these are recorded in order to determine a single      the main thrust of therapy may be for palliation
outcome – ‘time to becoming normo-tensive’. In         (rather than cure) so that aspects of QoL may
other situations, the successive values of DBP         be the primary concerns for any comparison of
themselves may be utilised in making the formal        alternative approaches to management and care
comparisons. If the number of observations made        of such patients. If a single aspect of this QoL
on each subject is the same, then the analysis         measured at one time point is to be used for
may be relatively straightforward, perhaps using       comparison purposes, then no new principles are
repeated measures analysis of variance. On the         required either for trial design purposes or anal-
other hand, if the numbers of observations             ysis. On the other hand, and more usually, there
recorded varies or if the intervals between            may be several aspects of the QoL instrument
successive observations vary from patient to           that may need to be compared between treat-
patient or if there is occasional missing data, then   ment groups and these features will usually be
the summary and analysis of such data may be           assessed over time. This is further complicated
quite complex. One option is to calculate the area     by often-unequal numbers of assessments avail-
under the curve (AUC) and use this as a single         able from each patient caused either by missing
measure for each patient, thus avoiding the use        assessments in the series for a variety of reasons
of more complex analytical methods.38                  related or unrelated to their health status or per-
   However, the AUC method is now being                haps in terminal patients by their death. Fayers
superseded somewhat in Phase III trials by the         and Machin42 and Fairclough43 discuss these fea-
use of general estimating equations and multi-         tures of QoL data in some detail.
level modelling. The technical details are beyond         As we have discussed previously, there is
the scope of this book but most good statistics        also a problem associated with the numerous
packages39 now include facilities for these types      statistical tests of significance of the multiple
of analyses. Nevertheless, these methods have not      QoL outcomes. These pose problems of inter-
yet had much impact on the reporting of clinical       pretation which have also been addressed by
trials, although a good example of their use has       Fayers and Machin42 (Chapter 14). In short, a
been provided by Brown et al.40                        cautious approach is needed to ensure apparently
                                               GENERAL ISSUES                                           27

                                         The SF-36TM Health Survey

Instructions for Completing the Questionnaire

Please answer every question. Some questions may look like others, but each
one is different. Please take the time to read and answer each question
carefully by filling in the bubble that best represents your response.


This is for your review. Do not answer this question. The questionnaire
begins with the section Your Health in General below.

For each question you will be asked to fill in a bubble, in each line.

1.    How strongly do you agree or disagree with each of the following statements?

                                          Strongly         Agree        Uncertain Disagree   Strongly
                                           agree                                             disagree

     a) I enjoy listening to music.
     b) I enjoy reading

Please begin answering the questions now.

                                           Your Health in General

1.    In general, would you say your health is:

       Excellent           Very good                 Good                  Fair          Poor

2.    Compared to one year ago, how would you rate your health now ?

      Much better Somewhat better About the                             Somewhat      Much worse
     now than one now than one    same as one                         worse now than now than one
       year ago      year ago       year ago                           one year ago    year ago

Please turn the page and continue

© Medical Outcomes Trust and John E. Ware, Jr. —All Rights Reserved

For permission to use contact: Dr John Ware, Medical Outcomes Trust, 20 Park Plaza
Suite 1014, Boston, MA 02116-4313, USA
Source : Reproduced from Ware and Sher bour ne,41 with permission.

                      Figure 2.8. 36-Item Short Form Health Survey (SF-36)
28                                   TEXTBOOK OF CLINICAL TRIALS

‘statistically significant’ differences are truly         If we were to design a trial primarily to com-
those. One way to overcome this problem is for        pare costs associated with different treatments
the clinical protocol to rank the domains of QoL      we would follow the basic ideas of blinding and
to be measured in terms of their relative impor-      randomisation and then record subsequent costs
tance and to confine the formal statistical tests      incurred by the patient and the health provider.
and confidence intervals to these only.                A very careful protocol would be necessary to
                                                      define which costs are being considered so that
                                                      this is measured consistently for all patients.
                                                      A treatment that is not very effective might,
                                                      for example, result in the patient needing more
Most trials are intended primarily to address         frequent consultations. The increased physician,
questions of efficacy. Safety is frequently an         nurse and other paramedical personnel contact
important (though secondary) objective. Health        time would then be recorded as a cost but it
economics is becoming increasingly important          needs to be clear whether patient travel costs,
and is often now evaluated as part of a ran-
                                                      for example (still direct costs, but not to the
domised controlled trial.
                                                      health service) are included, or not. However,
  There are four main types of cost analyses that
                                                      most trials are aimed primarily at assessing effi-
are usually considered:
                                                      ciency and a limitation of investigating costs in
• cost minimisation, simply to determine the best     a clinical trial is that the schedule of, and fre-
  treatment to minimise the total cost of treating    quency of, visits by the patient to the physician
  the disease;                                        may be very different to what it would be in
• cost effectiveness, a trade-off between the cost    routine clinical practice. Typically patients are
  of caring for a patient and the level of efficacy    monitored more frequently and more intensely
  offered by a treatment;                             in a trial setting than in routine clinical prac-
• cost benefit, a trade-off between the cost of        tice. The costs recorded, therefore, in a clinical
  caring for a patient and the overall benefit (not    trial may well be different (probably greater but
  restricted to efficacy);                             possibly less) than in clinical practice. This is
• cost utility, the trade-off between costs and       sometimes put forward as a major objection to
  all measures of ‘utility’ which may include         pharmacoeconomic analyses carried out in con-
  efficacy, quality of life, greater life expectancy   junction with clinical trials. The same limitation
  or increased productivity.                          does, of course, apply to efficacy evaluations: the
                                                      overall level of efficacy seen in clinical trials
   One of the big difficulties with pharmacoeco-       is often not realised in clinical practice. How-
nomic evaluations is determining what indirect        ever, if we keep in perspective that, in a clini-
costs should be considered. Direct costs are usu-     cal trial, it is the relative efficacy of one treat-
ally easier: costs of medication, costs of those      ment over another (even if one of them is a
giving the care (doctors, nurses, health visitors)    placebo) then this limitation, whilst still impor-
and the basic costs of occupation of a hospi-         tant, can be considered less of an overall objec-
tal bed. Indirect costs include loss of earnings      tion. The same argument should be applied in
and productivity, loss of earnings and produc-        pharmacoeconomic evaluations and the relative
tivity of spouses or other family members who         increase/decrease in costs of one treatment over
may care for a sick relative and contribution to      another can be reported.
hospital/pharmacy overhead costs. Because of the         Recommendations on trials incorporating health
ambiguity associated with these indirect costs,       economics assessment have been given by the
most pharmacoeconomic evaluations performed           BMJ Economic Evaluation Working Party.44
as part of a clinical trial tend to focus solely on   Neymark et al.45 discuss some of the method-
direct costs.                                         ological issues as they relate to cancer trials.
                                                GENERAL ISSUES                                              29

                    TRIAL SIZE                               these trials, some have an observed HR that
                                                             is above the hatched horizontal line. This line
When designing a new trial, a realistic assessment           has been drawn at a level that is thought to
of the potential benefit (the anticipated effect              represent a clinically worthwhile advantage to the
size) of the proposed test therapy must be made              test treatment. These specific points would have
at the onset. The history of clinical trials research        been outside the funnel had they been estimated
suggests that, in certain circumstances, rather              from more observed deaths. Thus we might
ambitious or over-optimistic views of potential              conclude from Figure 2.9 that, had these trials
benefit have been claimed at the design stage.                been larger, the corresponding treatments may
This has led to trials of inadequate size for the            have been observed to bring worthwhile benefit,
questions posed.                                             rather than being dismissed as ‘not statistically’
   The retrospective review by Machin et al.46 of            significant.
the published trials of the UK Medical Research                 However, it is a common error to assume that
Council in solid tumour cancers is summarised                the lack of statistical significance following a
in the funnel plot of Figure 2.9. The benefit                 test of hypothesis implies no difference between
observed, as expressed by the hazard ratio (HR)              groups. Conversely, a statistically significant
for the new treatment, is plotted against the                result does not necessarily imply a clinically
number of deaths reported in the trial publication.          significant (important) result. Nevertheless, the
Those trials within the left-hand section of the             message of Figure 2.9 is that potentially useful
funnel have relatively few deaths observed and               therapies may be overlooked if the trials are
so will be of correspondingly low power. Of                  too small.

                                             Designed to demonstrate equivalence
         W                                   Designed to demonstrate recurrence free survival
         O 2.0
         R 1.8
           1.6           CE02 PE
           1.4             BO02
                      ME               LU02
              1.2                            LU06
                     CE01 LU03b BO01 LU02           LU09
                     CEB            BAA               LU09 BR01
              1.0     HNA HNF              LU08           LU07
              0.9   BR03                                CR01
                                           CEA          CR01
              0.8          HNE PR01 OV01                                        BR02
          B                    PR01
          E   0.7                          LU03a
          T               HNB LU01
          T   0.6
          E         NE
          R                            HNC
              0.5                    LU05
                               100           200            300            400           500      600
                                                    Number of deaths
                                               Source : After Machin et al.46

Figure 2.9. Retrospective review of UK Medical Research Council trials in solid tumours published prior to 1996
30                                    TEXTBOOK OF CLINICAL TRIALS

     ANTICIPATED (PLANNING) EFFECT SIZE                and the alternative hypothesis a false negative
                                                       rate. The former is variously known also as the
A major factor in determining the size of a            Type I error rate, test size or significance level, α.
RCT is the anticipated effect size or clinically       The latter is the Type II error rate β, and 1 − β
worthwhile difference. In broad terms if this          is the power. When designing a clinical trial it
is not large then it should be of sufficient            is often convenient to think in hypothesis-testing
clinical, scientific or public health importance to     terms and so set α and β and a specific effect
warrant the consequentially large trial that will      size for consideration. For determining the size
be required to answer the question posed. If           of a trial, α and β are typically taken as small,
the anticipated effect is large, the RCT will be       for example α = 0.05 (5%) and β = 0.1 (10%)
relatively small in which case the investigators       or equivalently the power 1 − β = 0.9 (90%)
may need to question their own ‘optimistic’ view       is large.
of the potential benefit. In either case, a realistic      If the trial is ultimately to compare the means
view of the possible effect size is important.         obtained from the two treatment groups, then
In practice, it is usually important to calculate      with randomisation to each treatment in equal
sample size for a range of values of the effect        numbers, the total sample size, N , is given by
size. In this way the sensitivity of the resulting
sample sizes to this range of values will provide
                                                                          4(z1−α/2 + z1−β )2
options for the investigating team.                                 N=              2
                                                                                               ,      (2.1)
   Estimates of the anticipated effect size may
be obtained from the available literature, formal
meta-analyses of related trials or may be elicited     where z1−α/2 and z1−β are obtained from tables
from clinical opinion. In circumstances where          of the standardised normal distribution for given
there is little prior information available, Cohen47   α and β.
has proposed a standardised effect size, . In the         If we set in equation (2.1) a two-sided α =
case when the difference between two treatments        0.05 and a power of 1 − β = 0.9, then z1−α/2 =
A and B is expressed by the difference between         z0.975 = 1.96 and z1−β = z0.9 = 1.2816, so that
their means (µA − µB ) and σ is the standard           N = 42.028/ 2 ≈ 42/ 2 . For large, moderate
deviation (SD) of the endpoint variable which is       and small sizes of         of 1, 0.5 and 0.1 the
assumed to be a continuous measure, then =             corresponding sample sizes are 42, 168 and 4200,
(µA − µB )/σ . A value of ≤ 0.1 is considered          respectively. More realistically these may be
a small standardised effect, ≈ 0.5 as moderate         rounded to 50, 200 and 4500. For a large simple
and ≥ 1 as large (see also Day3 ). Experience          trial with = 0.05, this implies 16 000 patients
has suggested that in many clinical areas these        may be recruited.
can be taken as a good practical guide for design         This basic equation has to be modified to
purposes. However, for large simple trials, the        adapt to the specific trial design (parallel group,
equivalent of effects sizes as small as = 0.05         factorial, crossover or sequential), the type of
or less may be clinically important.                   randomisation, the allocation ratio, as well as the
                                                       particular type of endpoint under consideration.
                  SAMPLE SIZE                          Machin et al.48 provide examples for many
                                                       different situations.
Once the trial has been concluded, then a formal          A good clinical trial design is that which will
test of the null hypothesis of no difference           answer the question posed with the minimum
between treatments is often made. We emphasise         number of subjects possible. An excessively large
later that it is always important to provide an        trial not only incurs higher costs but is also uneth-
associated confidence interval for the estimate of      ical. Too small a trial size leads to inconclusive
treatment difference observed. The test of the null    results, since there is a greater chance of missing
hypothesis has an associated false positive rate       the clinically important difference, resulting in a
                                               GENERAL ISSUES                                            31

waste of resources. As Pocock4 states, this too         review. For example, the European Organization
is unethical.                                           for the Research on the Treatment of Cancer
                                                        has a standing committee of three clinical and
                                                        one statistical member, none of whom are
       MONITORING TRIAL PROGRESS                        involved in any way with the trials under review.
                                                        This independent DMC reviews reports on trial
     DATA MONITORING COMMITTEES                         progress prepared by the data centre teams and
                                                        makes specific recommendations to the relevant
It is clear that a randomised controlled trial is a
                                                        trial coordinating group. Early thoughts on the
major undertaking, which clearly involves human
                                                        structure of DMCs for the UK Medical Research
subjects in the process. Thus, as we have stated,
                                                        Council Cancer Therapy Committee are provided
it is important that some form of equipoise in
                                                        by Parmar and Machin.52 To emphasise the
respect to the treatments under test is required
                                                        importance of ‘independence’, such committees
to justify the randomisation. However, once the
                                                        sometimes choose the acronym IDMC.
trial is in progress, information accumulates and
as it does so it may be that the initial equipoise
becomes disturbed. Indeed the very point of a                                SAFETY
clinical trial is to upset the equipoise in favour of
the best (if indeed one truly is) treatment.            Although an IDMC will be concerned with
   Clearly there will be circumstances when             the relative efficacy of the treatments under
such early information may be sufficient to              test, issues of safety will also be paramount in
convincingly answer the question posed by the           many circumstances. In many cases, safety issues
trial. In which case the trial should close to          may dominate the early stages of a trial when
further patient entry. One circumstance when            relatively new and untested treatment modalities
this will arise is when the actual benefit far           are first put into wider use, whereas in the
exceeds that which the design team envisaged.           later stages detailed review of safety may not
For example, Lau et al.49 stopped a trial in            be required as no untoward experiences have
patients with resectable hepatocellular carcinoma       been observed in the early stages. In contrast,
after early results on 43 patients suggested            serious safety issues may force a recommendation
a substantial benefit to adjuvant intra-arterial         for early closure of the trial even in situations
iodine-131-labelled lipiodol. Their decision was        where early indications of benefit in terms of
subsequently criticised by Pocock and White,50          efficacy are present. Clearly the role of the
who suggested the result was ‘too good to be            IDMC or (in view of the ‘safety’ aspects) the
true’ as early stopping may yield biased estimates      IDMSC is to provide a balanced judgement on
of the treatment effect. A confirmatory trial is         these possibly conflicting aspects when making
now in progress to substantiate or refute these         their report. This judgement will derive from the
findings.51 Essentially, although very promising,        current evidence from the trial itself, external
in this case the trial results as published provided    evidence perhaps on new information since the
insufficient evidence for other clinical teams to        trial was inaugurated, and their own collective
adopt the test therapy for their patients.              experience.
   Nevertheless in this, and for the majority of
clinical trials, it is clearly important to monitor             INTERIM ANALYSIS AND EARLY
the accumulating data. It has also been recognised                    STOPPING RULES
that such monitoring should be reviewed (not by
the clinical teams involved in entering patients        At the planning stage of a clinical trial the design
into the trial themselves) but by an independent        team will be aware of the need to monitor the
DMC. The membership and remit of a DMC will             progress of the trial by reports to an IDMSC. On
usually depend on the particular trial(s) under         these occasions the data centre responsible for the
32                                    TEXTBOOK OF CLINICAL TRIALS

conduct of the trial will expect to prepare reports    published and negative studies tend not to be
on many aspects of trial progress including            published presents a distorted view of the true
especially safety and efficacy. This requirement is     situation. This approach to reporting is par-
often detailed in the trial protocol. The detail may   ticularly important for clinical trial overviews
specify those aspects that are likely to be of major   and meta-analysis where it is clearly impor-
concern and also the timing (often expressed in        tant to be able to include all relevant stud-
terms of patient numbers or events observed) of        ies (not just the published ones) in the overall
such reports.                                          synthesis.
   An interim report may include a formal                 The second aspect of reporting is the standard
(statistical) comparison of treatment efficacy.         of reporting, particularly the amount of neces-
This comparison will then be repeated on the           sary detail given in any trial report. The most
accumulating data for each IDMSC and finally            basic feature that has repeatedly been empha-
following the close of the trial once the relevant     sised is to give estimates (with confidence inter-
data are to hand. These repeated statistical tests     vals) of treatment effects and not just p-values.
raise the possibility of an increased chance
                                                       Guidelines for referees (useful also for authors)
of falsely declaring a difference in efficacy
                                                       have been published in several journals includ-
between treatments. To compensate for this,
                                                       ing the British Medical Journal.58 The Con-
methods of adjusting for the multiple looks
                                                       solidation of the Standards of Reporting Trials
at the accumulating data have been devised.
                                                       (CONSORT) statement is an international rec-
Many of these are reviewed by Piantadosi53
(Chapter 10).                                          ommendation adopted by many leading medical
   Several of these methods of interim analy-          journals.59
sis also include ‘stopping rules’; that is they           One particular feature of the CONSORT state-
incorporate procedures, or boundaries which once       ment is that the outcomes of ‘all’ patients ran-
crossed by the data under review, imply that the       domised to a clinical trial are to be reported.
trial should terminate. However, all these meth-       Thus a full note has to be provided on those,
ods are predicated on obtaining timely and com-        for example, who post-randomisation refuse the
plete data, very rapid analysis and report writing     allocation and perhaps then insist on the competi-
and immediate review by the IDMSC.54 They              tor treatment. Two examples of how the patient
also focus on only one aspect (usually efficacy)        flow through a trial is summarised are given in
and so do not provide a comprehensive view of          Figure 2.10.
the whole situation.                                      It is of some interest to note that the writing
   The nature of the essential balance required        team for Lau et al.49 were encouraged by the
between a formal statistical approach to interim       journal to include information on late (post-
looks at the data and the less structured nature       interim analysis) randomisations in their report.
of IDMSC decision-making is provided by                It is clear that no such stipulation was required
Ashby and Machin,55 Machin56 and Piantadosi53          of the MRC Renal Cancer Collaborators.28
(Chapter 10.8). Parmar et al.57 describe an               As indicated, the statistical guidelines referred
approach for monitoring large trials using             to, and the associated checklists for statistical
Bayesian methods.                                      review of papers for international journals,60
                                                       require confidence intervals (CIs) to be given
        REPORTING CLINICAL TRIALS                      for the main results. These are intended as an
                                                       important prerequisite to be supplemented by
The first rule after completing a clinical trial        the p-value from the associated hypothesis test.
is to report the results – whether they are pos-       Methods for calculating CIs are provided in
itive, negative or equivocal. Selective reporting      many standard statistical packages as well as the
whereby results of positive studies tend to be         specialist software of Altman et al.61
                                                  GENERAL ISSUES                                                      33

                                                                             116 liver resections for diagnosis
                                                                               of hepatocelluar carcinoma

                350 patients randomly                                         43 eligible patients randomised
                 assigned treatment

           174 assigned      176 assigned
                                                                        21 patients in               22 patients in
            interferon-α         MPA                                  131l-lipiodal
                                                                                  group              control group
7 excluded because              8 excluded because
entered after interim           entered after interim
                                                                     18 patients received
      analysis                        analysis                           131l-lipiodal

                                                                      3 patients did not
           167 included      168 included
            in interim        in interim
             analysis          analysis                            21 patients followed up      22 patients followed up
                                                                     and completed trial          and completed trial

                            Source : After MRC Renal Cancer Collaborators;28 Lau et al.49

                           Figure 2.10. Trial profiles following the CONSORT Guidelines

          INTENTION-TO-TREAT (ITT)                             B, then the trial is no longer properly ran-
                                                               domised and the resulting comparison may be
As we have indicated, once patients have been                  seriously biased.
randomised they should start treatment as spec-                   However, in certain circumstances, the ‘inten-
ified in the protocol as soon as it is practi-                  tion-to-treat’ may be replaced or supplemented by
cably possible. For the severely burnt patients                a ‘per protocol’ summary.62 For example, if the
either MEBO or C dressings can be immediately                  toxicity and/or side-effects profile of a new agent
applied. On the other hand if patients, once ran-              are to be summarised, any analysis including
domised, have then to be scheduled for surgery,                those patients who were randomised to the drug
then there may be considerable delay before ther-              but then did not receive it (for whatever reason)
apy is activated. This delay may provide a period              could seriously underestimate the true levels. If
in which the patients change their mind about                  this is indeed appropriate for such endpoints,
consent or indeed in those with life-threatening               then the trial protocol should state that such an
illness some may die before the scheduled date                 analysis is intended from the onset.
of surgery. Thus, the number of patients actu-                    One procedure that used to be in widespread
ally starting the protocol treatment allocated may             use was, once the protocol treatment and follow-
be less than the number randomised to receive                  up were complete, and all the trial-specific
it. The ‘intention-to-treat’ principle is that once            information collected on a patient, to review these
randomised the patient is retained in that group               data in detail. This review would, for example,
for analysis whatever occurs, even in situations               check that the patient eligibility criteria were
where a patient after consent is randomised to                 satisfied and that there had been no important
(say) A but then refuses and even insists on                   protocol deviations while on treatment. Any
being treated by option B. The effect of such                  patients following this review, then found to be
a patient is to dilute the estimate of the true dif-           ineligible or protocol violators would then, in
ference between A and B. However, if such a                    principle, be set aside and excluded from the
patient was analysed as if allocated to treatment              trial results.
34                                    TEXTBOOK OF CLINICAL TRIALS

   One particular problem is one in which patients     the texts we reference at the end of this chapter
are recruited to a trial on the basis of clinical      and many are covered in ICH E9 Expert Working
examination during which a biopsy specimen is          Group.65 However several aspects are fundamen-
taken and sent for review. In the meantime the         tal and these include the statistical significance
patient is randomised and treatment commenced          test, confidence intervals and analysis adjusted
but once the report is returned the patient is         for confounding (usually prognostic) variables.
found not to comply with the eligibility criteria.        The form of these techniques will depend on
The above review process would automatically           the design and especially the type of endpoint
exclude this patient, whereas Freedman and             variable under consideration. Thus if two means
Machin63 argue otherwise.                              are to be compared then comparisons are made
   Usually, this review would not be blind to the      using the Student t-test, for two proportions it
treatment received – in fact even if the trial is      is the χ 2 test which might be extended for an
double blind – there may be clues once the data        ordinal endpoint to the χ 2 test for trend. In
are examined in this way as to which treatment is      a survival time context, the difference between
which. As a consequence, this process would tend       treatments may, under certain conditions, be sum-
to exclude more patients on the more aggressive        marised by use of the hazard ratio (HR) and
treatment. For example, the review conducted           tested using the logrank test.66 Finally, whether
by Machin et al.46 of some early randomised            the endpoint variable is binary, ordered cate-
trials in patients with cancer conducted by the        gorical, continuous or a survival time, the cor-
UK Medical Research Council showed that the            responding between-treatment comparisons may
earlier publications systematically reported on        be adjusted for baseline characteristics of the
fewer patients in the more aggressive treatment        patients themselves using the appropriate regres-
arm despite a 1:1 randomisation. The exclusion         sion techniques. These are made by logistic
of a larger proportion of patients receiving the       regression, ordered logistic regression, linear
more aggressive therapy would tend to bias the         regression and Cox’s proportional hazards regres-
results in its favour. Thus any patients who           sion respectively.
had ‘difficulties’ with the treatment, perhaps the         Should the design include cluster randomisa-
more sick patients, were not included in the           tion, then Bland and Kerry67 state that the analy-
assessment of its efficacy. This type of exclusion      sis is done by group rather than on an individual
was widespread practice, the consequences of           subject basis.
which included the development of ITT policies
and standards for reporting clinical trials. The
                                                       TESTS OF HYPOTHESES AND CONFIDENCE
latter policy insisting that the progress of all the
randomised patients be reported.
   In general, the application of ITT is con-          If the data are continuous and can be summarised
servative in the sense that it will tend to            by the corresponding mean values in each of the
dilute between-treatment differences. Piaggio and      two treatment groups A and B, then a simple
Pinol64 have pointed out that for equivalence tri-     comparison is made using the difference d =
als ITT will not be conservative but will tend to      x A − x B and the test of the null hypothesis is
favour the equivalence hypothesis.                     made using
                                                                           z=                     (2.2)
                                                       Formally, this tests the null hypothesis that
It is not relevant to review all the analytical        the ‘true’ difference between treatments, δ, is
techniques that may be utilised in summarising         zero. For large trials z will have, under the
clinical trial data. Many of these are described in    assumption that the null hypothesis of equal
                                              GENERAL ISSUES                                          35

means is true, an approximately standard normal        scientific conferences. There are many types of
distribution from which the corresponding p-           graphics that can be used but careful thought
value can be obtained.                                 should be given to the purpose of any graph.
   However, as has been pointed out it is very         Graphs used for exploratory data analysis may
important to report the observed difference d          include histograms, scatter plots, etc. but these
together with an associated confidence interval         may not be appropriate for the final presentation
for the true difference δ. In large samples, the       of data. When presenting the results of clinical
100(1 − α)% CI is given by                             trials, the comparative nature of trials should be
                                                       kept in mind and graphics produced that help in
 d − z1−α/2 SE(d)    to   d + z1−α/2 SE(d) (2.3)       the communication of differences between treat-
                                                       ments. In trials using time as an endpoint measure
where z1−α/2 is obtained from tables of the            the Kaplan–Meier survival curves provide an ele-
normal distribution. For a 95% CI z1−α/2 =             gant summary (Figure 2.11).66
z0.975 = 1.96.
   Such a CI provides a sense of the precision              NUMBER NEEDED TO TREAT (NNT)
with which the observed difference between the
two treatments is provided by the data. In broad       Although many summary measures, for example
terms, the width of the interval is determined by      a difference in response rates or the hazard
the number of subjects recruited, the larger the       ratio, are utilised in clinical trials a measure
number the narrower the corresponding CI. In           unique to this context is the number needed
general, the 95% CI will exclude the null value        to treat. This is one very convenient way of
(zero in this instance) if the corresponding p-        assessing the treatment benefit from trials with a
value <0.05.                                           binary outcome. From the result of a randomised
   Although d provides a simple summary of             trial comparing a new treatment with a standard
the between-treatment group differences it is          treatment, the NNT is the number of patients
important to verify if this remains unchanged          who need to be treated with the new treatment
when taking full account of baseline character-        rather than the standard (control) treatment in
istics: sometimes termed confounding variables         order for one additional patient to benefit. It
or covariates. This is often achieved by using         can be obtained for any trial that has reported
regression techniques to adjust the observed dif-      a binary outcome.
ference, d, by the values of the baseline variables.      The NNT is calculated as the reciprocal of
In most circumstances, there will be some chance       the difference between treatments where this is
of imbalances in the values of the variables that      expressed as a difference of two proportions
may arise following randomisation. The adjust-         (say) pT and pC for test and control treatments
ment may affect the value of d itself as well as       under study. Thus NNT = 1/(pT − pC ) and a
the associated standard error, SE(d), and hence        large treatment effect thus leads to a small NNT.
the CI. Such adjustments for important covari-         A therapy that will lead to one life saved for
ates affecting prognosis may result in the esti-       every 10 patients treated is clearly better than a
mate d being reduced, essentially unchanged or         competing treatment that saves one life for every
increased – which of these occurs will depend on       50 treated. When there is no treatment effects the
the trial data itself.                                 risk difference is zero and the NNT is infinite.
                                                          A confidence interval for the NNT is obtained
                     GRAPHS                            by taking reciprocals of the values defining the
                                                       confidence interval for the treatment difference
Graphical presentation of data is invaluable to        itself. However, as Altman7 has pointed out there
communicate results in published journal arti-         are some difficulties if the treatment effect that
cles or in presentations or posters presented at       is not statistically significant and the confidence
36                                                             TEXTBOOK OF CLINICAL TRIALS


                           0.9                                             n         O             E      HR       95% CI for HR
                                                          Placebo         130        113       131.4       -             -
                           0.8                            TMX60            74         69        69.5     1.16       (0.86, 1.38)
                                                          TMX120          120        114        95.1     1.39       (1.07, 1.81)

     Cumulative survival






                           0.1                      TMX120

                                 0         2          4             6            8            10          12        14           16           18

                                                                        Months from randomisation
                            No. at risk (Death)
                            Placebo       130 (0)    77 (52)    48 (27)        32 (15)       18 (9)    14 (3)   11 (3)   7 (2)        4 (1)   4 (0)
                            TMX60          74 (0)    39 (35)    20 (19)        12 (5)        11 (1)     8 (3)    6 (2)   5 (1)        5 (0)   5 (0)
                            TMX120        120 (0)    66 (53)    26 (40)        16 (9)        11 (5)     5 (5)    3 (2)   1 (0)        0 (0)   0 (0)

                                                                        Source : After Chow et al.12

Figure 2.11. Kaplan–Meier estimates of survival in patients with inoperable hepatocellular carcinoma by
double-blind treatment group

interval includes the null value of 0 (see also the                                        comparison has an associated two-sided test size
comments by Hutton68 ). The NNT can also be                                                α. This is set as the boundary below which
obtained for survival analysis. For these studies                                          the p-value, calculated from the data for the
the NNT is not a single number, but varies                                                 primary endpoint of the trial, must fall to be
according to time since the start of treatment.                                            declared statistically significant. In this case the
                                                                                           null hypothesis of no difference between groups
                                 MULTIPLE COMPARISONS                                      is then rejected.
                                                                                              When this approach is utilised in the analysis
In a clinical trial in which two groups are                                                of a clinical trial comparing two groups and there
being compared, the formal statistical test of this                                        is truly no difference between the two groups,
                                              GENERAL ISSUES                                                37

despite this ‘no difference’ there is a 100α%             The problem of multiple comparisons is partic-
probability of a statistically significant result and   ularly acute in QoL assessments in clinical trials.
the false rejection of the null hypothesis.            Thus guidelines by Staquet et al.71 on reporting
   If more than one endpoint is measured for the       such trials explicitly state: ‘. . . in the case of mul-
two-group study in question then the situation         tiple comparisons, attention must be paid to the
becomes more complex. For example, if a                total number of comparisons, to the adjustment,
clinical trial is comparing two treatments (A          if any, of the significance level, and to the inter-
and B) but there are three different independent       pretation of the results’. Perneger72 concludes
outcomes being measured, then there are three          that: ‘Simply describing what tests of significance
comparisons to make between A and B and,               have been performed, and why, is generally the
in theory at least, three statistical tests. In        best way of dealing with multiple comparisons’.
this circumstance it can be shown that the             In contrast the American Journal of Public Health
false positive rate is no longer 100α% but             recommend the use of a method of adjustment
approximately 300α%. In fact for k (assumed            due to Holm.73 From a clinical trials perspec-
independent) outcome measures the false positive       tive these issues are reviewed by Proschan and
rate is approximately 100kα%. Clearly, the             Waclawiw.74
false positive rate increases as the number of
comparisons made increases.                                         SUBGROUP ANALYSIS
   In order to retain the false positive rate as       In designing a RCT, sample size is usually deter-
100α% the Bonferroni correction is often sug-          mined by considering a clinically worthwhile
gested. This implies only declaring differences as     effect which will be estimated from the trial data
statistically significant at the 100α% level if the     by a comparison of all patients randomised to one
observed p-value < α/k. In the case of α = 0.05        group as compared to the other. It is recognised
and k = 3, this implies p-value < 0.017. Equiv-        that the precision with which this effect size is
alently, and preferably, multiply the observed p-      estimated may be improved by a stratified anal-
value by k and declare this significant if less         ysis adjusted for baseline prognostic variables
than α.69                                              which are known to influence outcome irrespec-
   Similar considerations apply equally to CIs.        tive of the treatment received. However, if treat-
One approach that has been used to overcome this       ments are compared within these strata (thereby
difficulty is to quote 99% CIs rather than 95% CIs      ignoring information on patients not in that stra-
whenever more than a single outcome is regarded        tum) it is clear that the patient numbers must be
as primary. Thus the UK Prospective Diabetes           less than the RCT as a whole. Thus any such
Study Group70 report 21 distinct endpoints,            comparisons will usually lack sufficient statistical
ranging from fatal myocardial infarction to death      power and hence may be unreliable.
from unknown cause, and provide the 99%                   A common mistake is to observe a p-value
confidence intervals for the corresponding 21           in excess of 0.05 (and hence judged naively as
relative risks comparing tight with less tight         not significant) but then to report subgroup analy-
control of blood pressure. This is a ‘half-way         ses – perhaps repeating the treatment comparison
house’ proposal, since 0.01 (= 1 − 0.99) lies          within each disease stage group. In some cir-
between taking no account of the multiplicity          cumstances, one of these subgroup comparisons
and retaining 0.05 to define significance and the        may be ‘significant’ (p-value < 0.05) which will
Bonferroni corrected value of 0.05/21 = 0.0024.        almost certainly imply that those within the other
   Similar considerations of multiplicity may also     groups will not since the ‘all-data-combined’
apply in situations other than trials with multi-      analysis is not significant. In extreme cases, sub-
ple endpoints. For example, Green22 highlights         group analysis can appear to favour one treatment
this problem with respect to trials of a facto-        in one subgroup and the other in the other sub-
rial design.                                           group(s). This may then lead to a false conclusion
38                                    TEXTBOOK OF CLINICAL TRIALS

that the new treatment works for one group but                         COMPETING RISKS
not for the other. If a subgroup analysis is planned
for at the design stage, adjustment for this should    In some situations, a patient may fail following
be built into the sample size considerations.          apparently successful treatment from one of C
                                                       (≥2) so-called competing risk types, for example,
                                                       a local recurrence or a distant metastasis, which
                                                       are competing causes of ultimate mortality in can-
Although the standard of reporting of randomised       cer patients. If relapse is the outcome of interest
controlled trials has improved in many medi-           in the clinical trial, then usually it is the first event
cal journals, there remain many who have not           that is of primary importance to the clinician.
yet adopted the full rigours of the CONSORT            Thus, in a randomised trial of adjuvant therapy
Guidelines. There are also many situations in          in resected Dukes’ C colorectal carcinoma, 17-
which inappropriate and substandard analyses are       1A monoclonal therapy was thought to be most
conducted. Particular examples include statisti-       effective against individually dispersed cells and
cal significance tests of pre-randomisation (base-      less effective against local satellite tumour nod-
line) variables, often describing demographic and      ules or cell aggregates.78 Since the 17-1A anti-
patient eligibility criteria in the different treat-   body should be most effective in preventing or
ment groups, despite the allocation to groups          delaying distant metastases after surgery, distant
having been made by randomisation so that any          metastasis as a first event was thus a key endpoint
observed differences are by definition random.75        in this trial.
                                                          In the analysis of competing patterns of failure,
                                                       the Kaplan–Meier method and the associated
       OTHER MISUSED APPROACHES                        logrank test are frequently used to estimate
              TO ANALYSIS                              the comparative rates of, for example, local
                                                       recurrence and distant metastasis in patients
Anderson76 catalogues some commonly misused            receiving alternative treatments for their cancer in
approaches used in the analysis of clinical trials.    two distinct calculations. In one, local recurrence
These include in, for example, cancer clinical         as the first event is taken as the event of
trials with dual endpoints of tumour response          interest. In this situation, patients who do not
and overall survival, the analysis of survival by      have a local recurrence, or who have local
tumour response itself. In these cases survival is     recurrence as a second or subsequent event,
compared between those patients who respond            irrespective of whether or not they have distant
and those who do not. Such analysis may lead to        metastasis, are treated as censored observations in
a false conclusion that response ‘caused’ longer       the calculations. In the other calculations, distant
survival. Anderson states categorically that such      metastasis as the first event is taken as the event
comparisons are wrong unless an appropriate            of interest.
methodology such as one involving a landmark is           A preferred method, described in detail by Tai
used. Similar considerations apply if comparisons      et al.,79 is to use the cause-specific cumulative
are made between groups established on the basis       incidence functions and comparisons between
of the amount of (protocol defined) treatment           groups via the test developed by Gray.80 Gelman
received, dose intensity or toxicity. Anderson         et al.81 have pointed out that the Kaplan–Meier
et al.77 provide details of the landmark approach.     method produces estimates that are appreciably
   A common mistake is for investigators to            higher than those of the competing risks method.
provide treatment-specific CIs in their reports         Substantial differences have also been noted
for the endpoint(s) of concern, rather than for        in data from patients with Ewing’s sarcoma.79
a relevant measure of treatment comparison such        However a counter viewpoint on the use of the
as their difference or a hazard ratio.                 two approaches is given by Farley et al.,82 using
                                                GENERAL ISSUES                                             39

illustrations from clinical trials in contraceptive      However, the problems associated with ensuring
development.                                             this process is indeed in place in, for example,
                                                         a large multinational trial involving prolonged
  SOFTWARE FOR STATISTICAL ANALYSIS                      follow-up of subjects are considerable. Indeed
                                                         a whole new industry of Clinical Research
There are many statistical packages available for        Organisations (CROs) has developed to guarantee
the summary and analysis of clinical trials and          this process. Further, the Regulatory Agencies
additional features are continually being added.         rightly demand a guarantee of high quality data
Pertinent features that distinguish the packages         in any submission made to them for product
are the flexibility and quality of graphical output       registration.
and the presentation of statistical tables or results.      Information from randomised controlled trials
   Over the last decades, there have been many           provides key information when the pharmaceu-
statistical developments that have impacted on,          tical and allied industries apply to register a
for example, the endpoints that can be assessed,         new drug or device with the relevant regulatory
the design, size, analysis and summary. These            authorities. The authorities themselves impose
include the Kaplan–Meier method for summaris-            certain constraints on the way in which trials
ing survival time studies, the logrank test and          are conducted – these will include basics with
most influential of all the associated Cox pro-           respect to a justification of a sample size for
portional hazards model which allows between-            the trial but will also specify standards.65 These
treatment comparisons adjusted for potentially           too have impacted on the ways that trials are
confounding prognostic variables assessed at             designed, conducted, analysed and reported.
baseline. The Cox model can also accommodate
time-dependent variables, that is variables that
                                                                 PRINCIPLES OF QUALITY DATA
are assessed post-randomisation. These devel-
opments would have remained theoretical in
nature but for parallel developments in statisti-        In clinical trials, subjects are usually entered
cal software.
                                                         one at a time, and their responses to treatment
                                                         monitored sequentially. Regular monitoring of
       CLINICAL DATA MANAGEMENT                          trial progress, especially during the early stages,
                                                         is advisable, and prompt attention to data errors,
            GOOD QUALITY DATA                            inconsistencies or missing items on the CRFs
                                                         is required, so that corrections can be made
Although it is rather outside the scope of this          immediately. If inadequate control is exercised in
text, a vital component to the eventual success of       the management of clinical trials data, subsequent
any clinical trial protocol is the quality of the        analysis may be delayed or at worst wrong.
associated clinical record forms (CRFs). Good               The use of computers for data processing and
CRFs will be pleasant to the eye, logical in             statistical analysis requires careful planning and
layout, comprehensive yet focused on the key             execution by experienced personnel. Errors are
information required, easy to complete and easy          liable to happen in the recording of data in the
to process.                                              CRFs, as well as in the transfer of data to
   A key feature of any scientific study is the           the computer using a database management
implication that the data generated are of high          software.
quality. That is, that the observations made                In a typical trial the sequence of data collection
are carefully recorded at the point and time             might be registration and randomisation, a record
of observation, and then passed through to               of the patient’s name or code, trial number, date
the analysis stage without change. All this is           of birth, date of randomisation and allocated
equally true for clinical trials of whatever design.     treatment (if the trial is not blind) will be
40                                     TEXTBOOK OF CLINICAL TRIALS

entered into the database. The on-study form,            transcription, electronic data entry or delay in
which contains other demographic and baseline            returns of CRFs, rather than the information not
clinical information would be completed and              having been collected. Queries should be raised
added to the database in due course. Patients            for any discrepancies identified by these checks.
are then anticipated to return for follow-up             The data should be edited accordingly after
assessments often over an extended period of             clarification with the investigator or comparison
time. Since patients do not all enter the trial at       with source documents.
the same time, the amount of data collected at              Although information in the CRF should be
any one time may vary considerably as the trial          checked manually and discrepancies resolved by
progresses, and the management of the data on            the data manager prior to data entry, on-line edit-
a computer becomes increasingly complex and              ing checks via computer provides an additional
requires skilful intervention.                           means of detecting errors or missing data. The
   For repeated follow-up evaluations, a sepa-           validation rules would normally be specified and
rate record is normally kept for each evalua-            the associated data checks programmed in paral-
tion. For example, in a double-blind randomised          lel with the building of the database.
placebo controlled trial on inoperable hepatocel-
lular carcinoma,12 information on ECOG perfor-                  SOFTWARE FOR CLINICAL DATA
mance status, Okuda staging, serum albumin and                        MANAGEMENT
bilirubin is collected. In addition, QoL is evalu-       Several specialised software tools for managing
ated not only on entry into the trial, but also at       clinical trial data are commercially available. An
monthly intervals. Since patients may drop out of        early one written for the UK Medical Research
a trial at any time for a variety of reasons this fur-   Council was COMputer PAckage for Clinical
ther complicates the management of the database.         Trails (COMPACT)83 and this included many of
   Quality data management via computers entails         the features necessary for handling ragged data
careful planning and execution by well-trained           sets which arise in clinical trails involving pro-
data managers. As the processes of data tran-            longed follow-up. However, current requirements
scription and entry into computers are highly            of GCP demand, for example, more intensive
susceptible to producing errors, a series of checks      audit trail facilities that were not part of the early
for validity and completeness should be carried          systems. The newer systems, unlike standard
out immediately upon the return of CRFs. Items           spreadsheets, incorporate all the basic features of
that are commonly verified include range checks           a good clinical data management system.
for clinical parameters such as serum levels.               An ideal clinical data management process is
These may be excessively high or extremely low           one that delivers valid and accurate data which
(due to out-of-range or wrong units recorded),           aid the maintaining of data integrity through
or in the case of qualitative variables, a non-          facilities for verifying and validating data, as well
permitted code.                                          as through the implementation of an audit trail
   Logical checks identify any inconsistency in          to document database modifications. They also
information that may be captured in different            allow for automatic reporting of discrepancies,
parts of CRFs. For instance, dates of randomisa-         customised reports can be created and distributed
tion, follow-ups and death carry important infor-        to external sources such as the investigators
mation in clinical trials where survival is the          for resolution and have the ability to efficiently
endpoint. Thus it is important to check that these       handle repeated follow-up evaluations and track
dates as well as other crucial ones have been            status of patients throughout the trial.
recorded and entered correctly.                             These systems also provide global libraries to
   Routine checks on missing items or forms              store the definitions of standard code lists, and
should also be undertaken, as any missing                standard validation or derivation criteria, to opti-
information could be due to oversight in data            mise information input and access throughout the
                                                GENERAL ISSUES                                               41

operation. Standard codes can easily be com-              Senn SJ. Statistical Issues in Drug Development.
puted by defining appropriate derivation rules in            Chichester: John Wiley & Sons (1997).
the global libraries. These codes and rules can           Williams CJ, ed. Introducing New Treatments for
                                                            Cancer: Practical, Ethical and Legal Problems.
be tailored to meet the varying requirements of             Chichester: John Wiley & Sons (1992).
individual trials and can be re-used in subse-
quent databases.
   In multi-centre trials involving diverse and dis-                 DESIGN AND CONDUCT
tant locations, it is possible with these clinical                      OF CLINICAL TRIALS
data management systems to automatically propa-
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same validation rules, derivation criteria and code         Oncology. New York: Marcel Dekker (2000).
lists. This is implemented by means of remote             Jadad A. Randomised Controlled Trials: A User’s
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   With multiple sites and many users accessing           Jennison C, Turnbull BW. Group Sequential Methods
the same network, possibly performing different             with Applications to Clinical Trials. Boca Raton:
tasks, for example database design, entry and               Chapman & Hall/CRC (2000).
resolution by data managers, data retrieval, query        Matthews JNS. Introduction to Randomised Controlled
                                                            Clinical Trials. London: Arnold (2000).
and analysis by statisticians, the security of the
                                                          McFadden ET. Management of Data in Clinical Trials.
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trial system should allow network-wide security           Piantadosi S. Clinical Trials: A Methodologic Perspec-
standards to be enforced by enabling system                 tive. New York: John Wiley & Sons (1997).
administrators to assign, monitor and control             Pocock SJ. Clinical Trials: A Practical Approach.
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                                                          Senn SJ. Cross-over Trials in Clinical Research. 2nd
   For the purpose of statistical analyses, there           edn. Chichester: John Wiley & Sons (2002).
should also be fast, flexible and easy extraction          Whitehead J. Design and Analysis of Sequential Clini-
of data into a variety of user-defined file formats,          cal Trials, Revised 2nd edn. Chichester: John Wiley
such as those of the more commonly used                     & Sons (1997).
statistical packages.                                     Wooding WM. Planning Pharmaceutical Clinical Tri-
                                                            als. New York: John Wiley & Sons (1994).
   Ideally, a good clinical data management sys-
tem should have facilities for randomising treat-
ments, and registering all information captured at                        QUALITY OF LIFE
this stage directly into the database.
   McFadden84,85 provides further details on              Fairclough DL. Design and Analysis of Quality of
                                                            Life Studies in Clinical Trials. Andover: CRC Press
many aspects of clinical data management and                (2002).
associated areas.                                         Fayers PM, Machin D. Quality of Life: Assessment,
                                                            Analysis and Interpretation. Chichester: John Wiley
                                                            & Sons (2000).
        SELECTED FURTHER READING                          Staquet MJ, Hays R, Fayers PM. Quality of Life Clin-
             ON CLINICAL TRIALS                             ical Trials: Methods and Practice. Oxford: Oxford
                                                            Medical Publications (1998).

                                                                             SAMPLE SIZE
Day S. Dictionary for Clinical Trials. Chichester: John
  Wiley & Sons (1999).                                    Machin D, Campbell MJ, Fayers PM, Pinol APY.
Redmond C, Colton T, eds. Biostatistics in Clinical        Sample Size Tables for Clinical Studies. Oxford:
  Trials. Chichester: John Wiley & Sons (2000).            Blackwell Science (1997).
42                                       TEXTBOOK OF CLINICAL TRIALS

          EVIDENCE-BASED MEDICINE                                intravenous heparin in men with unstable coronary
                                                                 artery disease. Lancet (1990) 336: 827–30.
Altman DG, Chalmers I, eds. Systematic Reviews.            14.   The ATAC (Arimidex, Tamoxifen Alone or
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Sutton AJ, Abrams KR, Jones DR, Sheldon TA,                      alone or in combination with tamoxifen versus
  Song F. Methods of Meta-Analysis in Medical                    tamoxifen alone for adjuvant treatment of post-
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                                                                 results of the ATAC randomised trial. Lancet
                                                                 (2002) 359: 2131–9.
                                                           15.   Piya-Anant M, Koetsawang S, Patrasupapong N,
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                         Clinical Trials in Paediatrics
                                                 JOHAN P.E. KARLBERG
                                    Clinical Trials Centre and Department of Paediatrics,
                                      The University of Hong Kong, Hong Kong SAR

  WHY SHOULD WE DO CLINICAL TRIALS                                      ‘Children are not simply Small Adults’ and its
           IN CHILDREN?                                                 Guidelines for the Ethical Conduct of Studies to
                                                                        Evaluate, published in 1995, reported that:
Children are subject to many of the same diseases
as adults, and are often treated with the same                          • In 1973, 78% of medications included a dis-
drugs and biological products. However, many                              claimer or lack of dose information for children.
drugs on the market used to treat children are                          • In 1991, 81% of listed drugs were restricted
inadequately labelled for use with paediatric                             for certain age groups.
patients; and many carry disclaimers stating that                       • In 1992, 79% of 19 new molecular entities
safety and effectiveness in paediatric patients                           approved were not labelled for use in children.
have not been established. Information about the
safety and effectiveness of treatments for some                         As a result of effectively being denied access
paediatric age groups is particularly difficult                          to well-studied drugs, paediatricians either don’t
to find. Even today, no treatment is available                           treat children with potentially beneficial medica-
for many of the thousands of rare and serious                           tions, or treat them with medications based either
diseases that largely affect neonates, infants and                      on adult studies or anecdotal empirical experi-
children. Most drugs used to treat common                               ence in children. Such non-validated administra-
diseases in both children and adults have not been                      tion of medications may place more children at
investigated in children at all. Over 50% of all                        risk than if the drugs were administered as part
drugs prescribed in paediatric practice are either                      of well-designed, controlled clinical trials. There
‘unlicensed’ or ‘off label’.                                            is therefore a moral imperative to formally study
   The paediatric medical community has for                             drugs in children, so they can enjoy equal access
decades tried to persuade regulatory authorities                        to existing as well as new therapeutic agents.
and the pharmaceutical industry to test new drugs                          The US National Institute of Health (NIH)
in the paediatric population in parallel with the                       published regulations in 1999 clearly defining
adult studies. The motto of the campaign has been                       what human studies could be funded by NIH

Textbook of Clinical Trials. Edited by D. Machin, S. Day and S. Green
 2004 John Wiley & Sons, Ltd ISBN: 0-471-98787-5
46                                   TEXTBOOK OF CLINICAL TRIALS

to the exclusion of paediatric subjects. The          REGULATORY ISSUES OF CLINICAL TRIALS
exclusionary circumstances were:                                IN CHILDREN?

• Research topic irrelevant to children;              Regulatory authorities in the US and Europe
• Laws or regulations barring inclusion of chil-      have in recent years taken important steps to
  dren;                                               address the problem of inadequate paediatric test-
• The knowledge is available for children or will     ing and inadequate paediatric use information in
  be obtained from another ongoing study;             drug and biological product labelling. But these
• The relative rarity of the condition in children;   efforts have, thus far, not substantially increased
• The number of children is limited;                  the number of products entering the marketplace
• Insufficient data are available in adults to judge   with adequate paediatric labelling. The regulatory
  potential risk in children.                         authorities have therefore concluded that addi-
                                                      tional steps are necessary to ensure the safety
Not until recently have children been more reg-       and effectiveness of drug and biological products
ularly included in clinical studies to investi-       for paediatric patients. Manufacturers of new and
gate drugs. Considerable differences between          marketed drugs and biological products must now
the pharmacokinetics and pharmacodynamics             evaluate the safety and effectiveness of the prod-
of drugs in children and in adults frequently         ucts in paediatric patients if the product is likely
make it impossible to bridge conclusions from         to be used in a substantial number of children, or
data obtained in adults. Children cannot even         provide a more meaningful therapeutic benefit to
be considered a homogeneous group, since              paediatric patients than existing treatments.
age groups differ in their absorption, distri-           Since 2000 in both the US and Europe,
bution, metabolisation and excretion of drugs         pharmaceutical companies have been obliged
and their effect on developing organ sys-             to include paediatric data in all new drug
tems. The anatomical structure of children’s          applications and licence extensions provided that
organs differ from adults, causing different phar-    substantial use of the drug in children and a
macodynamic characteristics observed during           meaningful therapeutic benefit is expected. The
childhood.                                            strength of this legislation is however different
   The lack of paediatric safety information          in the two regions–and so is the extension of
in product labelling exposes paediatric patients      market exclusivity.
to the risk of age-specific adverse reactions             In recent years an independent ‘Orphan’ drug
unexpected from adult experience. The absence         regulation has been in force in the countries of
of paediatric testing and labelling may also          the European Community as well as in the US.
expose paediatric patients to ineffective treatment   This creates incentives for the development of
through under-dosing, or may deny paediatric          drugs for rare serious diseases, but is unlikely
patients therapeutic advances. Failure to develop     to achieve effective improvement in paediatric
a paediatric formulation of a drug or biological      drug therapy. The Food and Drug Administration
product, where younger paediatric populations         (FDA) Modernization Act established economic
cannot take the adult formulation, may also           incentives for pharmaceutical manufacturers to
deny paediatric patients access to important          conduct paediatric studies on drugs for which
new therapies.                                        patent protection or exclusivity is available
   Three conclusions can therefore be drawn           under the Drug Price Competition and Patent
about paediatric drug studies: studies must be        Term Restoration Act or the Orphan Drug Act.
made in different age groups; describing the phar-    These provisions attach six additional months of
macokinetics and pharmacodynamics is crucial;         marketing exclusivity to any existing exclusivity
and the safety of drugs must be studied to identify   or patent protection of a drug for which FDA has
potential severe side effects.                        requested paediatric studies.
                                     CLINICAL TRIALS IN PAEDIATRICS                                    47

   However, there is likely to be a consensus          development by Autumn 2002. This legislation
during the coming years–at least in the ICH            is considered by many to be pressing, creating
GCP regions–over requirements for conducting           the conditions needed to improve medicines for
clinical trials on new drugs and other thera-          children. Nearly all involved parties in Europe
pies in children. But before this consensus can        supported a legal and regulatory framework
be reached, a number of points have to be              for improving child health, especially regarding
addressed and discussed, underlined by the fol-        the labelling of medicines. The consultation
lowing two examples.                                   document concluded:

   EXAMPLE 1–ONGOING DISCUSSIONS                       • A robust ethical framework for European pae-
      OF THE CONSENT PROCESS IN                          diatric research needs to be created, includ-
           PAEDIATRIC TRIALS                             ing guidance for informed consent, ethical
                                                         review, recruitment of subjects, and safety
The significant increase in the number of chil-           and oversight.
dren participating in clinical trials continues to     • A robust paediatric clinical study infrastructure
raise ethical and procedural concerns. The FDA           needs to be created in Europe, since as a result
addressed this issue in April 2001, calling on           of reluctance to perform such studies up to
institutional review boards to review study proto-       now, there is a serious shortage of trained and
cols that include children and ensure they adopt         experienced people and centres of excellence.
safeguards to protect young research participants.     • Greater cooperation should be stimulated
A group in the US is currently examining the             between public sector research and private sec-
‘best practices’ related to research involving chil-     tor research in paediatrics, in the interest of
dren. The study will address:                            developing a European dimension to improv-
                                                         ing medicines for children.
• Process for obtaining informed consent and           • A clear framework should be developed for
  assent from children and their parents or legal        assembling international data and information
  representatives.                                       regarding paediatric trials and medicines–to
• How well participants in paediatric studies and        ensure that unnecessary trials are not carried
  their guardians understand direct benefits and          out in Europe, and that European paediatricians
  risks of study involvement?                            have the benefit of up-to-date and comprehen-
• Definition of “minimal risk” related to healthy         sive information regarding medicinal products
  and ill child study participants.                      for their patients, wherever in the world that
• Whether regulations and policies should vary           information has been generated.
  for children of different ages (for example,         • A greater public dialogue is required in Europe
  teenagers and infants)?                                regarding the benefits and risks of paediatric
• Appropriateness of payments to children, par-          research for individual children participating
  ents, or legal representatives for participation       in research, as well as for public health
  in research.                                           in general.
• Role of IRBs in monitoring compliance with
  regulations related to paediatric studies.
                                                        ICH GUIDELINE ON PAEDIATRIC STUDIES
 THE LEGISLATION OF PAEDIATRIC TRIALS                  The International Conference on Harmonisa-
                                                       tion (ICH) Guideline E11–Clinical Investigation
Based on feedback from a consultation document,        of Medicinal Products in the Pediatric Popu-
the European Commission was expecting to               lation–became operational in January 2001 in
prepare draft legislation on paediatric medicinal      the United States, Europe and Japan. The E11
48                                    TEXTBOOK OF CLINICAL TRIALS

guideline outlines critical issues in paediatric       • For medicinal products for diseases predom-
drug development. In summary, this new and               inantly or exclusively affecting paediatric
important ICH document states that paediatric            patients, the entire development programme
patients should be given medicines that have             will be conducted in the paediatric population,
been appropriately evaluated for their use. It says      except for initial safety and tolerability data,
safe and effective therapy in paediatric patients        which will usually be obtained in adults.
requires the timely development of information         • For medicinal products intended to treat seri-
on the proper use of medicinal products in pae-          ous or life-threatening diseases occurring in
diatric patients of various ages and, often, paedi-      both adults and paediatric patients, for which
atric formulations of those products. The goal of        there are currently no (or limited) therapeutic
this guideline is to encourage and facilitate timely     options, there is need for relatively urgent and
paediatric medicinal product development inter-          early initiation of paediatric studies.
nationally. This guideline addresses five issues,       • For medicinal products intended to treat other
namely considerations when initiating a paedi-           diseases and conditions there is less urgency.
atric programme, the timing of its initiation, type      Trials would usually begin at later phases of
of studies, age categories and ethics.                   clinical development or, if a safety concern
                                                         exists, even after a substantial post-marketing
   WHEN INITIATING A PAEDIATRIC                          period in adults. Testing of these medicinal
PROGRAMME? (SUMMARY POINTS OF ICH                        products in the paediatric population would
             GCP E11)                                    usually not begin until Phase II or III–since
                                                         very early initiation of testing in paediatric
The decision to proceed with a paediatric devel-         patients might needlessly expose them to a
opment programme for a certain medicinal prod-           compound of no benefit.
uct requires consideration of factors such as:
                                                          TYPES OF STUDIES (SUMMARY POINTS
• Prevalence of the condition in the paedi-                         OF ICH GCP E11)
  atric population;
• Seriousness of the condition;                        Selection of the type of study should be on the
• Availability and suitability of alternative treat-   same principles as studies planned for adults.
  ments;                                               However, several considerations are of specific
• Unique paediatric indications;                       importance for paediatric studies. Some of the
• Unique paediatric-specific endpoints;                 most important are:
• Age ranges of paediatric patients likely to
  be treated;                                          • When a medicinal product is to be used
• Unique paediatric safety concerns;                     in the paediatric population for the same
• Unique paediatric formulation development.             indication(s) as those studied and approved in
                                                         adults, the disease process is similar in adults
The most common considerations when dis-                 and paediatric patients, and the outcome is
cussing the need and timing of a paediatric pro-         likely to be comparable, extrapolation from
gramme are:                                              adult efficacy can be appropriate. In such cases,
                                                         pharmacokinetic (PK) studies in all the age
• Most important is the presence of a serious or         ranges of paediatric patients likely to receive
  life-threatening disease for which the medici-         the medicinal product, together with safety
  nal product represents a potentially important         studies, may provide adequate information.
  advance in therapy. This situation suggests rel-     • When a medicinal product is to be used in
  atively urgent and early initiation of paedi-          younger paediatric patients for the same indi-
  atric studies.                                         cation(s) as those studied in older paediatric
                                    CLINICAL TRIALS IN PAEDIATRICS                                     49

  patients, the disease process is similar, and the   Special considerations should be taken when
  outcome is likely to be comparable, extrapola-      blood is drawn more than once in paedi-
  tion of efficacy from older to younger paedi-        atric subjects, such as in PK/PD studies. Sev-
  atric patients may be possible. In such cases,      eral approaches can be used to minimise the
  pharmacokinetic studies in the relevant age         amount of blood drawn and/or the number of
  groups of paediatric patients together with         venipunctures:
  safety studies may be sufficient.
• Many diseases in preterm and term newborn           • Use of sensitive assays;
  infants are unique or have unique manifesta-        • Use of laboratories experienced in handling
  tions precluding extrapolation of efficacy from        small volumes;
  older paediatric patients and call for novel        • Using routine clinical blood samples for phar-
  methods of outcome assessment.                        macokinetic analysis;
• Where the disease course/outcome of therapy         • Use of indwelling catheters;
  in paediatric patients is expected to be similar    • Use of population pharmacokinetics and sparse
  to adults, but the appropriate blood levels           sampling.
  are not clear, it may be possible to use
  measurements of a pharmacodynamic (PD)                                   Efficacy
  effect related to clinical effectiveness. Thus,
  a PK/PD approach combined with safety and           The principles in study design, statistical consid-
  other relevant studies could avoid the need for     erations and choice of control groups are detailed
  clinical efficacy studies.                           in other ICH guidelines and apply to paediatric
• When unique indications are being sought for        efficacy studies. But there are also certain features
  the medicinal product in paediatric patients,       unique to paediatric studies.
  or when the disease course and outcome of
  therapy are likely to be different in adults and    • Extrapolation of efficacy from studies in adults
  paediatric patients, clinical efficacy studies in      to paediatric patients, or from older to younger
  the paediatric population are needed.                 paediatric patients, as mentioned above.
                                                      • For efficacy studies it may be important
               Pharmacokinetics                         to employ different endpoints for specific
                                                        age groups.
Pharmacokinetic studies generally should be per-      • Measurement of subjective symptoms requires
formed to support formulation development and           different assessment instruments for patients of
determine pharmacokinetic parameters in differ-         different ages.
ent age groups. Pharmacokinetic studies in the        • The response to a medicinal product may vary
paediatric population are generally conducted in        among patients because of the developmental
patients with the disease. Single-dose or steady-       stage of the patient.
state studies are the choice of pharmacoki-
netic study:                                                                Safety
• For medicinal products that exhibit linear phar-    ICH guidelines (E2 and E6) describe adverse
  macokinetics in adults, single-dose pharma-         event reporting and apply to paediatric studies.
  cokinetic studies in the paediatric population      But there are certain safety aspects unique to
  may be sufficient.                                   paediatric studies.
• When there is a nonlinearity in absorption,
  distribution and elimination in adults and          • Medicinal products may affect physical and
  difference in duration of effect between single       cognitive growth and development, and the
  and repeated dosing in adults suggests steady-        adverse event profile may differ in paediatric
  state studies in the paediatric population.           patients, compared with adults.
50                                   TEXTBOOK OF CLINICAL TRIALS

• The dynamic processes of growth and devel-          • Children (2 to 11 years): Most pathways of
  opment may not manifest an adverse event              drug clearance are exceeding adult values.
  at once, but at a later stage of growth               Changes in clearance of a drug may be
  and maturation.                                       dependent on maturation of specific metabolic
• Long-term studies or surveillance data may            pathways. The protocols should ascertain
  be needed to determine possible effects on            assessment of the effect of the medicinal prod-
  skeletal, behavioural, cognitive, sexual and          uct on growth and development. Recruitment
  immune maturation and development.                    of patients should ensure adequate represen-
• Post-marketing surveillance may provide im-           tation across the age range in this category.
  portant safety and/or efficacy information for         Puberty can affect the activity of enzymes that
  the paediatric population.                            metabolise drugs, and dose requirements for
• Age-appropriate, normal laboratory values and         some medicinal products may decrease dramat-
  clinical measurements should be used in               ically.
  adverse event reporting.                            • Adolescents (12 to 16–18 years (dependent on
                                                        region)): This is a period of sexual maturation
     AGE CLASSIFICATION OF PAEDIATRIC                   and medicinal products may interfere with the
     PATIENTS (SUMMARY POINTS OF ICH                    actions of sex hormones. Medicinal products
                  GCP E11)                              and illnesses that delay or accelerate the
                                                        onset of puberty can have a profound effect
Decisions on how to stratify studies and data by        and may affect final height. Many diseases
age need to take into consideration developmental       are also influenced by the hormonal changes
biology and pharmacology. The identification of          around puberty and hormonal changes may
which ages to study should be medicinal product-        thus influence the results of clinical studies.
specific and justified.                                   Noncompliance is a special problem and
                                                        compliance checks are important.
• Preterm newborn infants: Preterm newborn
  infants have a unique pathophysiology and             ETHICAL ISSUES IN PAEDIATRIC STUDIES
  responses to therapy. The complexity of and            (SUMMARY POINTS OF ICH GCP E11)
  ethical considerations involved in studying
  preterm newborn infants requires a careful          The paediatric population represents a vulnerable
  protocol development with expert input from         subgroup. Therefore, the following special mea-
  neonatologists and neonatal pharmacologists.        sures are needed to protect the rights of paediatric
  Only rarely can we extrapolate efficacy from         study participants.
  studies in adults or in older paediatric patients
  to the preterm newborn infant.                      • Participants in clinical studies are expected to
• Term newborn infants (0 to 27 days): Newborn          benefit from the clinical study, except under
  infants are more mature than preterm newborn          special circumstances.
  infants, but many of the physiologic and            • When protocols involving the paediatric pop-
  pharmacologic principles for preterm infants          ulation are reviewed, there should be IRB/IEC
  also apply to them.                                   members or experts consulted by the IRB/IEC
• Infants and toddlers (28 days to 23 months):          who are knowledgeable in paediatric ethical,
  This is a period of rapid CNS maturation,             clinical and psychosocial issues.
  immune system development and total body            • Paediatric study participants are dependent
  growth. By 1–2 years of age, clearance of             on their parent(s)/legal guardian to assume
  many drugs on a mg/kg basis may exceed adult          responsibility for their participation in clinical
  values and then it may be dependent on specific        studies. Participants of appropriate intellectual
  pathways of clearance.                                maturity should personally sign and date either
                                      CLINICAL TRIALS IN PAEDIATRICS                                    51

    a separately designed, written assent form or         First studies that promise no demonstrable ben-
    the written informed consent.                      efits to the child participating in the study or
•   Information that can be obtained in a less         to children in general should not be conducted,
    vulnerable, consenting population should not       irrespective of the minimal nature of the atten-
    be obtained in a more vulnerable population or     dant risks. The risks include discomfort, incon-
    one in which the patients are unable to provide    venience, pain, fright, separation from parents
    individual consent.                                or surroundings, effects on growth and develop-
•   Studies in handicapped or institutionalised        ment of organs, and size or volume of biologi-
    paediatric populations should be limited to        cal samples.
    diseases or conditions found principally in           The proposed research must be of value to
    these populations, or when it is expected          children in general and, in most instances, to the
    that the disease may alter the effects of a        individual child subject:
    medicinal product.
•   To minimise risk in paediatric clinical studies,   • The research design must take into consider-
    those conducting the study should be trained         ation the unique physiology, psychology and
    and experienced in studying the paediatric pop-      pharmacology of children and their special
    ulation, including the evaluation and manage-        needs and requirements as research subjects.
    ment of potential paediatric adverse events.       • The design should minimise risk while max-
•   In designing studies, every attempt should           imising benefits.
    be made to minimise the number of partici-         • The study design must take into account the
    pants and of procedures, consistent with good        racial, ethnic, gender and socioeconomic char-
    study design.                                        acteristics of the children and their parents.
•   To ensure that experiences of the study sub-       • A placebo/observational control group may
    jects are positive and to minimise discomfort        be acceptable when there is no commonly
    and distress.                                        accepted therapy, or the commonly used ther-
                                                         apy is of questionable efficacy, or the com-
ETHICAL CONSIDERATIONS IN PAEDIATRIC                     monly used therapy has high frequency of side
              STUDIES                                    effects, i.e. larger than the benefits.

Of all the problems surrounding research in                 PAEDIATRIC INFORMED CONSENT
children, the one that poses perhaps the most
complex question is research ethics. Children          Children are not legally able to provide consent
are not legally able to provide consent and the        and the extent to which children are able to under-
extent to which children are able to understand        stand the meaning, risks and potential benefits of
the meaning, risks and potential benefits of            participating in clinical trials varies enormously
participating in clinical trials varies enormously     according to age and background. Children are
according to age and background. For this              counted as members of a vulnerable population
reason it may be appropriate to address some           at risk for exploitation and are given special pro-
points related to the IRB review, including the        tection in clinical research. In paediatric trials,
informed consent process, in paediatric trials         just as in adult trials, materials in an understand-
more specifically than outlined in the ICH GCP          able language, opportunities to discuss the trial,
E11 guideline. One document that addresses this        and freedom to withdraw without penalty must
topic at more depth is the Review and Award            be provided to potential subjects.
Codes for the NIH Inclusion of Children Policy            Investigators are ultimately held responsible
from 1999. The following partly originates from        for ensuring adequate informed consent. More
this document, but also incorporates sources           than two decades of inquiry into the process
listed at the end of this chapter.                     of consent have shown that adults are less than
52                                  TEXTBOOK OF CLINICAL TRIALS

adequately informed about risks, benefits and par-    understand; and the purpose, risks and bene-
ticipation in research. The process is even more     fits of a study should be explained to them.
problematic for research involving individuals       The following guideline has therefore been pro-
with limited abilities in decision-making. The       posed:
evolving psychological and emotional develop-
ment of children and adolescents presents chal-      No greater than minimal risk
lenges to paediatric investigators not encountered
                                                     • Assent of the child and permission of at least
when dealing with adult subjects. Unless oppos-
                                                       one parent.
ing evidence is identified, capacity to understand
and provide informed consent has long been
                                                     Greater than minimal risk and prospect of
assumed in adults. Results from studies in healthy
                                                     direct benefit
and sick children suggest that also children have
this capacity. Several investigators have evalu-     • Assent of the child and permission of at least
ated the degree to which minors from school            one parent.
age through adolescence are capable of provid-       • Anticipated benefit justifies the risk.
ing assent. Even very young children demonstrate     • Anticipated benefit is as least as favourable as
inquisitiveness about the proposed research. By        alternative approaches.
the age of nine, children can understand purpose,
risk and the right to withdraw from the study.       Greater than minimal risk and no prospect of
Even seven-year-old children can understand the      direct benefit
purpose of a study. Such observations support
the requirement by most ethics boards that assent    • Assent of the child and permission of both
be obtained in children aged seven and older.          parents.
However, information regarding scientific versus      • Likely to yield generalisable knowledge about
therapeutic study objectives for both research and     the child’s disorder.
alternative treatment is not well understood in
seven to 20-year-old subjects. Paediatric subjects       SPECIFIC PROBLEMS OF PAEDIATRIC
can thus provide an informed agreement to partic-                    STUDIES
ipate, but the assent process should be conducted
using discussions that encourage questions.
                                                                SUBJECT RECRUITMENT

     Obtaining Informed Permission–Assent–to         Insufficient enrollment of children is the most
                    Participate                      common reason for discontinuing paediatric stud-
                                                     ies. Creating and expanding networks for paedi-
Regulations permit studies involving minimal         atric pharmacology studies, such as in the US and
risk in children, with the provision that permis-    Europe, are steps in the right direction to recruit
sion from parents and assent from subjects are       enough subjects. Many reasons for this poor
obtained. Research involving greater than min-       recruitment rate for paediatric studies include:
imal risk, but providing potential direct benefit
to the child, is also permitted with the same        • Strict inclusion and exclusion criteria;
provision. There are some exceptions to the          • Limited size of the paediatric population;
requirement for assent and consent. Assent is        • That each age group has to be consid-
not necessary for research expected to directly        ered separately;
benefit the child. Assent must be an active           • Inconvenience for the parents in having their
affirmation from any child with an intellectual         children participate in a clinical study;
age of seven years or older. Assent should be        • Fear of making one’s own child available as a
obtained from children who are competent to            ‘guinea pig for research’.
                                     CLINICAL TRIALS IN PAEDIATRICS                                       53

• Doctors are wary of jeopardising the doc-            Just taking adult protocols, then changing the age
  tor–patient relationship, or losing the trust        in the inclusion criteria and the dose, is not good
  of parents.                                          enough. With a limited number of investigators
                                                       and a limited number of potential subjects, study
                EARLY TESTING                          design is critical for successful development of
                                                       new safe and life-saving therapeutic entities for
There are no healthy paediatric volunteers. The        paediatric usage.
lack of volunteers for Phase I studies is a
special problem and makes the planning of
                                                                      FURTHER READING
therapeutic studies in children difficult. The
requirements for paediatric study designs are for
this and other reasons different from studies in                        PUBLICATIONS
adults. Alternative study designs and alternative
                                                       • Shirkey H. Therapeutic orphans (editorial com-
statistical methods are required.                        ment). J Pediatr (1968) 72: 119–20.
                                                       • Rogers LC, Cocchetto DM. Labeling prescription
            STUDY MANAGEMENT                             drugs for pediatric use in the United States. Appl
                                                         Clin Trials (1997) 50–6.
                                                       • Tarnowski KJ, Allen DM, Mayhall C, Kelly PA.
To obtain a sufficient number of subjects requires        Readability of pediatric biomedical research infor-
a large number of study centres. Moreover, the           med consent forms. Pediatr (1990) 85: 58–62.
cost for each individual step of a paediatric study    • Susman EJ, Dorn LD, Fletcher JF. Participation in
is usually higher than for studies in adults–both        biomedical research: the consent process as viewed
to pharmaceutical companies, as sponsors of the          by children, adolescents, young adults, and physi-
                                                         cians. J Pediatr (1992) 121: 547–52.
studies, and to the participating doctors. For         • Ethical Conduct of Studies to Evaluate Drugs in
instance, explaining the nature of a study–to            Pediatric Populations. Committee on Drug. Pedi-
obtain permission from parents and ensure their          atrics (1995) 95: 286–94.
cooperation during the course of the study–is          • Wechsler J. Science, pediatric studies, and surro-
a very time-consuming process. Explanatory               gates. Appl Clin Trials (1999) 28–33.
                                                       • Nahata MC. Lack of pediatric drug formulations.
material and information has to be prepared not          Pediatrics (1999) 104: 607–9.
only for parents, but also adapted for the children.   • Conroy S, McIntyre J, Choonara I. Unlicensed and
Caring for the children during their visits to           off label drug use in neonates. Arch Dis Childh:
the study centre also requires creativity, patience      Fetal Neonatal Edit (1999) 80: F142–5.
and time.                                              • Conroy S, McIntyre J, Choonara I, Stephenson T.
                                                         Drug trials in children: problems and the way
                                                         forward. Br J Clin Pharmacol (2000) 49: 93–7.
                                                       • Kauffman RE. Clinical trials in children: problems
              FINAL COMMENTS                             and pitfalls. Paediatr Drugs (2000) 2: 411–18.
                                                       • Simar MR. Pediatric drug development; the Interna-
                                                         tional Conference of Harmonization Focus on Clin-
Faced with heavy workloads, paediatricians may           ical Investigation in Children. Drug Inform J (2000)
often be reluctant to assume what looks like             34: 809–19.
the extra work of clinical trials. But a shortage
of investigators is not the only problem that              OFFICIAL DOCUMENTS/GUIDELINES
slows paediatric trials. It takes many subjects to
satisfy the requirements for an adult drug to be       • Review and award codes for the NIH inclusion of
adequately studied in children–and frequently the        children policy March 26, 1999.
population of paediatrics with a certain disease       • Regulation (EC) No. 141/2000 of the European
                                                         Parliament and the Council of 16 December 1999
does not exist. So not only do studies need to be        on orphan medicinal products.
designed to use small populations efficiently; they     • World Medical Association, Declaration of Helsinki
also need to be designed with children in mind.          (amended October 2000).
54                                    TEXTBOOK OF CLINICAL TRIALS

• Food and Drug Administration, Department of            information may produce health benefits in the
  Health and Human Services, The Pediatric Exclusiv-     paediatric population (May 20, 2001), Docket
  ity Provision January 2001 Status Report to Cong-      No. 98N0056ICH Topic Ell, ‘Clinical Investiga-
  ress.                                                  tion of Medicinal Products in the Pediatric Popu-
• Food and Drug Administration, Additional Safe-         lation’. CPMP/ICH/2711/99, January 2001, adopted
  guards of Children in Clinical Investigations of       July 2000.
  FDA-Regulated Products: Interim Rule, Federal        • European Commission, Better Medicines for Chil-
  Register 66 (79) 20589 (24 April 2001).                dren: Proposed regulatory actions on paediatric
• Food and Drug Administration, Update of list           medicinal products (European Commission, Brus-
  of approved drugs for which additional paediatric      sels, Belgium, 2002).
          Clinical Trials Involving Older People
                                 CAROL JAGGER AND ANTONY J. ARTHUR
                Department of Epidemiology and Public Health, University of Leicester, Leicester, UK

As few diseases or conditions present for the first                      80 years of age, found only 38% of studies
time in later life, there are few treatments pre-                       included subjects over 75 years of age.3
scribed solely to older people. There is also little                       Trials of the efficacy of interventions should
consensus on the definition of ‘the elderly’ since                       cover the age groups who are affected.4 Older
ageing can be considered a continuous process                           people have been explicitly excluded through
from birth to death. However the increasing like-                       the use of a maximum age for eligibility and
lihood of illness other than that under treatment                       obviously such trials provide little information
and greater mental and physical frailty with age-                       about the efficacy of treatments in older age
ing means that older people can be inherently                           groups. However implicit exclusion is also com-
different to younger adults and the numerous                            mon, through criteria such as the presence of co-
physiological changes that accompany the ageing                         morbid conditions. In addition certain recruitment
process may alter the way in which older people                         methods may result in study populations with
respond to drugs.1                                                      older people an under-representation of the gen-
   By 2010 in most of the developed countries,                          eral population likely to be treated. In these cases
the 65+ age group will form over 15% of the                             it may be difficult for the clinician to be aware of
total population and over 20% in Japan. In the                          the paucity of older people studied, resulting in
UK, those aged 65 years and over make up 18%                            the late recognition of serious side effects when
of the population but they receive nearly half of                       drugs tested on predominantly younger adult pop-
all prescriptions.2 Despite this, few trials, unless                    ulations are finally released and prescribed to
specially designed and conducted in this age                            larger numbers of older people. Perhaps the most
group, have sufficient numbers of older people,                          famous, or infamous, case of this was benoxapro-
particularly the ‘oldest-old’, to provide evidence                      fen, a non-steroidal anti-inflammatory drug mar-
of efficacy, even for treatments of diseases                             keted as Opren, which was withdrawn after a
and conditions that are seen predominantly in                           report of the death of five elderly patients who
later life. A recent review of clinical trials in                       had taken the drug.5
Parkinson’s disease, where prevalence increases                            In this chapter we will explore, in more
with age and incidence peaks between 70 and                             depth, the reasons why older people face a

Textbook of Clinical Trials. Edited by D. Machin, S. Day and S. Green
 2004 John Wiley & Sons, Ltd ISBN: 0-471-98787-5
56                                     TEXTBOOK OF CLINICAL TRIALS

number of barriers at each stage of a trial:               The process of patient selection and recruit-
eligibility, recruitment, gaining informed consent      ment mostly aims to produce an homogeneous
and follow-up. In addition we will discuss strate-      study population with the purpose of increas-
gies for increasing the number of older people in       ing the statistical power to detect the effects of
clinical trials, so that in future, those responsible   drugs.10 The resulting clinical trial, conducted in
for the treatment of older people will be able to       ‘sterile’ conditions, bears little resemblance to
base their practice on high-quality evidence.           practice and cannot be extrapolated to the gen-
                                                        eral population. Indeed, although tight eligibility
                                                        criteria may aim to produce very similar par-
                   ELIGIBILITY                          ticipants, inter-patient variability is such that a
                                                        truly homogeneous group of patients is difficult,
Despite recommendations to the contrary, older          if not impossible, to identify. Important prog-
people are still being excluded from clinical           nostic variables will be measured at baseline,
research on the basis of age alone, shown by an         but even if study participants are the same on
analysis of studies reported in four leading jour-      these criteria, they will still vary in the course
nals (BMJ, Gut, the Lancet and Thorax) which            of their disease and on unmeasured prognostic
found 35% (170) excluded older people with              factors.11 Thus the gain in attempting to study a
no justifiable reason.6 Reviews of trials in acute       group of homogeneous patients is outweighed by
myocardial infarction7 and Parkinson’s disease,3        the loss in generalisability and clinical applica-
conditions where prevalence and incidence are           bility of the results. Even when treatment trials
strongly related to advancing age, found that tri-      are specifically designed for older people, overly
als published later were more likely to exclude         stringent exclusion criteria can produce highly
older subjects. Moreover, since more women than         skewed and non-representative patient popula-
men survive to older age and in some cases, such        tions. Many trials of treatments for Alzheimer’s
as cardiovascular disease, women develop dis-           disease have excluded patients with behavioural
eases later in life than men, exclusion on the basis    problems despite such problems being common
of age disproportionately disadvantages women.8         with increasing cognitive impairment. Since there
   Operating an upper age limit for trials has          is considerable scope for improving such symp-
often been used to limit the problem of co-             toms with drugs that enhance cognition, these
morbid conditions and drug interactions that may        trials may well be missing opportunities.12
occur with increasing age, in the belief that              Studying a narrow group of patients also
most adverse drug reactions in older people             misses the potential to identify subgroups of
are simply a consequence of advancing age. A            patients who may respond particularly well to the
review of pertinent studies suggests that this          drug under test. A trial comparing the efficacy
may be misguided since the physiological and            of sertraline and nortriptyline in major depres-
functional characteristics of the patient, rather       sion included patients aged 60 years and over,
than chronological age per se, appear to be the         but a subgroup analysis of the 76 patients aged
most important in drug interactions.9                   70 years and over suggested that treatment with
   Even when age limits are not imposed, older          sertraline may confer even greater benefit in this
patients are often implicitly excluded because of       older age group than patients aged 60 years and
other exclusion criteria or because of investigator,    over.13 In trials of intervention packages or ser-
cultural or other biases in enrollment.8 In the         vices rather than drugs, similar tensions exist
review of acute myocardial infarction trials,           between maximising the detection of a significant
comparison of the age distributions of patients         effect of the intervention in a population unen-
in trials with and without age exclusions showed        cumbered with concurrent illness, and a need to
no differences, suggesting that factors other than      assess effectiveness as close as possible to deliv-
explicit age restrictions were at play.7                ery in practice after the trial. The advantages of
                                CLINICAL TRIALS INVOLVING OLDER PEOPLE                                   57

wide eligibility criteria for entering patients into      Although the experience of earlier trials on
clinical trials are summarised in Box 4.1.11           strategies to maximise recruitment may not
                                                       be immediately transferable across time and
                                                       place, they may provide researchers with ideas.
   Box 4.1 Advantages of wide eligibility              Experiences in recruiting older people to tri-
   criteria for entering patients into                 als have been described in the treatment of
   clinical trials                                     hypertension with both pharmacological15 and
                                                       non-pharmacological interventions16 and in tri-
   1. Easier screening and recruitment. Large
                                                       als of exercise.17 Many of the reports simply
      trials are more feasible and economical.
                                                       describe the experience of one or two particular
   2. Large study sizes reduce random error,
                                                       strategies, though mass mailing, media advertis-
      providing more reliable overall results.
   3. Wider applicability of results. There-
                                                       ing, community-based screening, clinical practice
      fore greater clinical and public                 screening, participant referrals and other recruit-
      health impact.                                   ment methods have been compared in a trial of
   4. Greater opportunity to test sub-                 the efficacy of weight loss and sodium reduction
      group hypotheses.                                for preventing hypertension in the elderly.16 This
                                                       study concluded that mass mailing of a brochure
   Source: Reproduced from Yusuf et al.11              or letter describing the study resulted in the great-
                                                       est yield in terms of percent randomised (76%;
                                                       N = 737) though it is less clear whether this
                                                       applied to all subgroups of the population. Tri-
                 RECRUITMENT                           als recruiting volunteers, although producing a
                                                       population who may be more likely to remain
                                                       throughout the length of the study, provide little
The recruitment, in sufficient numbers and within       evidence of applicability to the general elderly
the desired time frame, of motivated and compli-       population. Older volunteers tend to be more
ant subjects, representative of the wider group
                                                       likely than younger ones to be healthy and liv-
ultimately receiving treatment, is the goal of all
                                                       ing independently, of particular importance for
who design and execute clinical trials. Recruit-
                                                       trials of interventions involving exercise since
ing motivated participants is a problem for all
                                                       volunteers may not be the subjects most likely
clinical trials but particular difficulties are evi-
                                                       to benefit.17
dent when recruiting older patients. Clinical tri-
als are likely to involve more regular monitoring         Rarely does one single strategy succeed in
and follow-up assessments than would routinely         recruiting adequate numbers of representative
take place in practice and this in itself may be       patients. It is important therefore that the char-
too burdensome for older people who may have           acteristics of participants are regularly monitored
other health problems, which they may perceive         throughout the trial, and compared to the gen-
as more important, or lack access to transport.        eral population, so that, if necessary, specific
A longer enrollment phase, although deterring          demographic groups, such as the oldest-old or
some older subjects, may allow a more com-             particular ethnic groups may be targeted. Such
plete collection of data and more accurate pre-        mixed-mode recruitment has produced represen-
diction of patient compliance, again highlighting      tative samples of high-risk older people for a trial
the tension between pragmatic and explanatory          of geriatric evaluation and management.18 The
trials.14 If possible, assessments should be offered   final sample should aim to be as representative
at home or, where this is impossible, transporta-      as possible and a list of strategies that could be
tion to clinics provided at times convenient to        used if shortfalls occur during recruitment should
the subject.                                           be developed at the design stage of the trial.
58                                      TEXTBOOK OF CLINICAL TRIALS

        GAINING INFORMED CONSENT                          recalled, subjects found the concept of randomisa-
                                                          tion difficult to accept and were confused by terms
Obtaining informed consent from patients before           such as ‘trial’ and ‘random’ which have different
randomisation is a universal requirement, although        meanings to lay and professional groups.20
legal requirements across countries may differ.              Studies examining significant predictors of
As with eligibility and recruitment, the means of         enrollment into trials are equivocal in their find-
gaining informed consent from subjects enrolling          ings. A systematic review of literature on informed
should be addressed at the design stage of the trial      consent found evidence of impaired understand-
and the information that the patient requires to give     ing of the informed consent information in older
informed consent is listed in Box 4.2. A synopsis         subjects and those with less formal education,21
of the practicalities in obtaining informed consent       whilst the Recruitment and Enrollment Assess-
for clinical trials has been reported, stressing that     ment in Clinical Trials study, part of the Car-
gaining informed consent ‘should not be seen as           diac Arrythmia Suppression Trial (CAST), did not
an exercise in bureaucratic form filling, but as an        find education differences in enrollers and non-
essential part of the trial requiring time, insight and   enrollers, although enrollers were more likely to
communication skills’.19                                  have read the informed consent themselves and
                                                          to have understood it.22 The ability to understand
                                                          information about clinical trials, particularly the
     Box 4.2 Patient information necessary for            randomisation process, may well be correlated
     informed consent                                     with level of education.23 An instrument to assess
     1. Diagnosis.                                        understanding of information given to ascertain
     2. Available treatments and treatment                informed consent for ambulatory trials has been
        on trial.                                         developed, but its disadvantages are that it is study-
     3. Potential risks and benefits of treat-             specific and it was tested on relatively young and
        ment.                                             well-educated subjects.24
     4. Concept of a clinical trial (includ-                 Family members have also been found to play
        ing randomisation, use of placebos,               an important role in the informed consent pro-
        double-blind procedures).                         cess, approval by family members, particularly
     5. Discomforts or inconveniences associ-             spouses, being associated with successful enroll-
        ated with assessments.                            ment in a cardiovascular trial.25 This study also
     6. Number of follow-up visits or extra               found that the majority (96%) of those approached
        travel for trial.                                 by a physician agreed to enrol, compared to 66%
                                                          of those approached by an experienced cardio-
                                                          vascular nurse. Reasons given by a subsample of
   Clinicians may see relaying the concept of a           those enrolled by the physician were predomi-
randomised controlled trial as admittance of igno-        nantly the trust and respect subjects had for their
rance about the best treatment for the patient, or        doctor, though a small number admitted to agree-
may make ageist assumptions concerning the abil-          ing through fear.
ity of older people to consent to a trial. Further-          Much healthcare provision is imperialistic and
more, the clinical trial design is complex and even       this may re-enforce the belief, held by some older
if explained carefully, patients may not under-           people, that all decisions relating to their treatment
stand fully enough to give true informed consent.         rest with their doctor. It should be remembered that
A qualitative study, as part of a set of trials of        not all older people however want active treatment
the effectiveness of treatments for men with uri-         in all cases and there may be reluctance to take
nary retention and benign prostatic disease, found        medication for certain conditions. A recent trial
that, although information given was accurately           of selective serotonin reuptake inhibitors in the
                                CLINICAL TRIALS INVOLVING OLDER PEOPLE                                     59

treatment of depression and anxiety in community-       gaining informed consent generally for trials, not
dwelling older people found that, whilst 11 of          just those specifically for dementia treatments.
67 people with clinically diagnosed depression             Currently, informed consent is usually gained
and/or a phobic anxiety disorder fulfilled one           from proxies on behalf of dementia patients,
or more of the exclusion criteria, 89% of the           although technically only the subject may provide
remaining subjects eligible refused medication,26       consent to be entered into a trial. Within clinical
inferring that the process by which older people        care there has been encouragement for patients to
make decisions to participate in clinical trials is a   prepare advanced directives or living wills to cover
complex one, meriting further research.                 the eventuality that they may not have the capacity
   The nature of the trial may well be another          to agree to treatment being given or withdrawn. At
important factor in the decision by older peo-          first sight this might appear a solution for dementia
ple to enrol. Trials including invasive procedures      research also, but the strong motivational factors
such as venepuncture, which may be necessary to         for individuals with clinical care are unlikely to
determine compliance may not be seen as nec-            be present for dementia research.30 In addition,
essary to the subject and may therefore be more         the number of people preparing living wills is
likely to lead to refusal.27 Our experience of non-     still very small and tends to be the well-educated,
randomised studies of the health of older peo-          higher social class groups. A more realistic future
ple suggests that, on the whole, older people will      goal might be that people are encouraged to name
participate in lengthy interviews and are keen to       proxies and state broad beliefs about research in
assist with research that they perceive will help       advanced directives.
others,28 confirming findings from cardiovascular            Rather than immediately approaching a proxy
trials.25 When the study involves an assessment         for consent with dementia patients, it may be
at an outpatients’ clinic or an invasive procedure      best to promote the pragmatic view of decision-
such as providing a blood sample, refusal rates can     making capacity that if an individual appears com-
increase noticeably, making it necessary for trial      petent then they are.31 Dementia patients have been
personnel to explain clearly not only the need for      shown to be capable of understanding and differ-
randomisation but also the importance of subse-         entiating the risk/benefit ratio between different
quent assessments to monitor health. This should,       treatments and of expressing their contentment
of course, be balanced by any inconvenience the         with having a proxy make decisions on involve-
patient might incur by extra visits.                    ment in research although the proxies themselves
   After World War II, the Nuremberg code               tended to be more protective with their relatives
required the ‘voluntary consent of the human sub-       than with themselves.31 A more pressing problem
ject’ in experimental research and that ‘the per-       is the lack of suitable proxies to provide informed
son should have legal capacity to give consent’.        consent on behalf of patients, one trial of palliative
Ethicists argue that to make a properly informed        care of patients with advanced dementia who had
choice to enter a clinical trial, subjects should       been hospitalised finding that almost half (72/146)
not only have been provided with the necessary          of eligible patients could not be enrolled.32 In only
information about the trial but should also have        four cases was this due to the proxy refusing con-
understood it. The two aspects of having sufficient      sent, the proxies themselves lacking the capacity
understanding to give consent without coercion are      to understand the protocol in 18% of cases and in
key, but if taken literally, for example by being       almost one-third no functional proxy being found.
required to pass a test of competency, research on      None of the patients for whom a proxy could not
the efficacy of treatments and management strate-        be found had made a living will.
gies for dementia patients, particularly those with        It is when older people with dementia are res-
advanced dementia, would be impossible.29 The           ident in nursing homes–with their dependency
increasing prevalence and incidence of dementia         and vulnerability–that the process of informed
with advancing age may also pose problems for           consent is most complex.33 Certainly the high
60                                     TEXTBOOK OF CLINICAL TRIALS

prevalence of dementia within long-term care set-        accommodate incomplete data. Finally, outcomes
tings exacerbates the problems already stated,           such as mortality that may be easy to measure and
although the more immediate barrier from a               important for younger populations may, in older
researcher’s point of view may be the home-              people, be valued less than quality of life and the
owner acting as gatekeeper. Experience of con-           ability to function independently.37
ducting censuses of older residents in all types
of long-term care within Leicestershire over the
last 20 years has shown, from the falling response                       CONCLUSIONS
rates of homes, the increasing difficulty over
time in gaining access to residents or staff.34,35       If clinicians and other professionals caring for
It is important that the inherent problems in            older people are to provide optimal treatment and
conducting research within long-term care set-           the elderly are to benefit from new advances in
tings are recognised by researchers at the out-          treatments, decisions need to be based on firm
set and that the shortage of staff time and often        evidence of efficacy in older people. At present this
rigid regimes in homes are taken into consid-            is noticeably lacking in many aspects of care. We
eration when designing trials, particularly those        have discussed the reasons why older people have
of interventions.36 In these care settings, careful      been and are still being excluded both explicitly
explanation to home-owners and staff of the pur-         and implicitly from trials. We cannot give any
pose of the trial is likely to be vital to the success   definitive solutions to ensure that older people
of the study.                                            are recruited and enrolled in large numbers into
                                                         trials, since the setting for the trial (community,
                   FOLLOW-UP                             nursing home, outpatient clinic) will influence the
                                                         feasibility of different design options as well as
Even when older people have been enrolled                the country in which the research is conducted.
into trials, greater risk of the development of          However we list below important features that
co-morbid conditions, cognitive impairment and           should be considered when designing trials of
polypharmacy will mean that they are more likely         future therapies that may ultimately be used by
to withdraw before the final outcome assessment.          large numbers of older people:
To some extent this can be planned for in advance
by allowing for a realistic withdrawal rate in the       • Aim for as wide eligibility criteria as possible
sample size calculation. Provision of information          to ensure smaller random error, a wider appli-
about the trial should not be considered a ‘once and       cability of results and a greater opportunity to
for all’ activity at the commencement of the trial,        test pre-planned subgroup hypotheses.
and opportunities to re-enforce the importance of        • At the design stage, agree a list of strategies
the participants’ role in the success of the trial         for recruiting specific subgroups (the very
(for example at interim assessments) should be             elderly, ethnic minorities) if these become
exploited. More flexible timing of follow-up visits         under-represented during recruitment.
may also help and these days should not pose any         • Regularly monitor the characteristics of subjects
problems for analysis.                                     enrolled to ensure good representation of the
   Missing data is still likely to be present and          general population.
more complex data analysis techniques should be          • Give careful thought to the information to be
used to maximise the use of the data that are              given to subjects and the method by which it will
present. Some statistical packages for repeated            be given, to gain informed consent. Consider
measures data analysis–a common analysis for               whether and when consent will need to be
trials with regular follow-ups–ignore cases with           obtained from a proxy.
data missing. Newer techniques such as multi-            • If possible offer home assessments or, where
level modelling and random effects models can              this is impossible, provide transportation to
                                   CLINICAL TRIALS INVOLVING OLDER PEOPLE                                          61

  clinics at times convenient to the subject and             10. Yastrubetskaya O, Chiu E, O’Connell S. Is good
  their caregivers.                                              clinical research practice for clinical trials good
• Design a realistic withdrawal rate into the                    clinical practice? Int J Geriat Psychiatry (1997)
                                                                 12: 227–31.
  sample size calculation.                                   11. Yusuf S, Held P, Teo K. Selection of patients for
                                                                 randomized controlled trials: implications of wide
Finally, many clinical trials fail because of poor               or narrow eligibility criteria. Stat Med (1990) 9:
recruitment, lack of adherence to protocols and                  73–86.
contamination between trial arms. The problems               12. Schneider LS, Olin JT, Lyness SA, Chui HC. Eli-
outlined in this chapter may mean that this is a                 gibility of Alzheimer’s disease clinic patients
                                                                 for clinical trials. J Am Geriatr Soc (1997) 45:
particular issue for trials involving older people.              923–8.
There are useful lessons to be learnt from these             13. Finkel SI, Richter EM, Clary CM. Comparative
experiences, yet by definition, these are rarely                  efficacy and safety of sertraline versus nortriptyline
shared in the published literature. Methodological               in major depression in patients 70 and older. Int
issues that arise from others’ mistakes in carrying              Psychogeriat (1999) 11: 85–99.
out clinical trials involving older people need to           14. Applegate WB, Curb JB. Designing and executing
                                                                 randomized clinical trials involving elderly per-
be aired and discussed in journals. If the quality               sons. J Am Geriatr Soc (1990) 38: 943–50.
of the evidence is improved then older people can            15. Petrovich H, Byington R, Bailey G, et al. Systolic
expect to see an improvement in the quality of their             Hypertension in the Elderly Program (SHEP)
health care.                                                     Part 2: Screening and recruitment. Hypertension
                                                                 (1991) 17(Suppl II): 16–23.
                                                             16. Whelton PK, Bahnson J, Appel LJ, et al. Recruit-
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                                                                 in the Elderly (TONE). J Am Geriatr Soc (1997)
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    son’s Disease. Arch Intern Med (1997) 157:                   M379–84.
    1393–8.                                                  19. Wager E, Tooley PJH, Emanuel MB, Wood SF.
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    support of special populations: Geriatrics (1993).
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 5. Taggart HMcA, Allardice JM. Fatal cholestatic
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 6. Bugeja G, Kumar A, Banerjee AK. Exclusion of                 participation in a randomised controlled trial. Br
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    1417–22.                                                     cal trial enrollers vs. nonenrollers: the Cardiac
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      thal ML, Welsh PA, Topol EJ. Are we promoting               Morrison RS. Barriers to obtaining consent in
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                             Complementary Medicine
                                                   PING-CHUNG LEUNG
                  Institute of Chinese Medicine, The Chinese University of Hong Kong, Hong Kong

                    INTRODUCTION                                           What followed must have been more and
                                                                        more observations on more and more grasses
Medicine has been an art of healing. Although                           and leaves which became considered as ‘herbs’.
there is no absolute account on its history of                          Herb taking as a means to remove symptoms
development in the prehistorical and extreme                            and ailments is, therefore, the standard early
primitive days, it must be closely related to the                       stage of the healing art in human history.1,2 The
very ancient people’s eating habits and animal                          valuable observations and experiences were kept
behaviour. Ancient people fallen sick must prefer                       until today.
light meals with plenty of drinks. The latter might                        All primitive tribal populations today are still
mean fruits and plant-related products, which are                       using herb treatment, as the standard popular
the forerunners of medicinal herbs.                                     method of healing. The practice does not rule out
   Ancient people lived with animals: either                            trial uses of new herbs and their combinations,
keeping them as domestic friends or observing                           but the major practice depends on past experience
them closely in the fields. Animal instincts and                         and documentations. These early clinical trials
behaviour lent the ancient people much wisdom                           were not the result of imagination but were ini-
of healing. When dogs and cats bit and ate up                           tiated after observations on the anecdotal effects
special grasses and leaves when they fell sick,                         of different herbs.3,4
followed by vomiting or diarrhoea, sometimes                               Traditionally there was no real need for large-
bringing out special unwanted ingested food or                          scale clinical trials for complementary medicine.
worms, the ancient people noted the special                             The need came only when scientific healers
grasses and leaves. When they desired to clear                          became interested in complementary medicine
up their guts under difficult circumstances, they                        and started making use of herbs and other meth-
recalled those grasses and leaves their animals                         ods in their attempts to supplement modern
ate and hence they imitated the animals, hoping                         medicine. They wanted to know whether, by util-
to achieve the same healing. In this way, the                           ising the same logic of analysis commonly prac-
primitive art of healing started.                                       tised in modern medicine, they could prove that

Textbook of Clinical Trials. Edited by D. Machin, S. Day and S. Green
 2004 John Wiley & Sons, Ltd ISBN: 0-471-98787-5
64                                   TEXTBOOK OF CLINICAL TRIALS

herbal treatment constituted a logical substitution    3.   Massage
or supplement to scientific medicine.                   4.   Chiropractice
   This chapter explores the promises and fal-         5.   Spiritual healing by others
lacies of clinical trials in herbal medicine and       6.   Megavitamins
some other complementary medicine; identifies           7.   Self-help groups
the similarities and difficulties, the developments     8.   Imagery
and limitations.                                       9.   Commercial diets
                                                      10.   Folk remedies
     TYPES OF COMPLEMENTARY MEDICINE                  11.   Lifestyle diets
                                                      12.   Energy healing
                                                      13.   Homeopathy
The current main stream of medicine is the
                                                      14.   Hypnosis
scientific variety. Other forms of health care
                                                      15.   Biofeedback
outside the main stream fall into the category of
                                                      16.   Acupuncture
complementary or alternative medicine.
                                                      17.   Self-prayer
   If one uses history as the criterion of iden-
tification and considers ancient medicine was          Of these varieties, the one that commanded the
equivalent to complementary medicine, one sees        highest popularity was acupuncture as a form of
four main systems of ancient healing. They are:       pain control.
Chinese, Indian, Greek and Egyptian. Geograph-           The author cannot possibly be knowledge-
ically, the four systems are separated and yet,       able about all the varieties of complementary
the nearby areas do carry similarities. China and     medicine, and is not able to discuss all their
India certainly did communicate. So did Greece        clinical trials. Rather, he will concentrate on the
and Egypt. China probably also obtained infor-        two varieties that he is familiar with, herbal
mation from Greece, i.e. Europe, later in history     medicine and acupuncture. While discussions are
through the ‘silk route’.5                            being made, examples of clinical trials will be
   The four different systems have two main           given, based on personal interests and experi-
unique features. The Greek and Egyptian systems       ences.
concentrate on the use of single herbs, while the
Chinese and Indian systems use multiple combi-
nations. Combined formulae are most commonly           FUNDAMENTAL CONSIDERATIONS FOR
prescribed in Chinese herbal medicine.                 CLINICAL TRIALS ON CHINESE MEDICINE
   After thousands of years, the four ancient
systems of medicine still survive well. Greek         How should clinical trials of Chinese medicine be
medicine in Europe has established itself as a        conducted? Are there differences between such
homeopathic healing art, while the other three        trials and others designed for modern medicine?
systems enjoy persistent but varying popularities.       We have explained earlier that originally,
   In the modern sense, alternative/complemen-        complementary medicine and its practitioners did
tary medicine includes not only the herbal            not demand clinical trials. However, clinical trials
streams, but any other form of medicine that is       are indicated for modern scientists because once
unrelated to the modern scientific stream. When        the efficacy is proven, an alternative methodology
the American Medical Association did a survey in      of treatment can be endorsed.7
the USA aimed at the revelation of the populari-         If modern medicine were not totally successful,
ties and users of alternative medicine, 17 modali-    there would be a real need for supplementing
ties were targeted.6 These included the following:    with alternative medicine. Generally speaking,
                                                      the successes of modern medicine are well
 1. Relaxation techniques                             known in most areas. It is therefore necessary
 2. Herbal medicine                                   to look to complementary medicine only in
                                       COMPLEMENTARY MEDICINE                                          65

those areas where the scientific main stream has          INDICATIONS AND PHILOSOPHY OF
deficiencies.                                            APPLYING COMPLEMENTARY MEDICINE

       WHERE ARE THE DEFICIENCIES?                    Current medical treatment emphasises the effec-
                                                      tiveness and statistical chances of obtaining good
The deficient areas lie where modern medicine,         results. Modern medicine has developed as direct
in spite of recent advances, yet fails to get         corrective measures. Hence when it is effective,
good solutions.                                       the probability of arriving at good results is
   Modern medicine has developed from the logic       very high. Unless not available, there is there-
of modern science which follows the deductive         fore no reason why modern medicine should not
approach. The problem is first thoroughly under-       be endorsed as the primary mainline treatment.
stood by identifying the cause. The cause could           Although there are still confident herbal prac-
then be removed by working out an effective           titioners who believe and declare that whatever
means. In the situation of a disease when the         the modern scientific practitioners can do, they
cause is simple and straightforward, removing it      could substitute with other herbal remedies, the
would be easy. On the other hand, when the cause      number who remain that committed is getting less
is either complicated, not well understood or mul-    and less. Indeed today, most herbal practitioners
tiple, removal becomes difficult or impossible.        accept the role of functioning as supplementary
Simple disease-inducing causes include straight-      or alternative healers in a combined effort of cure
forward infections and simple hormonal deficien-       and care.11
cies. The former is easily tackled with an efficient       In this context, complementary herbal treat-
antibiotic while the latter could be treated with     ment is seldom used as the only healing modality.
hormonal replacement.                                 Instead, it is often given as an adjuvant treatment,
   When the causative agent is not yet thor-          either together with the mainline or after comple-
oughly known, e.g. viral infections, treatment        tion of the mainline. Users of herbal preparations,
becomes difficult.                                     moreover, frequently look forward to a tonic sup-
   When the cause is complicated, e.g. in allergic    portive effect, rather than a curative effect.
conditions, treatment does not guarantee effec-
tive results.                                           HOW DOES HERBAL MEDICINE REALLY
   When the cause is complicated, e.g. involv-                     WORK?
ing many factors such as physiological, social
and psychological, modern scientific medicine          Traditionally the system of herbal medicine was
becomes obviously deficient or incapable.8 – 10        built on the rich experience of herb users or
   Therefore the deficient areas in modern medi-       herbalists, accumulated over more than two thou-
cine that deserve contributions from complemen-       sand years in China since the early Chinese
tary medicine include:                                culture. For some reason, while basic medical
                                                      sciences, e.g. anatomy and physiology, devel-
•   Allergic conditions                               oped gradually in European territories around the
•   Autoimmune diseases                               Renaissance period, Chinese healers never felt
•   Cancers                                           the need to explore these basic medical sciences.
•   Chronic pain                                      Without sound knowledge of anatomy and phys-
•   Chronic derangements                              iology, i.e. biological structure and function of
•   Degenerative diseases                             the human body, it would not be possible to
•   Nerve damages                                     explore abnormal structures and functions, i.e.
•   Viral infections                                  pathology. Without understanding the pathology,
•   Other areas that modern conventional ther-        it would not be possible to apply a direct means
    apy fails.                                        of removing the pathology. Herbal practitioners
66                                  TEXTBOOK OF CLINICAL TRIALS

therefore try to heal, not by direct confrontation   superficial and deep, empty and solid. The causes
with the pathological problem, but by indirectly     of imbalance could be traced to a lack of bal-
supporting the individual to overcome his own        ance of any pair of opposing forces. In the
difficulties.12,13                                    actual treatment, therefore, all efforts are spent
                                                     on the maintenance of balance, by a supple-
 HOW DOES THE INDIVIDUAL OVERCOME                    ment of the deficient force, or a decrement of
  HIS OWN PATHOLOGICAL PROBLEMS?                     the excessive.
                                                         Since the pathological causes of the symptoma-
Firstly by surviving the harmful disturbances        tology are unclear to the herbal expert, he would
imposed by the pathological processes. Secondly      need to observe the changes of symptoms and
by supporting the unaffected organs and systems      adjust his day-to-day protocol accordingly. This
in their proper functions. Thirdly by preventing     approach differs very much from conventional
future pathological mishappenings while the          modern medicine, which successfully identifies a
current problem is being solved.                     pathological cause of disease, chooses a method
   The herbal practitioner has means to suppress     of cure with good chance of success, then admin-
the symptoms which are manifestations of the         isters it with all effort and commitment, until the
pathology. Suppression of symptoms like cough,       total removal of the pathology is achieved.
diarrhoea or dyspnoea helps the sick individual          While the aetiology, epidemiology and natural
to survive.                                          course of a disease affect the design of clinical
   While waiting for the pathological damages        trials for modern medicine, it is now clear that
to heal naturally, the unaffected organs and         in Chinese medicine, there is little analogy of
systems need to be supported to maintain their       aetiological and epidemiological considerations.
efficient function, which in turn will support the    The course of events in a disease, for a herbal
overall function and metabolic harmony of the        expert, is the appearance of the symptoms: the
living individual.                                   loss of biological well-being due to the lack
                                                     of balance between the vital forces. The aim
   Prevention in the modern biological sense
                                                     of treatment is the re-establishment of balance;
frequently refers to an immunological mecha-
                                                     once balance is re-established, either naturally or
nism through which the individual becomes more
                                                     through herbal intervention, well-being will be
resistant to future attacks of similar pathologi-
                                                     re-established. Treatment consists of a dynamic
cal nature.
                                                     application of symptomatic relief with the goal
   The main focus of disease management for
                                                     of re-establishing the balance.14
Chinese medicine is often the control of adverse
                                                         Clinical trials for Chinese medicine or herbal
symptoms. The ultimate goal is maintaining the
                                                     medicine therefore could follow the line of
well-being of the biological system. The aeti-
                                                     thought for scientific planning on data collection
ological consideration is therefore not directed
                                                     and subsequent data meta-analysis. However, the
towards the actual cause of the disease (of which
                                                     pre-treatment data would be confined mainly to
the herbal expert has no idea), but a general
                                                     symptomatology. Other parameters would carry
conceptual state of the biological balance of the
                                                     little weight for the herbal expert; but could
human bodily functions. The ancient healers cor-
                                                     still be included for more scientific knowledge
related this conceptual state with the Taoist phi-
                                                     in clinical trials.
losophy and imagined that bodily function was
kept at a balanced state between Yin and Yang
(i.e. negative and positive). Any loss of balance    GENERAL CONSIDERATIONS FOR CLINICAL
led to ailment and disease.                                    TRIALS ON HERBS
   The aim of treatment is therefore to main-
tain the balance. Yin and Yang includes other        In the modern scientific world, only up-to-date
contrasting opposing forces like cold and heat,      methodologies should be adopted. The set of
                                       COMPLEMENTARY MEDICINE                                           67

common methodologies for conducting clinical          and metabolic pathways before clinical tests be
trials on modern medicine has been logical,           conducted. What is the chemistry of specific
useful and has made wonderful contributions to        herbs? What are the pathways of action and
the clinical testing of new drugs and new meth-       metabolic degradation? Are there adverse effects
ods of clinical treatment. The proper analysis        in the process of metabolism? A lot of work
of data and the use of statistics have revealed       has been done in the past 50 years on this basic
the trustworthiness of certain accumulated expe-      understanding and not much has come out. Each
rience, while at the same time the fallacies of       and every herb contains so much complicated
some even well accepted and widely practised          chemistry that many years of research might
methods.15                                            not yield much fruit. Actually at least four
   The common methodology of random selec-            hundred herbs are popular and possess records
tion, blinding and placebo control, followed by       of therapeutic action and impressive efficacy. To
statistical analysis, should be adopted. In the       demand thorough knowledge on just this popular
design of the trial, good clinical practice should    proportion of herbs is not practical, not to speak
be the aim. However, due to the nature of the         of the less commonly used extra one to two
herbs, which come from different origins and          thousand varieties.17
carry different species, it is not uncommon to           Uniformity is another difficult area. Strictly
encounter situations where basic principles that      speaking, since herbs are agricultural products,
cannot be strictly kept.16                            uniformity should start with the sites of agricul-
                                                      tural production. The sites of production have
           THE OLD APPROACHES                         different weather, different soil contents, and the
                                                      methods of plantation are also different. At the
The herbal experts fervently respect case reports     moment, maybe over 50% of popular Chinese
and anecdotal reports, particularly when results      herbs are produced on special farms in China.
appear promising. Of course the reason behind         However, these farms are scattered over different
it is that they don’t make use of statistics.         provinces, which have widely different climatic
Moreover, they believe that treatment results         and soil environments. Good agricultural practice
are different with different patients. Once good      demands that environmental and nurturing proce-
results are known to be possible, the expert could    dures be uniformly ensured. Procedures include
try to achieve equally good results by wisely         soil care, watering, fertilisers, pest prevention and
manipulating the varieties of treatment.              harvests. When such procedures are not uniform
   In this chapter, we do not endorse this            and there are no means to ensure a common prac-
traditional approach. We do want to apply modern      tice, good agricultural practice is not possible.
assessment tools for a better understanding of           Not only is there a lack of uniformity in the
herbal or Chinese medicine treatment while at the     mode of herb production, but different species
same time we need not argue against the value         of the same herb are found or planted in dif-
of anecdotal observations in Chinese medicine.        ferent regions and provinces. These different
After all, the development of this system of          species may have different detailed chemical con-
healing depends solely on anecdotal analysis.         tents. Herbal experts have extensive experience
   Good clinical practice insists that the pre-       and knowledge about some special correlations
scribed drug for the clinical trial should be         between the effectiveness of particular herbs and
thoroughly known and uniform. However, using          their sites of production. Some commonly used
herbal preparations for clinical trials faces diffi-   herbs are even labelled jointly with the best sites
culties of thorough technical knowledge and uni-      of production. With the development of molec-
formity.                                              ular biology, coupled with modern means of
   Pharmaceutical tests demand that details be        assessment for active ingredients within a chem-
known about the chemistry, the mode of action         ical product, species-specific criteria could be
68                                     TEXTBOOK OF CLINICAL TRIALS

identified, using the ‘finger-printing’ technique.        We need to acquire an updated understanding on
Uniformity today should include screening using         the effectiveness of the herbal preparations on
‘finger-printing’ techniques.                            disease entities. That is why we could not be sat-
   When we consider the other 50% of herbs that         isfied with records on efficacy alone, but should
are only available from the wilderness, i.e. around     start a series of clinical trials to further prove the
mountains, highlands or swamps, and cannot be           efficacy of the herbs.19
grown on agricultural farms, the insistence on             The National Institutes of Health of the United
product uniformity becomes even more difficult.          States have openly endorsed the approach of
   Putting together what we have discussed, to          accepting traditional methods of healing as safe
strictly insist on good clinical practice in clinical   measures and then putting them to proper clini-
trials for herbal medicine is largely impossible.       cal trials.20 The recognition of acupuncture as a
We have to accept a compromise. Indeed in the           practical effective means of pain control started
past 50 years, many attempts have been made at          in 1998.21 The subsequent formation of a spe-
a proper analytical study of herbal preparations.       cial section devoted to research on complemen-
The intention was: to put the herb to processes         tary/alternative treatment followed. The National
of extraction, analyse the important ingredients,       Centre for Complementary, Alternative Treat-
then try to work out the chemical formulae which        ment (NCCAM) was properly formed and given
could be responsible for the clinical effects.          a substantially large budget.
   Extraction eliminates the useless components            Clinical trials to be discussed within this
and concentrates the effective components, which        chapter follow the efficacy-driven principle. They
not only cuts down the volume of herbs used but         are planned strictly according to the principles set
also intensifies the biological actions. Knowing         out under the modern philosophy of clinical tri-
the actual effective ingredients and working            als aimed at the production of objective evidence
out the chemical formulae would be ideal for            of the effectiveness of the methods used. It is
modernisation of herbal preparations with the           however understood that product uniformity and
aim of converting the preparations into proper          quality could not be absolutely guaranteed and
pharmaceuticals.                                        that although GMP (Good Manufacturing Pro-
   In spite of the efforts and resources put into       cess) could be assured, GCP (Good Clinical Prac-
herbal extractions and chemical analyses in the         tice) could not be absolutely ensured because of
past 50 years, successful examples have not been        the lack of guarantee for any herbal preparations.
impressive. The results of such efforts certainly          In our discussion full reference will be given
do not match the resources put in.18                    to what is being recommended in China, which
   The unsatisfactory outcome has initiated a new       undoubtedly harbours most activity in Chi-
approach. Instead of following the scientific path-      nese medicine.
way already taken by pharmaceuticals, which has
                                                                  HERBAL DRUGS IN CHINA
shown too many difficulties rather than promises,
a more practical line has been endorsed. Since          In 1999 the National Bureau on Drug Control
most, if not all, the herbs have been used for hun-     defined new drugs as ‘a manufactured product
dreds of years, there should be sufficient amount        for medical treatment that is produced for the first
of reliability on the safety and efficacy of the         time or an old product reproduced with different
herbs. The safety and efficacy of the herbs are          formulation and different indications’.
already well documented, but their practical util-         New drugs are divided into five categories:
isation in specific clinical circumstances needs
to be further established. The traditional use of        I. Group 1
the herbs had been focused on symptomatic con-              Artificial derivatives from Chinese herbs
trol. Nowadays, the aim of clinical management              Newly discovered Chinese herbs and deriva-
is directed towards curing of a disease entity.             tives
                                        COMPLEMENTARY MEDICINE                                           69

       Extracts from Chinese herbs and derivatives    laboratory research and clinical trials. When
       Extracts from decortions of herbs              studies on the pharmacology, pharmacodynamics
 II.   Group 2                                        and pharmacokinetics are carried out after the
       Herbal injections                              clinical trials, positive values, in support of the
       Herbal preparations processed inside animals   clinical observations, might not be impressive.
       Extracts from complex decortions                  The possible explanation to this observation
III.   Group 3                                        may lie in the fact that the clinical consump-
       New preparations of decortions                 tion of the herbal preparations involves multiple,
       Combined herbal and chemical preparations      complex in vivo biological interactions, whereas
       Imported herbal preparations                   laboratory tests consist of only simple unidirec-
IV.    Group 4                                        tional biological interactions.
       Converted formulary
       Cultivated herbal and domestic animal prepa-     HOW DO CONCEPTS OF TRADITIONAL
       rations                                          HEALING AFFECT CLINICAL TRIALS ON
V.     Group 5                                                 CHINESE MEDICINE?
       Herbal preparations with extended uses
                                                      Earlier in this chapter, the author has already
       STAGES RECOMMENDED FOR HERBAL                  touched on the unique concepts in Chinese
                  RESEARCH                            medicine, which are different from modern sci-
                                                      entific medicine. The application of modern con-
The usual four stages are recommended.                cepts in the direction of clinical trials leads to the
   Phase I : Study on the general acceptance of       inevitable sacrifice of some of the fundamental
the human being after consumption of the herbal       principles. Experienced herbal experts, therefore,
preparation. Normally Phase I refers to a toxicity    might not like to participate.
study. The code of practice given under ‘Code            The following list includes the important
of Practice for the Scrutiny of New Drugs’ in         concepts in Chinese medicine practice being
China, however, recommends that the general           sacrificed:
well-being of the individual after consumption be
observed.22 The logic of skipping toxicity tests is   1. Symptom and syndrome Identification Principle
probably based on an assumption that Chinese             Following this principle, the herbal expert
herbal preparations have been used safely for            adjusts details of his treatment according to
centuries, therefore a special toxic screening is        observations on the day-by-day changes of
not necessary. The author has strong reservations        symptomatology. He may then use different
on this attitude and would recommend that                drugs for the same symptoms or use the same
toxicity clearance should remain the first phase          drug for different symptoms. Proper clinical
of clinical trials.                                      trials could only use a uniform choice of
   Phase II : Study on the safety and efficacy            treatment modality. This violates the symptom
while working out the effective dosage.                  and syndrome identification principle.
   Phase III : Expands on Phase II study, col-        2. Holistic Approach
lecting more reliable confirmation on the safety          Chinese medicine emphasises holistic care
and efficacy.                                             and holistic response, whereas clinical trials
   Phase IV : Further study on the safety and            prefer objective, specific data as endpoints.
efficacy after the new drug is put to market. More        The inclusion of specific data into herbal
observations on adverse effects are expected.            research probably does not invite objection
   It has been pointed out that, as far as herbal        from the herbal expert, as long as general data
medicine is concerned, it is not unusual to              like different aspects of well-being, i.e. quality
find that correlation does not exist between              of life, are included.
70                                  TEXTBOOK OF CLINICAL TRIALS

3. Response to Pathological Processes                6. Establish unique outcome studies.
   Chinese medicine emphasises the responses         7. Establish unique quality of life assessments.
   of healthy organs to diseases. The ability of     8. Insist on using modern statistics.
   the healthy organs to respond to pathological
   changes ensures that the individual would
                                                                    ADVERSE EFFECTS
   be able to better resist adversities. Modern
   clinical trials aim mostly at diseased organs.
4. Old System of Clinical Observation                Historically, great herbal masters in China in
   Herbal experts utilise a system of clinical       the ancient days did produce records on adverse
   observations which today might be considered      effects and toxic problems of some herbs. As
   obsolete and over-subjective. This system of      early as the Han dynasty (second century)
   clinical signs includes tongue observation,       documents were produced on herbs that need
   pulse detection and a collection of subjective    to be utilised with care or extreme care.25 This
   feelings.23 Modern clinical trials insist on      tradition was followed closely in the subsequent
   objective data that could be monitored. We        centuries.26
   therefore have to either develop means to            More reports were available on methods and
   objectively assess the subjective signs in the    means with which toxicities and adverse effects
   tongue and the pulse or we sacrifice the whole     could be reduced.27
   system of observations. Herbal experts might         In spite of the good past experience, the preva-
                                                     lent belief is that Chinese medicinal herbs are
   not appreciate either choice.
                                                     safe. On the other hand, more and more reports
5. Strong Tradition
                                                     appeared on adverse effects and toxicities, and
   Herbal experts place genuine confidence on
                                                     non-users of herbs tend to exaggerate the reports.
   anecdotal observations and experience of sin-
                                                        When new preparations come into the market,
   gle patients. Insisting on the need to investi-
                                                     the innovative processes of extraction and/or
   gate collective observations and condemning
                                                     production might have produced or initiated new
   single-case experience would not be wel-
                                                     possibilities of adverse effects or toxicity. This
   comed by herbal experts. This conceptual
                                                     experience is already well recorded in a number
   difference directly affects the participation
                                                     of modernised preparations, particularly those for
   and cooperation of the traditional and mod-
                                                     injection.28 Among the adverse effects, allergic
   ern experts.
                                                     reactions are commonest.
                                                        To date, standard instructions on clinical trials
   While thoroughly recognising the unique nature    for Chinese medicine define adverse drug reac-
of Chinese medicine and having pointed out the       tion in exactly the same way as modern scientific
lack of harmony between the old tradition and        clinical trials, and explanations of the reactions
modern science, one realises that the current        have been identically identified.29
compromise adopted in China is to insist on a           Categories of adverse reactions include the
modern scientific approach as far as possible.        following:
Hence in standard textbooks, the following are
advocated24 as standard instructions for clinical    1. Reactions to herbs
trials:                                                 Reactions are defined as harmful and unex-
                                                        pected effects while the standard dosages are
1. Use the principles of randomisation, blinding        used in certain drug trials. It is specially
   and repetition.                                      pointed out that for Chinese medicine, the
2. Adopt good protocols for clinical trials.            harmful reactions could be due to the qual-
3. Avoid bias at all cost.                              ity of the herb and poor choice of indica-
4. Eliminate chance factors.                            tion. These reactions do not include aller-
5. Establish new standards of clinical assessment.      gic responses.
                                      COMPLEMENTARY MEDICINE                                           71

2. Dosage-related adverse effects                    for Chinese medicine trials is that of Naranjo.31
   Using an unnecessarily high dose could induce     Naranjo’s system of grading adverse effects
   excessive effects, side effects or even toxic     according to fact-finding results is shown in
   effects. Secondary effects like electrolyte       Table 5.2. Overall assessment:
   imbalance might also be observed.
3. Dosage-unrelated adverse effects                  ADR   confirmed         ≥9
   These adverse effects could be the result         ADR   likely           5–8
   of unfavourable preparation, contaminants in      ADR   possible         1–4
   the herbs, sensitivity of the consumer, aller-    ADR   unlikely         ≤0
   gic reactions or specific inductive effects of
   the herb.                                            Detection and recording of adverse effects
4. Drug interactions                                 should bear different emphases at different phases
   Classically, records are available in old Chi-    of the trial, e.g. Phase I trial aims at detection of
   nese medicinal literature on combined effects     adverse effects in relation to dosage, Phase II and
   of herbs, their facilitatory and antagonistic     III collect details, whereas Phase IV is concerned
   effects. Nowadays, not only drug interactions     mainly with marketed drugs.
   between herbs are important, but possible            Whatever is the situation, detection of adverse
   interactions between herbs and commonly           effects should include both clinical observations
   used pharmaceutical preparations are becom-       and laboratory data, and detection should be
   ing issues of great concern since users of        followed with follow-up observations. The sum-
   herbal preparations are greatly increasing. In    mation of observations should be thoroughly
   the area of anaesthesia, drug interactions        analysed so that explanations of the adverse
   between herbs and modern medicine could           effects may eventually be worked out.
   induce life-threatening reactions. Table 5.1
   illustrates some studies currently done on this         REPORTING OF ADVERSE EFFECTS
5. Delayed adverse effects                           It is currently required in China that adverse
   Adverse effects of delayed nature include         effects should be reported to the relevant mon-
   induction to cancer formation, foetal abnor-      itoring body as soon as possible. Once a drug is
   malities and even blockage of bacterial sensi-    marketed, adverse effects should be continuously
   tivities.                                         reported to the National Control Bureau, within
6. Drug dependence                                   the first five years.
   There might be suspicions that herbal prepa-         Adverse effects detected at the post-market
   rations might lead to drug dependence. Apart      Phase IV might be particularly important for Chi-
   from a few opium-related herbs, Chinese herbs     nese medicine trials. Since herbal preparations
   in fact are well known to be non-addictive        do not have clear, definite information about the
   because of their gross lack of specificities.      effective contents of the herbs, bias and chances
                                                     might be more likely than other trials on simpler
  From the above account it might appear             drugs at the early phases. The large trial popu-
obvious that adverse effects in clinical trials      lation during Phase IV gives a better chance of
using Chinese medicine in fact follow closely the    elimination of bias and allows a better oppor-
experience encountered in other drug trials.         tunity of objective detection of adverse effects.
  As far as the grading of adverse effects is        During the Phase IV trial, the following aspects
concerned, it would be appropriate to categorise     would deserve particular attention:
the effects as mild, moderate and severe.
  With regard to the overall assessment of           1. Actual danger level of the adverse effects.
adverse effects, a convenient recommendation            Degree of danger of course depends on the
72                                    TEXTBOOK OF CLINICAL TRIALS

Table 5.1. Examples of Herb-Drug Interaction

Herb                                  Drug                Interaction                  Mechanism
Radix Salviae              Warfarin                 Increased INR               Danshen decreases
  Miltiorrhizae                                       Prolonged PT/PTT           elimination of Warfarin
  (Danshen)                                                                      in rats
Radix Angelicae            Warfarin                 Increased INR and           Danggui contains
  Sinensis (Danggui)                                  widespread bruising        coumarins
Ginseng (Radix Ginseng)    Alcohol                  Increased alcohol           Ginseng decreases the
                                                      clearance                   activity of alcohol
                                                                                  dehydrogenase and
                                                                                  dehydrogenase in mice
Garlic                     Warfarin                 Increased INR               Post-operative bleeding
                                                                                  and spontaneous spinal
                                                                                  epidural haemorrhage
Herbal ephedrae (Ma        Pargyline, Isoniazid,    Headache, nausea,           Pargyline, Isoniazid, and
 Huang)                      Furazolidone            vomiting, bellyache,         Furazolidone interfere
                                                     blood pressure               with the inactivation of
                                                     increase                     noradrenalin and
                                                                                  dopamine; ephedrine in
                                                                                  herbal ephedrine can
                                                                                  promote the release of
                                                                                  noradrenalin and
Ginkgo Biloba              Aspirin                  Spontaneous hyphema         Ginkgolides are potent
                                                                                  inhibitors of (PAF)
Cornu cervi                adrenomimetic            Strengthens the effect of   Natural MAOIs in Cornu
  pantotrichum Fructus                                 increasing blood          cervi pantotrichum,
  crataegi                                             pressure                  Fructus crataegi and
                                                                                 Radix polygoni
                                                                                 multiflori inhibited the
                                                                                 metabolism of
                                                                                 levodopa and opium
Radix polygoni multiflori   Levodopa                 Increased blood pressure
                                                      and heart rate
                           Opium                    Central excitation
Bitter melon               Chlorpropamide           Decreased urea glucose      Bitter melon decreased
                                                                                  the concentration of
                                                                                  blood glucose
Liquorice                  Oral contraceptives      Hypertension, oedema,       Oral contraceptive may
                                                     hypokalaemia                 increase sensitivity to
                                                                                  glycyrrhizin acid
St. John’s wort            Warfarin                 Decreased INR               Decreased the activity of
                           Cyclosporin              Decreased
                                                     concentration in
                                                 COMPLEMENTARY MEDICINE                                              73

Table 5.1. (continued )

Herb                                         Drug                           Interaction              Mechanism
Radix Isatidis                    Trimethoprin (TMP)                Significantly increase
  (Banlangen)                                                         anti-inflammation
Liu Shen pill                     Digoxin                           Frequent ventricular
                                                                      premature beat
Tamarind                          Aspirin                           Increased the
                                                                      bioavailability of
Yohimbine                         Tricyclic antidepressants         Hypertension
Note : ACE   angiotension-converting enzyme
       INR   international normalised ratio
       PT    prothrombin time
       PTT   partial thromboplastin time
       PAF   platelet-activating factor
       AUC   area under the concentration/time curve
       MAOIs monoamine oxidase inhibitors

Source: Reproduced from De Smet and D’Arcy,30 with permission from Springer-Verlag.

                Table 5.2. Questions to be asked about adverse Drug Reactions

                                                                                 Yes       No    Not clear
                 1. Are there decisive records about the ADR?                     +1        0        0
                 2. Are the ADRs found after consumption of                       +2        −1       0
                       other drugs?
                 3. Are the ADRs improved after consumption                       +1        0        0
                       of antidote?
                 4. Are there repeated ADRs or repeated                           +2        −1       0
                 5. Are there other predisposing factors?                         −1        +2       0
                 6. Are there ADRs after placebo?                                 −1        +1       0
                 7. Has the blood level of drug giving ADRs                       +1        0        0
                       been investigated?
                 8. Do the ADRs correlate to dosages?                             +1        0        0
                 9. Is there past history?                                        +1        0        0
                10. Is there objective proof                                      +1        0        0

   incidence of occurrence. The requirement for                           of comparisons before results can be instruc-
   treatment and the financial implications are                            tive. Case reports might still be useful, but
   also important.                                                        might function as special warning signals to
2. More thorough studies at Phase IV should be                            calls for more serious studies.32
   considered according to epidemiological prin-
   ciples. Randomised controlled trials should                                         QUALITY OF LIFE
   be insisted on. Cohort studies might be con-
   venient and useful, but there need to be                           While clinical trials aim at a thorough scien-
   markedly obvious differences between series                        tific understanding of the effectiveness of specific
74                                   TEXTBOOK OF CLINICAL TRIALS

forms of treatment, endpoints of measurement          rehabilitation underway. Different specialties and
are set to give objective standards of evaluation.    special areas of concern have created charts of
Primary endpoints are unique, focused, specific        their own and all these provide valuable infor-
criteria which indicate the situation of the target   mation when equivalent studies come up. Usu-
against which the trial is directed. Changes of       ally they are adopted right away or after vali-
primary endpoints illustrate the efficacy directly.    dation. Hence there are charts already developed
Secondary endpoints are supplementary crite-          for children and the elderly, and different med-
ria created to support observations on changes        ical specialties and subspecialties likewise have
and efficacy. Secondary endpoints become more          created their own charts. Just to mention a few,
important when, predictably, primary endpoints        special QoL charts are available for the men-
do not give clear-cut, impressive results. Sec-       tally ill, cardiovascular diseases, rheumatologi-
ondary endpoints become more important when           cal disease, respiratory problems, gynaecological
primary endpoints are expected to change slowly       problems and special infections.36 QoL charts for
and would be particularly important when chronic      Chinese medicinal studies need to be developed.
problems are being faced.
   Since Chinese medicine, under most circum-
stances, does not operate via a direct confronta-     WHAT ARE THE RECOMMENDATIONS FOR
tion route but rather acts indirectly to support      CLINICAL TRIALS OF CHINESE MEDICINE?
the healthy organs and helps to maintain vitality
and prevent functional deterioration, critical and    The simplest thing to do is to make reference to
detailed assessment of the secondary endpoints is     the available charts in whichever clinical trial is
therefore of utmost importance.                       being conducted and think about amendments to
   Quality of life (QoL) is an important aspect       make them even more suitable.
on the assessment of care given to the chron-
ically ill. QoL often measures the competency         ARE THERE UNIQUE FEATURES THAT NEED
of the care and the ethical standard of the                     TO BE OBSERVED?
society in mental disorders and other disor-
ders that demonstrate strong social orientations.     There are features related to health which are
Not infrequently, using technical endpoints as        derived from the philosophy of Chinese medicine
results of clinical trials a reasonable outcome       ever since its initial development. Chinese people
is observed, and yet patients might not be sat-       in all walks of life are influenced by this
isfied with their QoL. QoL is therefore multi-         philosophy without being aware of it at all stages
focal: it differs between developed and under-        of their life. The belief that health depends on
developed areas, it also differs under differ-        a harmony between contrasting forces prompts
ent cultural circles.33 Different countries and       the individual to feel either ‘hot or cold’,
regions therefore try to develop their own data       ‘light’ or ‘heavy’, ‘sick inside’ or ‘sick outside’.
to be included within their own studies on            After treatment, the feeling might remain, might
QoL.34 Meanwhile global, generally acceptable         reverse or might get balanced. The feeling is
QoL charts are also being planned, examined and       subjective, but in any clinical trial including the
validated.35                                          data of QoL, could one ignore the outcome of the
   Before an acceptable general data chart is         philosophical guideline responsible for the whole
ready, one has to accept the achievements already     system of healing art?
revealed in different fields. Generally speaking,         Henceforth, it is obvious the QoL studies
QoL data sheets take in information about phys-       are particularly important for clinical trials of
iological well-being, psychological well-being,       Chinese medicine and research should be done
social well-being and the individual’s subjec-        on special inclusions of data which are unique
tive feeling on the treatment received and the        for Chinese medicine.
                                    COMPLEMENTARY MEDICINE                                         75

          CHINESE MEDICINE                         parallel study. Patients will be randomised
To give more solid information about clinical      to one of the four treatment groups and
trials on Chinese medicine being done in Hong      treated for a duration of 6 months.
Kong, the following paragraphs are devoted to
summaries of such trials.                          Study Population: A minimum of 85
                                                   hepatitis B patients will be enrolled, 25
Synopsis I                                         subjects per treatment group, 10 subjects
                                                   in the control group, a total of four groups.
  Name of Study Medication: Phyllanthus            Definition of Endpoints:
  SP. Compound
                                                   • The primary safety endpoint is tolerabil-
  Title of Study: A Prospective Randomised,          ity.
  Double-Blind, Placebo-Controlled, Parallel       • Tolerability failure is defined as a per-
  Study to Evaluate the Effect of Phyllanthus        manent discontinuation of Phyllanthus
  SP. Compound in the Treatment of Chronic           PLUS as the result of an adverse event.
  Hepatitus B Virus Infection.                     • The primary endpoint is a reduction in
                                                     HBV DNA level from the baseline.
  Study Centre: Single-centre
                                                   • The secondary endpoint is HbeAg nega-
  Objective:                                         tive, anti-Hbe positive and a decrease in
                                                     ALT level from baseline.
                                                   Study Regimen: Subjects will be randomly
  • To evaluate the efficacy of normalisa-          and alternatively assigned to receive Phyl-
    tion of liver enzyme, seroconversion of        lanthus PLUS or placebo for 6 months
    HbeAg and disappearance of HBV DNA             prospective parallel study.
    in serum.
  • To evaluate the safety of Phyllanthus SP.      Duration of Treatment: 6 months
    Compound in patients with hepatitis B.
                                                   Statistical Methods: Efficacy: Summary
  Secondary                                        statistics for the change of HBV DNA,
  • Proportion of patients with end-of-treat-      HbsAG, HbeAg and ALT from baseline
    ment HbeAg seroconversion (HbeAg               will be generated and provided for each
    to anti-Hbe, normalisation of ALT and          treatment group.
    disappearance of HBV DNA at the end
    of treatment).                                 Safety
  • Proportion of patients with HbeAg to
    anti-Hbe.                                      • The incidence of adverse events and
  • Proportion of patients with sustained            laboratory toxicity will be summarised
    normalisation of ALT.                            by treatment group and severity. Change
  • Proportion of patients with undetectable         from baseline in vital signs will be
    HBV DNA.                                         summarised by treatment group.
                                                   • Group differences with an error proba-
  Design: A single-centre, prospective ran-          bility of less than 5% (p < 0.05) will be
  domised, double-blind, placebo-controlled,         considered statistically significant.
76                                    TEXTBOOK OF CLINICAL TRIALS

     • The statistical analyses will be made              a permanent discontinuation of Danggui
       with SPSS for Windows 10.0.                        Buxue Tang as the result of an adverse
                                                        • The primary efficacy endpoint is the
                                                          change in severity and frequency of hot
Synopsis II                                               flushes and night sweats.
                                                        • The secondary efficacy endpoint is the
     Name of Study TCM: Danggui Buxue                     changes in score for the domains mea-
     Tang                                                 sured in the Menopause Specific Quality
                                                          of Life Questionnaire.
     Title of Study: A Randomised, Double-
     Blind, Comparison Study of the Effect of           Study Regimen: Subjects will be randomly
     Danggui Buxue Tang with Oestradiol on              and alternatively assigned to receive Dang-
     Menopausal Symptoms and Quality of Life            gui Buxue Tang or placebo for 6 months.
     in Hong Kong Chinese Women.
                                                        Duration of Treatment: 6 months treat-
     Study Centre: Single-centre                        ment period and 18-month follow-up.
     Objective:                                         Statistical Methods:
     Primary                                            • Data will be processed to give group
     • To compare the effects of Danggui                  mean values and standard deviations
       Buxue Tang with Oestradiol on meno-                where appropriate.
       pausal symptoms of hot flushes and                • Mann–Whitney U-test will be used to
       sweating.                                          compare the differences between the two
     • To evaluate the safety of Danggui Buxue            groups of treatment. Group differences
       Tang in patients with menopausal symp-             with an error probability of less than 5%
       toms.                                              (p < 0.05) will be considered statisti-
                                                          cally significant.
     Secondary                                          • The statistical analyses will be made
                                                          with SPSS 10.0 for Windows.
     • To evaluate the quality of life of the
       patients with menopausal symptoms.

     Design: A single-centre, randomised, dou-
     ble-blind and comparison study. Subjects        Synopsis III
     will be randomised to one of the two treat-
     ment groups and treated for a duration of          Name of Study TCM: Danggui Buxue
     6 months with follow-up of 18 months.              Tang

     Study Population: A minimum of 100                 Title of Study: A Randomised Comparison
     patients with menopausal symptoms will be          Study of the Effect of Danggui Buxue Tang
     enrolled, 50 subjects per treatment group.         with Tranexamic Acid on Dysfunctional
                                                        Uterine Bleeding and Quality of Life in
     Definition of Endpoints:
                                                        Hong Kong Chinese Women.
     • The primary safety endpoint is tolera-
       bility. Tolerability failure is defined as        Study Centre: Single-centre
                                   COMPLEMENTARY MEDICINE                                      77

Objective:                                        Danggui Buxue Tang or Tranexamic acid
                                                  for 6 months treatment and 24 months
Primary                                           follow-up.
• To compare the effects of Danggui
  Buxue Tang with Tranexamic acid on              Duration of Treatment: 6 months treat-
  menstrual blood loss per month.                 ment and 24 months follow-up.
• To compare the patient’s satisfaction
  between using Danggui Buxue Tang and            Statistical Methods:
  Tranexamic acid.
• To evaluate the safety of Danggui Buxue         • Data will be processed to give group
  Tang in patients with dysfunctional uter-         mean values and standard deviations
  ine bleeding.                                     where appropriate.
                                                  • All the data in the outcome measure are
Secondary                                           continuous variables. Mann–Whitney U-
                                                    test will be used to compare the differ-
• To evaluate the improvement of anaemia.
                                                    ences between the two groups of treat-
• To evaluate the status of iron deficiency.
                                                    ment. The level of significance will be
• To evaluate the unwanted side effects.
                                                    set at p < 0.05.
Design: A single-centre, randomised com-          • The statistical analyses will be made
parison study. Subjects will be randomised          with SPSS 10.0 for Windows.
to one of the two treatment groups and
treated for a duration of 6 months with
follow-up of 24 months.
                                                Synopsis IV
Study Population: A minimum of 125
patients with dysfunctional uterine bleeding
                                                  Name of Study TCM: Formula A and
will be enrolled, 63 subjects in the Danggui
                                                  Formula B
Buxue Tang group and 62 subjects in the
Tranexamic acid group.                            Title of Study: A Randomised, Double-
                                                  Blind, Placebo-Controlled Study on the
Definition of Endpoints:                           Clinical Effects of Integrated Western
                                                  Medicine and Traditional Chinese Medicine
• The primary safety endpoint is tolera-
                                                  for Diabetic Foot Ulcer.
  bility. Tolerability failure is defined as
  a permanent discontinuation of Danggui          Study Centre: Multi-centre
  Buxue Tang as the result of an adverse
  event.                                          Objective:
• The primary efficacy endpoint is change
  in frequency and severity of menstrual          Primary
  bleeding.                                       • To evaluate the wound healing effect of
• The secondary efficacy endpoint is im-             Formula A and Formula B in patients
  proving anaemia and iron deficiency.               with diabetic foot ulcer.
                                                  • To evaluate the safety of Formula A
Study Regimen: Subjects will be ran-                and Formula B in patients with diabetic
domly and alternatively assigned to receive         foot ulcer.
78                                      TEXTBOOK OF CLINICAL TRIALS

                                                       Synopsis V
                                                          Name of Study TCM: Relieve Wheezing
     • To evaluate the effect of control of the           Tablet
       local infection.
                                                          Title of Study: A Randomised, Double-
     Design: A multi-centre, randomised, dou-             Blind, Placebo-Controlled Parallel Study of
     ble-blind, placebo-controlled study. Sub-            the Effect of Relieve Wheezing Tablet in
     jects will be randomised to one of the two           the Treatment of Childhood Asthma.
     treatment groups and treated for a duration
     of 6 months.                                         Study Centre: Single-centre

     Study Population: A minimum of 80                    Objective:
     diabetic foot ulcer patients will be enrolled,
     40 subjects per treatment group.                     Primary
                                                          • To evaluate the medication score, includ-
     Definition of Endpoints:                                ing daily use of inhaled steroids.
                                                          • To evaluate the symptom score, includ-
     • The primary safety endpoint is tolerabil-            ing cough on daytime and nighttime,
       ity. Tolerability failure is defined as a             wheeze/chest tightness on daytime and
       permanent discontinuation of formula A               nighttime, degree of shortness of breath
       and Formula B as the result of an adverse            on exertion.
     • The primary efficacy endpoint is diabetic           Secondary
       foot ulcer healing and to avoid leg
       amputation.                                        • To evaluate the spirometry lung function
     • The secondary efficacy endpoint is the                result.
       control of local infection.                        • To evaluate the breakthrough attacks
                                                            requiring medical attention from A/E
                                                            doctors, family physicians on hospital-
     Study Regimen: Subjects will be randomly               isation.
     and alternatively assigned to receive For-           • To evaluate the degree of skin allergy.
     mula A and Formula B or placebo of a                 • To evaluate the changes in peripheral
     6-month prospective parallel study.                    blood and Eosinophilic Cationic Pro-
                                                            tein (ECP).
     Duration of Treatment: 6 months
                                                          Design: A single-centre, randomised, dou-
     Statistical Methods:                                 ble-blind, placebo-controlled, parallel study.
                                                          Subjects will be randomised to one of the
     • Results will be presented as the mean ±            two treatment groups and treated for a
       SE per group.                                      duration of 6 months.
     • Group differences with an error proba-
       bility of less than 5% (p < 0.05) will be          Study Population: A minimum of 80
       considered statistically significant.               patients with moderate to severe perennial
     • The statistical analysis will be made with         asthma will be enrolled, 40 subjects per
       SPSS 10.0 for Windows.                             treatment group.
                                    COMPLEMENTARY MEDICINE                                       79

  Definition of Endpoints:                          Secondary

  • The primary safety endpoint is tolera-         • To evaluate the lipid and homocysteine-
    bility. Tolerability failure is defined as        lowering effect of Danshen and Radix
    a permanent discontinuation of Relieve           Puerariae Compound.
    Wheezing Tablet as the result of an
    adverse event.                                 Design: A single-centre, prospective ran-
  • The primary efficacy endpoint is a              domised, double-blind, placebo-controlled,
    change in improving the symptoms of            parallel study. Patients will be randomised
    asthmatic children and use of inhaled          to one of the two treatment groups and
    steroids.                                      receive Danshen and Radix Puerariae Com-
  • The secondary efficacy endpoint is im-          pound or placebo for a duration of 24
    provement of lung function.                    weeks.

  Study Regimen: Subjects will be ran-             Study Population: A total of 100 patients
  domly and alternatively assigned to receive      with Coronary Artery Disease (CAD) will
  Relieve Wheezing Tablet or placebo for           be enrolled, 50 subjects treated with Dan-
  6 months.                                        shen and Radix Pruerariae Compound and
                                                   50 treated with placebo.

                                                   Definition of Endpoints:

Synopsis VI                                        • The primary safety endpoint is tolerabil-
  Name of Study Medication: Danshen and            • Tolerability failure is defined as a per-
  Radix Puerariae Compound                           manent discontinuation of Danshen and
                                                     Radix Puerariae Compound as the result
  Title of Study: A Prospective Randomised,
                                                     of an adverse event.
  Double-Blind, Placebo-Controlled, Parallel
                                                   • The primary endpoint is improving car-
  Study to Evaluate the Effect of a Herbal
                                                     diovascular function (endothelial func-
  Preparation with Compound Formula of
                                                     tion and carotid intima-medial thickness)
  Danshen and Radix Puerariae as Cardio-
                                                     from the baseline.
  vascular Tonic in Cardiac Patients.
                                                   • The secondary endpoint is decrease of
  Study Centre: Single-centre                        plasma lipid and homocysteine lev-
                                                   Study Regimen: Subjects will be randomly
  Primary                                          assigned to receive Danshen and Radix
  • To evaluate the safety of Danshen and          Puerariae Compound (TCM) or placebo
    Radix Puerariae Compound as adjunc-            for 24 weeks in a prospective parallel
    tive therapy in patients with coronary         study.
    artery disease.
  • To evaluate the efficacy of treatment           Duration of Treatment: 24 weeks
    and secondary prevention of cardiovas-
                                                   Duration of Project: 30 months
    cular diseases.
80                                    TEXTBOOK OF CLINICAL TRIALS

                                                       surface, to varying depths of soft tissue, then
     Statistical Analyses                              allowing the needles to stay for some minutes.
                                                       While the needles stay inside the soft tissue,
     • The statistical significance of changes          the puncturist may give regular or occasional
       between TCM and placebo groups will             rotary movements on the nail. In recent years,
       be assessed by one-way analysis of              acupuncturists have applied direct electrical cur-
       variance.                                       rent stimulation, so as to unify the stimulations,
     • Group differences with an error proba-          widen the effects and save manpower. Acupunc-
       bility of less than 5% (p < 0.05) were          ture is an invasive process directly aiming at the
       considered statistically significant.            removal of symptoms. It is easy to imagine then,
     • The statistical analyses were made with         that patients would not agree to participate in a
       SPSS for Windows 10.0.                          study where they would not be able to enjoy the
                                                       puncture treatment and function as recipients of
                                                       ‘sham’ puncture. Likewise, if there were other
                                                       placebo punctures which fulfil the requirement
                 ACUPUNCTURE                           of randomisation and placebo control, very few
                                                       patents would be willing to participate.37,38
Acupuncture is a practical procedure using a
                                                          However, studies on placebo acupuncture have
special needle to enter special regions of the
                                                       started and the varieties included the following:
human body surface by which symptoms suffered
by the patient are removed. Like other aspects of      1. Placebo points–entry points are sites outside
Chinese medicine, it aims at symptom control,             the acupuncture meridians.
not at the treatment of a specific disease entity.      2. Sham puncture–puncture lightly then with-
The most popular use must be in the field of               draw.
pain control.                                          3. Hiding entry points–while entry points are
   In 1998, the National Institutes of Health in the      hidden, it might be possible to achieve real
USA held a consensus conference on the use of             placebo effect. Hiding of entry points may be
acupuncture for pain control. The conclusion was          achieved by puncturing through plastic tubes
that acupuncture should be accepted as an effec-          or soft plastic blocks.
tive means of pain control for musculo-skeletal        4. Camouflage puncture by which a needle is just
problems and under other specific situations.21            taped to the skin.
Since then, interest in the use of acupuncture in
the United States grew and many clinical studies          None of these methods could be endorsed
were started.                                          because the requirements for placebo in the strict
   Of course, acupuncture has been used for the        sense are far from being satisfied; most recipi-
control of other symptoms. Examples include            ents could differentiate right away whether it is
nerve damages, allergic conditions like rhinitis,      true or false puncture. The conventional appli-
asthmatic attacks and general feelings of being        cation of acupuncture depends on a subjective
‘unwell’, often labelled as ‘derangement’.             feeling of ‘numbness’ felt within the punctured
   How are clinical trials on acupuncture being        area. Puncturing without checking this feeling
conducted? Could the clinical trials on acupunc-       is not considered appropriate. This requirement
ture be put in line with modern epidemiological        makes ‘placebo’ puncture impossible. The use
requirements? Or would it be even more difficult        of electrical stimulation is a means to enhance
compared with herbal medicine? We have first            the effects in modern situations where there is
of all, to look at the procedures involved and the     insufficient experience on acupoint identification
explanations given to the effects produced.            and actual puncturing techniques. It is also con-
   Acupuncture involves the insertion of thin nee-     sidered as a method of modernising acupunc-
dles, through specific acupoints on the body            ture. When electrical stimulation is used, placebo
                                       COMPLEMENTARY MEDICINE                                          81

becomes absolutely impossible because the elec-       the spinal cord, loss of neurological and sec-
trical stimulation is always felt.                    ondary muscular functions becomes permanent.
   The considerations are further complicated by      Acupuncture is widely used under such difficult
the theories of acupuncture. There are two accept-    situations. Although many reports of impressive
able theories–the neurological and the humoral.       results are available, it is difficult to realise the
The neurological theory observes that since some      real value. Scientific data coming from well-
of the meridians and most of the acupunc-             planned cohort studies for the observation of
ture points are related to the peripheral nerves,     functional restoration is still difficult to inter-
stimulation of these points leading to physio-        pret, since the damage could not be uniform and
logical effects could be working via neurolog-        the factors affecting the different aspects of reha-
ical pathways, possibly through proprioceptive        bilitation and functional return are multiple and
receptors.39 The humoral theory assumes that          complicated.
needle stimulation produces humoral (hormonal)           We are therefore still relying on careful
reactions, manifested as serological appearance       case studies. However, one does not need to
of functional factors which possess pain control      get upset with the obvious limitations. After
effects and other regulatory functions.40             all, in the field of rehabilitation, experience in
   Whichever theory is at work, it specifies           the last three decades has already shown that
that the tiny area of puncture is producing           qualified, broad, trustworthy clinical trials are
chain reactions, either directly or indirectly. An    not possible.41 Although meta-analysis has ruled
apparently harmless, non-productive action on         out the absolute scientific justification for all
the skin and soft tissue, imitating acupuncture,      the rehabilitation attempts like different forms
might trigger off similar effects and would be far    of physiotherapy, massage, bracing and even
from being a placebo.                                 invasive means like injections and surgery, we
   Therefore standard epidemiological planning        could still rely on them because we have to
for clinical trials in Chinese medicine including     release our patients from suffering. We are all
acupuncture would be very difficult, if at all         aware of the fact that we are not certain which
possible. Randomisation would not be acceptable       patient is the best candidate to receive which
to patients, whereas in situations of acupuncture,    treatment.42
if sham puncture is insisted on, it is both
unacceptable to patients and falls short of the                        CONCLUSION
placebo requirements.
   Carefully planned cohort studies aiming to         Complementary medicine does not have any
compare the effects of different means of pain        history of modern scientific development. It
control and other treatment expectations are          built up its knowledge relying on observations
therefore the only reasonable means to objec-         and experience. Now that we try to make
tively look at the clinical effects of acupuncture.   use of this traditional stream of medicine in
Many cohort studies of this nature are being done     a scientific world, we need to explain why it
for the study of back pain, neck pain, arthritis of   works in the area of our concern. Very often,
the knee, etc. The effects of puncture were com-      these areas are not well served by scientific
pared with conventional techniques using phys-        medicine. This makes the scientific explanations
iotherapy and other means.                            even more important.
   Another common application for acupunc-               The way to go about giving scientific expla-
ture is the restoration of nerve function. Dam-       nations to healing processes involves the appli-
aged neurological tissues suffer from a real lack     cation of methodologies that are well known and
of regeneration. Peripheral damage feasible for       accepted by all clinical scientists. The standard
repair carries reasonable promise. When cell          way to start a scientific approach to clinical
bodies are involved, either intra-cranially or in     trials using traditional Chinese medicine would
82                                    TEXTBOOK OF CLINICAL TRIALS

just be an application of the same methodolo-                and patterns of use. New Engl J Med (1998)
gies. However this approach is not feasible and              328(4): 246–52.
                                                       11.   Fair WR. The role of complementary medicine in
would probably remain unfeasible in spite of
                                                             urology. J Urol (1999) 162: 411–20.
enthusiasms. We are barred from a smooth appli-        12.   Leung PC. Traditional Chinese Medicine in China.
cation of the scientific methodology, basically               Seminar on Health Care in Modern China,
because of the different philosophy behind the               Yale–China Association (2001).
traditional Chinese way of healing. Moreover, the      13.   Leung PC. Development of traditional Chinese
                                                             medicine in Hong Kong and its implications for
lack of knowledge about the exact chemistry of               orthopaedic surgery. Hong Kong J Orthopaed surg
the active component of the herbal remedy when               (2002) 6(1): 1–5.
herbal drug trials are being carried out further       14.   Ho T. An anthropologist’s view on traditional
jeopardises the validity of the clinical trials.             chinese medicine. In: A Practical Guide to Chinese
   In spite of the essential difficulties, efficacy-           Medicine. Singapore: World Scientific (2002).
                                                       15.   Chalmers I. The Cochrane Collaboration: prepar-
driven trials are still carried out, utilising prin-         ing, maintaining and disseminating systemic re-
ciples of evidence-based medicine. As long as                views of the effects of health care. Ann NY Acad
the scientific gap is successfully narrowed, the              Sci (1993) 203: 166–72.
practical use of complementary medicine will           16.   Tyler VE. Herbs of Choice: The Therapeutic use
become safer, more logical and would deserve                 of Phytomedicinals. New York: Pharmaceutical
                                                             Product Press (1994).
wider applications. At the same time, workers          17.   Ernst E. Harmless herbs? A review of the recent
on complementary medicine should workout a                   literature. Am J Med (1996) 104: 170–8.
unique, relevant system of assessment for the          18.   Bisset Ng. Herbal Drugs and Phytopharmaceuti-
clinical effects.                                            cals. Boca Raton: Medpharm Scientific Publisher
                                                       19.   Leung PC. Clinical trials in Chinese medicine –
                  REFERENCES                                 the efficacy driven approach. Hospital Authority
                                                             Convention, Hong Kong (2001).
                                                       20.   NIH. National Centre for Complementary and
 1. Bensky D, Gamble A. Chinese Herbal Medicine.             Alternative Medicine Five Year Strategic Plan
    Materia Medica. Seattle: Eastland Press (1993).          2001–2005. NIH Document (2000).
 2. Tang W, Eisenberg G. Chinese Drugs of Plant        21.   NIH. Acupuncture. NIH Consensus Statement
    Origin: Chemistry, Pharmacology and Use in               (1997) 15(5): 1–34.
    Traditional and Modern Medicine. New York:         22.   Wang PY. New Chinese Medicine: Research, Pro-
    Springer-Verlag (1992).                                  duction and Registration. China: Chinese Medi-
 3. Su WT. History of Drugs. Beijing: United Medical         cine Press (1995).
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 4. McGuire MB. Ritual Healing in Suburban Amer-             China Health Publisher (1996).
    ica. Newbrunswick: Rutgers University Press        24.   Lai SL, ed., Clinical Trials of Traditional Chi-
    (1988).                                                  nese Materia Medica, Chapter 2, 3, 4. Guang-
 5. Kong YC. Formulation’s from South-West Asia.             dong: People’s Publishing House (2001).
    Beijing: Chinese University Press (1998).          25.   Chang CK (Han Dynasty). Discussions of Fever.
 6. Eisenberg DM, Roger DB. Trends in alternative            Classics.
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    (1998) 280(18): 1569–75.                           27.   Suen TM (Tang Dynasty). Important Prescrip-
 7. Lai SL. Clinical Trials of Traditional Chinese           tions. Classics.
    Materia Medica, Chapter 1. Guangdong: People’s     28.   National Bureau on Drug Supervision. Regulations
    Publishing House (2000).                                 on Clinical Trials Using Drugs and Herbs. Bureau
 8. Leung PC. Editorial – Seminar series on evi-             Publication (1999).
    dence-based alternative medicine. Hong Kong        29.   Suen TY, Wang SF, Wang KL. Adverse Effects of
    Med J (2001) 7(4): 332–4.                                Drug Treatment. Beijing: People’s Health Press
 9. Kaptchuk TJ, Eisenberg DM. The persuasive ap-            (1998).
    peal of alternative medicine Ann Int Med (1998)    30.   De Smet P, D’Arcy PF, eds. Drug interactions
    129(12): 1061–5.                                         with herbal and other non-toxic remedies. In:
10. Eisenberg DM, Kessler RC, Foster C. Unconven-            Mechanisms of Drug Interactions. Berlin: Sprin-
    tional medicine in the USA – prevalence, costs           ger-Verlag, (1996).
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31. Sackett DL. Clinical Epidemiology, 2nd edn.            37. Park J, White AD, Lee H, Ernst ED. Develop-
    Boston: Little, Brown & Co. (1991) 297–9.                  ment of a new sham needle. Acupunct Med (1999)
32. Uppsala Monitoring Centre, WHO. Safety moni-               17(2): 347–52.
    toring of medicinal products: guidelines for set-      38. Streiberger K, Kleinhenz J. Introducing a placebo
    ting up and running a pharmacovigilance centre             needle into acupuncture research. The Lancet
    (2000).                                                    (1998) 352: 364–5.
33. Jaeschke R, Singer J. Measurement of health sta-       39. Godfrey CM, Morgan P. A controlled trial of the
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Textbook of Clinical Trials. Edited by D. Machin, S. Day and S. Green
 2004 John Wiley & Sons, Ltd ISBN: 0-471-98787-5
                                               Breast Cancer
Department of Biostatistics, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA

                    INTRODUCTION                                        in situ (DCIS) increased by about sixfold, from
                                                                        about 5 cases per 100 000 women in 1980 to more
More than 200 000 women in the United States                            than 30 per 100 000 in 1998.
are diagnosed annually with breast cancer. About                           Despite the increasing incidence of breast
40 000 women die from the disease each year.                            cancer among US women since the early 1980s,
Among women, it is the most common malig-                               and perhaps indirectly because of this increase,
nancy, and is exceeded only by lung cancer as the                       the annual age-adjusted rate of breast cancer
leading cause of cancer death. Although the risk                        mortality has decreased by almost 2% per year
of breast cancer is substantially higher in older                       in the 1990s. Researchers generally attribute
women, many cases occur in young women. Of                              this improvement in breast cancer survival to
cases diagnosed in the US in 1998, 5% occurred                          increased use of screening mammography and to
in women under the age of 35, 30% in women                              improvements in the treatment of breast cancer.
aged 35 to 49, 31% in women aged 50 to 64, and                          Efforts are underway to better delineate the
33% in women aged 65 or older.1 For US women,                           relative impacts of factors influencing breast
the lifetime risk of developing breast cancer is                        cancer survival (see CISNET2 for additional
about 13%. About 0.1% of US women carry an                              information).
inherited mutation of a breast/ovarian cancer sus-                         An important development for breast cancer
ceptibility gene, BRCA1 or BRCA2, and so have                           research in the 1980s and 1990s was not directly
a lifetime risk in excess of 50%.                                       related to science. These years saw the for-
   From 1940 to the early 1980s, breast cancer                          mation of strong advocacy groups that worked
incidence in the US increased by a fraction                             to promote research in breast cancer. Federal
of a percent per year when adjusted for age.                            funding has increased more than sixfold since
Chiefly because of the widespread dissemination                          1990, and grass-roots action has resulted in
of screening mammography beginning in the                               an unprecedented programme of breast cancer
early 1980s, invasive breast cancer incidence has                       research funding administered by the Depart-
increased by 3–4% per year into the 1990s. Over                         ment of Defense. In addition, patient advocates
the same period, the rate of ductal carcinoma                           have become highly educated about research

Textbook of Clinical Trials. Edited by D. Machin, S. Day and S. Green
 2004 John Wiley & Sons, Ltd ISBN: 0-471-98787-5
88                                    TEXTBOOK OF CLINICAL TRIALS

issues and many serve regularly alongside profes-      0 through Stage IV disease are 21%, 42%, 29%,
sional scientists on various governmental boards       5% and 4%, respectively.1 An additional tumour
guiding the direction of research expenditures         classification method based on histopathologic
and treatment recommendations. Patient advo-           examination has limited discrimination ability
cates also serve on cooperative group committees       because 70–80% of tumours are of a single type:
that plan clinical trials in breast cancer, institu-   infiltrating ductal carcinoma.
tional review boards, and data safety monitor-
ing boards.
   Advocacy groups have worked to increase the
number of women who participate in clinical tri-
                                                       Breast cancer is heterogeneous. Many breast
als. The Clinical Trial Initiative of the National
                                                       cancers are slowly growing and their carriers
Breast Cancer Coalition Fund (NBCCF) main-
                                                       survive for many years and die of other causes.
tains a registry of clinical trials and urges women
                                                       Other tumours are very aggressive and may
with breast cancer to participate (see NBCCF3 ).
                                                       have spread to distant sites by the time the
Before a clinical trial can be included in their
                                                       primary tumour is diagnosed. This heterogeneity
registry, experts from the NBCCF ascertain that
                                                       has implications for research in all phases of the
it addresses an important, novel research ques-
                                                       disease, beginning with screening and diagnostic
tion related to breast cancer, and that its design
                                                       methods through the evaluation of treatments for
is scientifically rigorous and employs appropriate
                                                       advanced disease.
and meaningful outcomes.
                                                          Stage is the most widely recognised deter-
                                                       minant of patient outcome. Stage IV disease is
                                                       generally regarded to be incurable, with median
                                                       survival in the range of 18 to 24 months, although
                                                       a small fraction of patients with Stage IV disease
Breast cancer is staged using a system developed       achieve complete remission following systemic
by the American Joint Committee on Cancer,             chemotherapy, and survive for many years.6 On
and based on the size and other characteristics        the other hand, patients with Stage I disease, con-
of primary tumour (T), the status of ipsilateral       sisting of a small primary tumour and no involved
lymph nodes (N), and the presence or absence           lymph nodes, have at least a 90% probability
of distant metastases (M) (AJCC4 and Singletary        of being disease-free after five years. Lymph
et al.5 ). The stage of disease, ranging from 0        node involvement is associated with a worse
to IV, is based on combinations of these TNM           prognosis, with five-year disease-free rates rang-
rankings.                                              ing from 50–75%. Tumour grade, proliferative
   Stage 0 consists of ductal and lobular carci-       activity and menopausal status play relatively
noma in situ (DCIS, LCIS), non-invasive and            minor roles.
possibly non-malignant forms of the disease.              Although stage is an important prognostic
Stages I to III are invasive stages in which the       factor, it is of limited use as a determinant
tumour is confined to the breast or its immedi-         of treatment outcome. The relative benefits
ate vicinity. Higher stage indicates larger primary    of treatment are reasonably consistent across
tumours or greater locoregional tumour involve-        stages – although the absolute benefit can be
ment. Patients having evidence of distant metas-       much greater for higher stage disease. Much cur-
tasis are classified as Stage IV.                       rent research focuses on factors that may predict
   Distribution of disease stage at the time           clinical benefit from certain treatment approaches
of breast cancer diagnosis varies by country,          (‘predictive factors’) in contrast to the more con-
depending on the health care system’s approach         ventional ‘prognostic factors’ which are regarded
to diagnosis and reporting. In the US, the approxi-    as indicators of general tumour aggressiveness,
mate proportions of women diagnosed with Stage         irrespective of type of therapy.
                                              BREAST CANCER                                              89

   The best-studied predictive factor is oestrogen-    breast cancer throughout the first half of the cen-
receptor (ER) status, which is an important            tury, sometimes combined with radiotherapy.
indicator of whether a tumour will respond to             When the concept of large-scale randomised
hormonal treatment. Tamoxifen and other selec-         clinical trials to investigate alternative therapies
tive oestrogen-receptor modulators (SERMs) are         was proposed in the 1960s, controversy arose
highly effective in patients with hormone-             among breast cancer researchers as well as in
sensitive breast cancer, but they have no              other medical fields. In a heated exchange, a
benefit in patients whose tumours are ER neg-           prominent breast cancer surgeon denounced such
ative and progesterone-receptor negative (Early        studies as ‘a great leap backward in the treat-
Breast Cancer Trialists’ Collaborative Group           ment of breast cancer’.17 Despite such opposition,
[EBCTCG]7 ). Patients who benefit from SERMs            pioneers in the field persisted in designing tri-
may also benefit from aromatase inhibitors.8            als to address important therapeutic questions of
   HER-2 (also referred to as HER-2/neu, ErbB2,        the time, and moreover, were able to persuade
c-erbB-2) is a member of the epidermal growth          patients to participate in this novel idea of assign-
factor receptor family that is overexpressed in        ing treatment by randomisation. These early tri-
20% to 40% of breast tumours, and has been             als compared various surgical and radiotherapy
cited in numerous reports as conveying poor            approaches. In a trial of almost 1700 women
prognosis.9 Studies in early breast cancer have        implemented in 1971, there were no significant
suggested that patients with HER-2 positive            survival differences between conventional radi-
tumours are more likely to benefit from anthra-         cal mastectomy, total mastectomy with radiation,
cycline therapy.10 – 12 Trastuzumab, a monoclonal      and total mastectomy with removal of axillary
antibody against HER-2, is effective in delay-         nodes.18,19 Results of this and other trials of the
ing progression in Stage IV disease that over-         era challenged long-held views of the disease and
expresses HER-2,13 and is being evaluated for          gradually convinced researchers that their con-
its efficacy in treating HER-2-overexpressing pri-      cept of breast cancer as a local disease which
mary tumours.                                          could best be treated by radical local treatment
                                                       techniques was incorrect. Rather, breast cancer
                                                       came to be understood as a systemic disease that
  HISTORICAL PERSPECTIVE ON CLINICAL                   could benefit from systemic therapy, and radi-
       TRIALS IN BREAST CANCER                         cal local therapies were no longer regarded as
                                                       essential for prolonging survival.
Scientific understanding of the biology of breast
cancer has changed radically in the past 50 years.     Cytotoxic agents for treatment of solid tumours
Results of large randomised trials have played a       were first developed in the 1950s. Breast cancer
major role in this transition. From the nineteenth     proved to be highly sensitive to several of these,
century and up into the 1970s, breast cancer was       when used as single agents in small trials. Subse-
understood to be a local/regional disease that         quently, combinations of these cytotoxic agents
spread by direct extension along lymphatic path-       were evaluated, one of the earliest being the
ways to distant sites. This concept gave rise to the   Cooper regimen (cyclophosphamide, methotrex-
surgical methods promoted by W.S. Halsted14 – 16       ate, 5-fluorouracil, vincristine and prednisone).20
around the turn of the twentieth century, i.e.,        With the understanding of breast cancer as a sys-
extensive resection of the breast, regional lym-       temic disease and the proven sensitivity of breast
phatics, lymph nodes and muscle. This surgi-           cancer cells to cytotoxic agents, the stage was set
cal technique, known as radical mastectomy,            for the rapid development of adjuvant chemother-
remained the principal approach to treatment of        apy once this concept was introduced in the
90                                   TEXTBOOK OF CLINICAL TRIALS

1970s. A randomised trial comparing surgery fol-      most important advance in treating breast cancer.
lowed by combination chemotherapy to surgery          Questions remain about the optimum treatment
alone demonstrated that disease recurrence could      duration even though a trial conducted by the
be significantly reduced using this adjuvant ther-     National Surgical Adjuvant Breast and Bowel
apy approach.21                                       Project (NSABP) comparing 5 and 10 years of
   The introduction of doxorubicin for treatment      tamoxifen therapy concluded there was little or
of breast cancer is illustrative of the series of     no advantage to longer therapy.26
clinical trials typically undertaken for the devel-
opment of new agents. Small trials conducted          HIGH-DOSE CHEMOTHERAPY WITH BONE
in solid tumours in the early 1970s established          MARROW TRANSPLANT OR STEM
safety and dosing, and these were quickly fol-                   CELL SUPPORT
lowed by Phase II trials of the agent in metastatic
breast cancer. Subsequently, doxorubicin was          An unresolved question in therapy of breast can-
evaluated in combination with other agents, and       cer that has presented an unusual challenge for
randomised trials established that higher response    the conduct of clinical trials is that of high-
rates could be achieved in metastatic disease with    dose chemotherapy supported by autologous bone
combinations that included doxorubicin. These         marrow transplant or peripheral blood progenitor
successes prompted the introduction of various        cells. Ten trials addressing the question of high-
doxorubicin and other anthracycline-containing        dose versus standard-dose chemotherapy have
combinations as adjuvant therapy for primary          been reported. Two of these were subsequently
breast cancer. Known by such acronyms as              discredited following an international investiga-
‘FAC’ = ‘CAF’, ‘FEC’, ‘AC’, these combina-            tion. Only two of the remaining eight trials
tions continue to play a prominent role in the        entered more than 200 patients. Financial issues,
treatment of breast cancer.22,23 Anthracycline-       patient and physician acceptance and competing
containing therapies further reduce the risk of       treatment strategies have compromised accrual,
recurrence and favourably impact survival in          and it is unclear if ongoing trials can be com-
early breast cancer.24                                pleted. The available evidence suggests that high-
                                                      dose therapy provides little or no benefit for
            HORMONAL THERAPY                          patients regardless of their disease stage.27,28

Hormonal therapy is a key component of therapy                      MAMMOGRAPHY
when tumours are hormone-receptor positive.
Early trials focused on ovarian ablation by           Eight large randomised trials conducted since
surgery or chemical means. The anti-oestrogen         1963 assessed the value of screening mam-
agent tamoxifen was introduced in the 1970s,          mography for reducing breast cancer mortal-
at a time when there was high regard for the          ity. These are of particular interest for the
potential of cytotoxic agents, but little interest    scrutiny they have undergone in recent years.
in hormonal therapies. Early small trials in          The preponderance of evidence from the ran-
metastatic breast cancer were equivocal and could     domised trials indicates a benefit associated with
have led to abandoning the agent. However, the        screening mammography.29 – 31 However, a meta-
weight of evidence from laboratory studies and        analysis concluded that six of the eight trials
several small trials pointed to superior efficacy      were seriously flawed and the remaining two
with prolonged administration in ER positive          trials showed insignificant breast-cancer mortal-
disease. After a series of large randomised trials,   ity differences between the screened and non-
tamoxifen is now regarded as standard therapy         screened groups.32 The National Cancer Institute
for pre- and post-menopausal women with ER            recommends screening mammography every 1
positive tumours.25 Tamoxifen may be the single       to 2 years for women aged 40 and older, while
                                             BREAST CANCER                                            91

recognising that there are risks associated with      Oxford University, serves as a centre for data
false-positive results.                               synthesis rather than actual conduct of clinical
                                                      trials. Beginning in 1983, this group has col-
                 PREVENTION                           lected data from virtually all major randomised
                                                      trials conducted in early breast cancer, published
Beginning in the 1990s, coinciding with the           or not. Data from more that 200 000 women
detection of methods for identifying women at         have been analysed, using statistical techniques
high risk of breast cancer, the first large-scale      for meta-analysis, with results published at the
trials were mounted to determine if the incidence     end of each five-year analysis cycle, beginning in
of breast cancer could be reduced in targeted         1985. These publications have addressed the role
high-risk groups. These trials established that       of radiation, ovarian ablation, polychemotherapy,
breast cancer incidence could be greatly reduced      tamoxifen and quality of life; these ‘overview’
by daily doses of tamoxifen.33,34 This reduction      articles are frequently cited in support of treat-
was due entirely to a lower incidence of ER           ment approaches.7,24,25,37 – 42 The weaknesses of
positive tumours with no change in the incidence      meta-analysis have been widely discussed in the
of ER negative tumours. This suggests that            statistical literature, chief among these being the
prophylactic tamoxifen will not have as great         issue of heterogeneity among the trials being
an impact on survival as it does on incidence,        combined. For example, the overviewers com-
although none of the prevention trials address        bine various therapeutic regimens under the sin-
survival as an endpoint. An ongoing trial (STAR:      gle rubric ‘polychemotherapy’. However, these
the Study of Tamoxifen and Raloxifene) will           overview reports have allowed researchers to reli-
recruit 22 000 women at high risk of breast cancer    ably assess moderate-size treatment effects which
in order to compare the effects of tamoxifen and      could not have been detected in individual trials.
another SERM, raloxifene, on the incidence of         Treatments causing even moderate reductions in
primary breast cancer.35                              mortality, if implemented widely among women
                                                      with breast cancer, could prevent or delay thou-
                                                      sands of deaths due to the disease. The meta-
                                                      analysis has also addressed questions of treatment
One of the largest cooperative groups conduct-        efficacy within subsets, for example the confir-
ing trials in breast cancer in the US is the          mation of benefit of adjuvant tamoxifen in ER
NSABP. Trials from this group are often referred      positive pre-menopausal women7 as well as in
to by their ‘B’ numbers, e.g., B-06, which estab-     post-menopausal women.
lished the equivalence of lumpectomy to total
mastectomy.36 Other major cooperative groups
conducting clinical trials in breast cancer are the           TIME-DEPENDENT HAZARDS
Eastern Cooperative Oncology Group (ECOG),
Cancer and Leukemia Group B (CALGB), South-           In this section we address a methodological
west Oncology Group (SWOG), Breast Cancer             issue that arises quite generally in survival
International Research Group (BCIRG), Euro-           analysis. Consider disease-free survival. This is
pean Organisation for Research and Treatment of       the usual primary outcome measure in evaluating
Cancer (EORTC), North Central Cancer Treat-           adjuvant therapies, with results presented in
ment Group (NCCTG), and the National Cancer           the form of Kaplan–Meier survival curves and
Institute of Canada (NCIC).                           compared using statistical tests that take into
   An important information resource regarding        account the entire survival distributions. The
the benefits of treatment for early breast cancer      simple hazard function, which is in effect the
is the Early Breast Cancer Trialists’ Collabo-        derivative of the survival curve, can serve as an
rative Group (EBCTCG). This group, based at           effective graphical aid to understanding treatment
92                                     TEXTBOOK OF CLINICAL TRIALS

and covariate effects. Moreover, it can reveal         then the second-year hazard is 10/90 = 11%.
important effects that are not apparent in the         When calculating hazards from survival plots
survival curves, themselves.                           such as those in Figure 6.1 (which incorporate
   We will use trial CALGB 8541 as an                  censored observations), we subtract the current
example.43 This trial considered three differ-         year’s survival proportion from the previous
ent dose schedules of CAF (cyclophosphamide,           year’s survival proportion and divide by the
doxorubicin and 5-fluorouracil) in node positive        previous year’s survival proportion. The resulting
breast cancer. The schedules consisted of four         yearly values are shown in Figure 6.2.
cycles of CAF at 600, 60, 600 mg/m2 (high dose),          Some authors like to smooth hazard estimates
six cycles at 400, 40, 400 mg/m2 (moderate dose)       over time. We prefer to show the raw estimates.
or four cycles at 300, 30, 300 mg/m2 (low dose).       The reason is that each time period provides a
The primary endpoint was disease-free survival,        ‘nearly independent’ trial of therapeutic compar-
which is shown in Figure 6.1 for the three dose        isons. Depending on what assumptions are made
groups using Kaplan–Meier plots. Details of the        about the underlying survival distribution, these
comparison are provided in the original report,        trials may not be truly independent, but events
and will not be repeated here.                         that have occurred previously are set aside and
   Time-to-event curves such as those in Figure        a ‘new trial’ is begun. Each time period has
6.1 do not tell the whole story regarding any          the potential for confirming observations made
benefit of increasing dose and dose intensity. A        in other time periods.
clearer picture is contained in plots of hazard over      A striking observation from Figure 6.2 is that
time. The hazard in any particular time period         all three hazards decrease over time (after year
is the proportion of events occurring during that      2). This is a reflection of the heterogeneity of
time period in comparison with the number of           breast cancer. The most aggressive tumours recur
patients who are at risk at the beginning of the       early, yielding the high hazards evident in the
period. For example, if there are 100 patients         first few years. Once their tumours have recurred,
in a group and 10 of these recur in the first           patients are removed from the at-risk population.
year, then the first-year hazard is 10%. Going          The remaining tumours tend to be less aggressive
into the second year, only 90 patients are at          and so they recur at a lower rate.
risk. If another 10 recur in the second year,

     1.0                                                0.15
     0.7                      Mod                       0.10
     0.5           Low
     0.4                                                                 High
     0.0                                                0.00
           0   2   4     6    8 10 12 14 16 18                 0   2.5          5   7.5     10   12.5   15
                              Years                                                 Years

Figure 6.1. Disease-free survival proportion for the   Figure 6.2. Hazards for the three CAF dose groups of
three CAF dose groups of CALGB 8541                    CALGB 8541, derived from Figure 6.1
                                               BREAST CANCER                                                  93

   As regards treatment-arm effect, the apparent         0.35
benefit of a regimen of high-dose chemotherapy
is restricted to the first five years or so. Actually,     0.30
the hazard for a high dose is lower than those                             10+
of the other two arms in each of the first six
years (although it is not much lower in years            0.20
4, 5 and 6, and it is not much lower than that
for a moderate-dose regimen in any of the six            0.15                                            *
years). In view of the ‘near independence’ of the                   4−9

six time periods, this observation is impressive.        0.10
Another important observation from Figure 6.2 is
                                                         0.05             1−3
that after five years the risks of all three groups
come together, with the annual risk of recurrence
being approximately 5% in all three groups.                     0         2.5    5    7.5    10   12.5       15
   The reduction in hazard of recurrence for high                                    Years
versus low doses is 14% over the 18 years of
follow-up (95% confidence interval: 6–22%).              Figure 6.3. Hazards for the three categories of
This is an average over these years (weighted           positive lymph nodes (1–3, 4–9 and 10 or more)
over time because of differences in at-risk sample      for CALGB 8541. There are few patients at risk in the
sizes over time), but since there is no reduction       later years, especially in the 10+ group, and for two
at all in the later years, the overall reduction is     reasons. One is that this was the smallest group to
                                                        start with (174 of the 1550 patients in the trial), and
being carried by the early years. Restricting to the
                                                        the other is that most recurred early. For example, the
first three years, the reduction is 24% (13–33%).        asterisk at 13 years indicates a time point at which
A benefit of chemotherapy that is restricted to the      there were only 24 patients at risk, and three of these
first few years is typical in breast cancer trials. An   recurred in the 13th year
implication is that a hazard reduction seen early
in a trial, say one with a median of three years
of follow-up, will deteriorate over time. This is       no positive nodes. The effects of both the number
because the comparison will eventually involve          of positive nodes and dose of CAF have elapsed
averaging over periods where there is no longer         after five years.
a treatment benefit.                                        An important aspect of CALGB 8541 is the
   In the later years, the hazards of about 5%          role of tumour HER-2/neu expression and in
are very similar to the annual hazard for node          particular its interaction with dose of CAF.10
negative breast cancer patients. Interestingly,         HER-2/neu assessment was carried out for a
convergence to about 5% applies irrespective of         subset of 992 patients from the original study. Its
the number of positive lymph nodes. Figure 6.3          interaction with dose was shown to be significant
shows this effect. It gives hazard plots for three      in a multivariate proportional hazards model.
categories of positive nodes: 1–3, 4–9 and 10 or        But the manner of interaction is easiest to
more (for the three dose groups combined). Early        understand using hazards. Figure 6.4 shows the
in the trial, patients with 10+ positive nodes have     effect of dose of CAF separately for patients
a very high annual recurrence rate of 20–30%.           with HER-2/neu negative tumours (n = 720) and
However, after five years or so, the annual hazard       HER-2/neu positive tumours (n = 272). HER-
is about 5% in all three groups. A patient with         2/neu negatives show no dose effect. The entire
a large number of positive nodes who has not            benefit of high dose over moderate dose and
experienced recurrence in the first five years or         high dose over low dose that is observed in
so has the same updated prognosis as a patient          these patients is concentrated in patients whose
with a small number of positive nodes, including        tumours are HER-2/neu positive. Moreover, this
94                                               TEXTBOOK OF CLINICAL TRIALS

     0.20                                                      0.20

     0.15                     Mod                              0.15

                Low                                                                          Mod
     0.10                                                      0.10

     0.05                                                      0.05

     0.00                                                      0.00
            0   1     2   3   4   5   6 7    8    9 10 11 12          0    1     2   3   4    5    6 7    8   9 10 11 12
                                      Year                                                         Year

Figure 6.4. Annual disease-free survival hazards for a subset of patients (n = 992) in CALGB for whom
expression of HER-2/neu in the patient’s tumour was assessed. Patients in the left-hand panel had tumours that
were HER-2/neu negative and the tumours of those in the right-hand panel were HER-2/neu positive

benefit occurs through a reduction in hazard in                  The information available about these hazards
each of the first three to four years. Again,                    is shown in Figure 6.2. For predicting when
each year is a separate study and so each of                    and whether a patient recurs, hazards should be
these years provides a separate confirmation of                  considered one year at a time, and based on the
the overall conclusion. The hazard reduction in                 current year of follow-up.
the first three years for high dose as compared
with the other two groups combined was 65%
among patients whose tumours were HER-2/neu                               ASSESSING LONG-TERM IMPACTS
positive. HER-2/neu overexpression apparently                                      OF THERAPY
conveys a poor prognosis for lower doses but
not for a high dose – it might even provide a                   Showing that a cancer therapy is beneficial using
favourable prognosis for a high dose.                           logrank tests or proportional hazards regression
   Many of the above conclusions would have                     models or whatever other analysis one uses, does
been difficult or impossible without considering                 not allow for concluding the nature of the benefit.
hazards over time. A final comment regarding                     It may be that some patients are cured of their
hazards relates to the common problem of                        disease; or the therapy may delay the disease’s
predicting survival results into the future for                 progress in some patients; or the effect may be
patients already accrued to a trial. Consider                   a mixture of the two. Deciding among these
Figure 6.1. Some patients have as little as                     possibilities may be possible when all or almost
10 years of follow-up information. As more                      all events occur in a modest amount of follow-
follow-up information becomes available, there                  up time. In primary breast cancer, a goodly
will be no change in these curves prior to the 10-              proportion of patients never recur. Therefore,
year time point, but they may change subsequent                 such a decision is difficult or impossible to make.
to 10 years. Because the focus is on patients who                  Figure 6.5 illustrates the difficulty in discrim-
have not yet recurred, the way the curves will                  inating between cure and prolonging survival in
change depends on the hazards beyond 10 years.                  breast cancer trials. Consider a clinical trial that
                                                   BREAST CANCER                                           95

                1.0                                        long. Moreover, information beyond 20 years
                                                           is relatively sparse because earlier events and
                                                           competing risks (such as cardiovascular disease)
                0.8                                        will have removed patients from the at-risk
                0.7                                        population. To make inferential matters worse,
Survival Prob

                0.6                                        there is an enormous array of possible curves that
                                                           are similar to the two shown in the figure, with
                0.5                              Cure      some having cure rates and others not. Finally,
                0.4                                        the ‘current’ survival distribution assumes that
                0.3       Current                          all breast cancer is fatal (although survival times
                                                           vary). More realistically, some breast cancer
                                                           (including some invasive as well as in situ breast
                                                           cancer) will never kill the patient. Deciding
                0.0                                        whether a new therapy cures some patients is
                      0   5         10      15     20      even more difficult if a proportion of patients is
                                    Years                  assumed to have non-fatal disease.
                                                              This inability to distinguish between curing
Figure 6.5. Hypothetical survival curves comparing         patients and prolonging survival has further
cure and prolonging survival                               implications in the evaluation of screening and
                                                           diagnostic methods. It is possible that breast
is designed to evaluate a new therapy, one that            cancers become lethal or not in their very
may improve survival. Suppose further that in the          early development, as suggested by studies of
population of interest, the current annual rate of         tumour markers purported to identify especially
breast cancer mortality is 8%. The correspond-             aggressive tumours. If this is so, then early
ing survival distribution is shown by the dashed           detection may not help, and the observed benefits
survival curve labelled ‘current’ in Figure 6.5.           of therapy, however substantial, may be the result
It assumes exponential survival (although the              of slowing the progress of the disease rather than
same effect holds for any parametric form) and             curing it. Such slowing may be beneficial whether
so the current median survival is 8.66 years.              it comes early or late in the disease.
The goal of the new therapy is to improve this
by 1/3 to 11.55 years. If this happens then it
                                                             ADAPTIVE DESIGNS OF CLINICAL TRIALS
may be through prolonging every patient’s sur-
vival by reducing the annual mortality rate to
6% – the curve labelled ‘prolong’ – or by leav-            Adaptive designs have the dual goals of efficient
ing the annual rate unchanged (at 8%) for most             learning from all relevant results and effective
of the patients but curing a fraction of them – the        treatment of patients. They are more flexible than
curve labelled ‘cure’. To have the same median             conventional designs, and have application in all
(11.55 years) as ‘prolong’ implies a cure rate             phases of drug development. Such designs can
of 17.1%.                                                  be implemented using Bayesian methodology as
   In view of the sampling variability present in          a means to incorporate new information into the
empirical survival information, it is impossible           trial design.
to discriminate between the ‘prolong’ and ‘cure’              Designs of clinical trials for breast cancer
curves shown in Figure 6.5 on the basis of                 are usually static in the sense that the sample
results of even impossibly large clinical trials.          size and any prescription for assigning treatment,
Indeed, the critical part of the follow-up period          including the randomisation of patients, are fixed
for this discrimination is 20 years and beyond,            in advance. While designs may include stopping
and few trials have followed patients for this             rules, such as the two-stage Phase II trial design
96                                       TEXTBOOK OF CLINICAL TRIALS

of Simon,44 or the interim comparisons in Phase            possibilities are considered in light of the accu-
III designs,45,46 the criteria for early stopping          mulating information.
are very conservative and therefore few trials                Adaptive designs also include unbalanced ran-
actually stop early. The simplicity of trials              domisation, in which the degree of imbalance
with static design makes them solid inferential            depends on the accumulating data. For example,
tools. The sample sizes tend to be large, with             arms that give more information about the
a straightforward treatment comparison as the              hypothesis in question or that are performing
objective. Despite their virtues, static trials result     better than other arms can be weighted more
in slow and unnecessarily costly development of            heavily.47 Current (Bayesian) probabilities that
new therapeutic agents.                                    each of several doses or agents surpass standard
   The tradition of drug development is to evalu-          or placebo therapy are calculated. These calcu-
ate a single drug at a time. Given the fast pace of        lations use all information from patients treated
current new drug discovery (there are hundreds             to date. A new patient is then assigned to
of known experimental drugs with potential bene-           treatment randomly, with weights proportional
fits in breast cancer), these inefficient evaluation         to these probabilities. The assignments involve
methods are no longer adequate. In addition to             some degree of randomisation, but all patients
the traditional focus on false-positive and false-         are more likely to receive treatments that are per-
negative errors in standard drug testing, another          forming better. Those that are doing sufficiently
kind of error applies to drugs not under investi-          poorly become inadmissible in the sense that their
gation. Every such drug is a false neutral. Given          assignment weight becomes 0. When and if we
the limited resources available to the medical             learn that a new agent is effective (or ineffective),
establishment to develop new therapies, resource           we stop the trial. Patients in the trial benefit from
allocation must be approached in a more rational           data collected in the trial. The explicit goal is
way. This is as true in breast cancer, for which a         to treat patients more effectively, but in addition
relatively large number of women are willing to            we learn about the new agents more efficiently.
participate in clinical trials, as it is for other forms   Initially we evaluate each design’s frequentist
of cancer. Pharmaceutical companies and medi-              operating characteristics using Monte Carlo sim-
cal researchers generally must be able to consider         ulation, possibly modifying the parameters of the
hundreds of drugs for development at the same              assignment algorithm to achieve the desired char-
time. Static trials inhibit the simultaneous pro-          acteristics.
cessing of many drugs. They cannot efficiently                 Adaptive designs are being used increasingly
address dose–response questions or prioritisation          in cancer trials. This is true for trials sponsored by
of similar agents when many drugs are under con-           pharmaceutical companies, and more generally.
sideration. Dynamic designs that are integrated            A variety of trials at The University of Texas
with the drug development process are necessary            M.D. Anderson Cancer Centre (MDACC) are
for reasonable progress in medical research.               prospectively adaptive. For example, we are
   Using an adaptive design means examining                building the foundation for a Phase II trial
the accumulating data periodically – or even con-          for evaluating drugs for breast cancer that is
tinually – with the goal of modifying the trial’s          more a process than a trial. The idea is an
design. These modifications depend on what                  extension of more general adaptive assignment
the data show about the unknown hypotheses.                strategies. We start with a number of treatment
Among the modifications possible are stopping               arms plus a control – possibly a standard therapy.
early, restricting eligibility criteria, expanding         We randomise to the arms and learn about their
accrual to additional sites, extending accrual             relative efficacy as the trial proceeds. Arms that
beyond the trial’s original sample size if its             perform better get used more often. An arm that
conclusion is still not clear, dropping arms or            performs sufficiently poorly gets dropped. An
doses, and adding arms or doses. All of these              arm that does well enough graduates to Phase III,
                                               BREAST CANCER                                              97

and if it does sufficiently well it might even           yet fully evaluable. Other improvements to dose-
replace the control. As more treatments become          finding methods are underway. These include
available, they are added to the mix and the            the simultaneous incorporation of efficacy results
process can continue indefinitely.                       into the design, and the use of toxicity severity
   A trial of a new agent for treatment of              rather than the usual assumption that toxicity is
metastatic breast cancer is being compared to the       dichotomous.
current standard therapy in a dynamic manner
that allows the incorporation of newly available                         CONCLUSION
treatments in the randomisation process, as well
as the elimination of treatments when a lack of         Breast cancer clinical trials are not fundamentally
improved efficacy can be established. Patients are       different from those of other cancers. However,
randomised to treatments with weights propor-           breast cancer stands out for several reasons. First,
tional to the probability that a treatment is better    it is common, and it is becoming even more
than the standard therapy. The result is that supe-     common with the improvements in and greater
rior therapies move through quickly and poorer          use of detection methods. That implies a greater
therapies get dropped. Patients in the trial are pro-   ability to investigate the potential for therapeutic
vided with better treatment (when the arms are          agents and combinations. As a consequence, there
not equally good). Patients outside the trial get       have been hundreds of randomised clinical trials
access to better treatments more rapidly.               conducted in breast cancer, more by far than in
   Dose-finding trials of new agents are also con-       any other cancer. Second, it is a disease that is
ducted adaptively at MDACC, with dose assign-           fatal in only a minority of cases. Third, patient
ment based on Bayesian updating of a model              advocates in the breast cancer community have
                                                        been very influential, both as a research force
which relates dose and toxicity, using results
                                                        and a political force, in lobbying for research
from preceding patients. The model is the con-
                                                        funding. Fourth, breast cancer has been shown
tinual reassessment method or CRM.48,49 Each
                                                        to be sensitive to a number of chemotherapies
patient is assigned to the dose having a prob-
                                                        and hormonal therapies. The advances that have
ability of toxicity closest to some predetermined       been made in breast cancer therapy are more
target value. This is the Bayesian posterior proba-     impressive than for any other type of cancer,
bility calculated from the data available up to that    except for testicular cancer and some forms of
point (and so it is based on sufficient statistics).     leukaemia that commonly affect children. These
   The CRM more effectively finds the maximum            advances have been built on a foundation of
tolerated dose (MTD) than does the conventional         clinical trials.
3 + 3 design.50 A way in which both the 3 +
3 and CRM designs are crude is the need
to pause accrual while waiting for toxicity
information.51 Such pauses are inefficient and            1. Surveillance, Epidemiology, and End Results
they cause logistical problems. Trials should be            Program (SEER) Public-Use Data (1973–1998),
paused or stopped if there are safety concerns,             National Cancer Institute, DCCPS, Surveillance
not because the design cannot get out of its own            Research Program, Cancer Statistics Branch,
                                                            Bethesda, MD, August 2000 submission; released
way. In getting information about toxicity (or              April 2001 [online database, available at http://
efficacy), there is seldom a magical dose that the           seer.cancer.gov].
next patient must get. All doses are potentially         2. Cancer Intervention and Surveillance Modeling
informative. Rather than stopping, one should               Network (CISNET) [online information site].
                                                            Available through the National Cancer Institute,
use a design that models dose–response (toxicity            US government, at http://cisnet.cancer.gov/about.
and efficacy) and is able to assign a next dose           3. National Breast Cancer Coalition Fund (NBCCF).
even though patients previously treated are not             A patient guide to quality breast cancer care
98                                         TEXTBOOK OF CLINICAL TRIALS

      [online information site]. Available at http://www.    14. Halsted WS. The results of operations for the cure
      natlbcc.org/nbccf.                                         of cancer of the breast performed at the Johns
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      cancerstaging.org.                                     15. Halsted WS. The results of radical operations for
 5.   Singletary SE, Allred C, Ashley P, Bassett LW,             the cure of carcinoma of the breast. Ann Surg
      Berry D, Bland KI, Borgen PI, Clark G, Edge SB,            (1907) SLVI: 1–19.
      Hayes DF, Hughes LL, Hutter RBP, Morrow M,             16. Buchanan EB. A century of breast cancer surgery.
      Page DL, Recht A, Theriault RL, Thor A, Weaver             Cancer Invest (1996) 14: 371–7.
      DL, Wieand HS, Greene FL. Revision of the              17. Haagensen CD. A great leap backward in the
      American Joint Committee on Cancer Staging                 treatment of carcinoma of the breast. JAMA (1973)
      System for Breast Cancer. J Clin Oncol (2002)              224: 1181–3.
      20: 3628–36.                                           18. Fisher B, Montague E, Redmond C, Barton B,
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      Greenberg PA, Hortob´ gyi GN, Smith TL, Ziegler            Borland D, Fisher ER, Deutsch M, Schwarz G,
      LD, Frye DK, Buzdar AU. Long-term follow-up                Margolese R, Donegan W, Volk H, Konvolinka C,
      of patients with complete remission following              Gardner B, Cohn I, Lesnick G, Cruz AB, Law-
      combination chemotherapy for metastatic breast             rence W, Nealon T, Butcher H, Lawton R. Com-
      cancer. J Clin Oncol (1996) 14: 2197–205.                  parison of radical mastectomy with alternative
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      (EBCTCG). Tamoxifen for early breast cancer: an            of results from a prospective randomized clinical
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      351: 1451–67.                                          19. Fisher B, Jeong J-H, Anderson S, Bryant J, Fisher
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      inhibition: clinical efficacy and tolerability in the       randomized trial comparing radical mastectomy,
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      Kute T, Henderson IC, Barcos M, Cirrincione C,             Tancini G, Bajetta E, Musumeci R, Veronesi U.
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      Ingle J, Pritchard K, Shepard L, Davidson N,               (1998) 352: 930–42.
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                                         Childhood Cancer
                        SHARON B. MURPHY1 AND JONATHAN J. SHUSTER2
              Children’s Cancer Research Institute, University of Texas Health Science Centre, San Antonio,
                                                 TX 78229-3900, USA
                       College of Medicine, University of Florida, Gainesville, FL 32610-0212, USA

                    INTRODUCTION                                        tumours, such as Wilm’s tumour, retinoblastoma,
                                                                        rhabdomyosarcoma, neuroblastoma, Ewing’s sar-
                                                                        coma and osteogenic sarcoma, for example, that
There are substantial differences in the conduct                        are either exclusively or predominantly paediatric
of clinical cancer research in children com-                            in nature. In contrast, carcinomas of differenti-
pared to adults. First, childhood cancer is com-                        ated epithelial tissues, like the aerodigestive tract
paratively rare. According to statistics released                       or breast or prostate, do not occur in children.
by the National Cancer Institute SEER pro-                              Thanks to the usual lack of co-morbid conditions
gramme in 1999,1 it is estimated that approxi-                          and concomitant illnesses, children usually have
mately 12 400 children and adolescents, younger                         a greater tolerance to cancer therapy than adults.
than 20 years of age, are diagnosed annually                            Taken together with the differing spectrum of
with cancer. Stated another way, the average                            cancer seen, the host differences related to age
annual age-adjusted incidence rate for all child-                       necessitate that paediatric studies of anti-cancer
hood cancers is 150 per million persons, aged                           drug dosage, efficacy and safety are needed.
<20. This is under 2% of the total cancers                              Recognising that children are not just small adults
diagnosed in the USA. Despite the rarity and                            and that special considerations apply, the FDA
notwithstanding the spectacular success in treat-                       has issued regulations mandating the testing of
ment of paediatric cancer, compared to inci-                            new drugs in paediatric patients.
dence and mortality rates of cancer occurring                              Given the fact that modern treatments result in
among adults, cancer is the leading cause of                            cure of 75–80% of all children and adolescents
death from disease among children and adoles-                           with cancer who are managed appropriately, the
cents. Only accidents and firearms kill more chil-                       long-term consequences of therapy for children
dren than cancer. Further, the distribution of can-                     are also potentially much greater than in adults,
cer diagnoses in children is very different from                        as the therapy can interfere with normal growth
that in adults. There are a number of major                             and development, leaving them exposed for

Textbook of Clinical Trials. Edited by D. Machin, S. Day and S. Green
 2004 John Wiley & Sons, Ltd ISBN: 0-471-98787-5
102                                  TEXTBOOK OF CLINICAL TRIALS

decades at risk for serious sequelae, major           Table 7.1. Major categories of paediatric cancer and
organ disturbance, such as cardiac damage and         projected annual accrual of the Children’s Oncology
cognitive dysfunction, or second malignancies.        Group
Children diagnosed with cancer generally also         Leukaemia
have less of a problem with competing mortality
                                                        Infant ALLa : 50
risks, when compared to adult cancer.                   ‘Standard Risk’ B-Precursor ALLa : 1100
   Given these factors, to adequately size child-       ‘High Risk’ B-Precursor ALLa : 600
hood cancer research studies, a substantial pro-        T-Cell ALLa : 240
                                                        Philadelphia Chromosome Positive (Ph+) ALLa : 20
portion of the incident cases must be enrolled.         B-Cell (SIg+)ALLa : 45
In fact, in some situations, such as randomised         ANLLa : 300
Phase III trials of new regimens compared to
already effective front-line treatments, nation-      Lymphoma
wide multi-institutional trials are a necessity.        Hodgkin’s Disease: 250
These trials will need to enroll nearly every child     ‘Early Stage’ NHLa : 90
                                                        ‘Advanced Stage’ Lymphoblastic NHLa : 90
in the target population with the disease being         ‘Advanced Stage’ Large Cell NHLa : 80
studied for three to five years, with many years of      ‘Advanced Stage’ Small Non-Cleaved Cell NHLa : 125
follow-up needed to assess long-term outcomes.
Accrual duration in childhood trials may be con-      Brain Tumours
siderably longer than a corresponding adult trial.      Astrocytoma: 140
However, since clinical practice closely approx-        Medulloblastoma: 140
                                                        Glioma: 70
imates that of the ongoing study, it is rare that       Ependymoma: 35
progress from an external source ever renders the
study question obsolete. Finally, given the rar-      Sarcomas
ity of childhood cancer, and the desirability of
                                                        Ewing’s Sarcoma: 80
study designs of maximal efficiency, it is often         Osteosarcoma: 170
desirable to conduct ‘2 × 2 factorial studies’,         ‘Low Risk’ Rhabdomyosarcoma: 64
where two interventions are used in the same trial      ‘Intermediate Risk’ Rhabdomyosarcoma: 99
                                                        ‘High Risk’ Rhabdomyosarcoma: 21
(Standard vs. Standard + A vs. Standard + B vs.
Standard + A + B). Such designs carry some risk       Kidney
where there is a qualitative interaction between
                                                        Wilm’s Tumour: 480
the two interventions. For example, this would
occur if the impact of A is highly dependent          Embryonal
upon whether B is given or not. Hence the choice
                                                        ‘Low Risk’ Neuroblastoma: 200
of randomised interventions needs to take this          ‘Intermediate Risk’ Neuroblastoma: 110
pitfall into account when such factorial designs        ‘High Risk’ Neuroblastoma: 150
are considered.                                         Hepatoblastoma: 65
                                                        Germ Cell Tumours: 25
   Based on previous trials and internal registry
data of the major national paediatric coopera-        a
                                                        ALL = Acute Lymphoblastic Leukaemia
                                                      AML = Acute Non-Lymphoblastic Leukaemia
tive oncology groups, Table 7.1 provides esti-        NHL = Non-Hodgkin’s Lymphoma.
mates of the potential accrual to the Children’s
Oncology Group (COG), a consortium of about
230 American, Canadian, European and Aus-             Study Group (NWTSG). Virtually every US or
tralasian medical centres. COG was formed in          Canadian hospital with a childhood paediatric
2000 by the merger of the Pediatric Oncol-            haematology/oncology division belongs to COG.
ogy Group (POG), the Children’s Cancer Group          Note that the anticipated annual accrual to COG
(CCG), the Intergroup Rhabdomyosarcoma Study          trials does not mirror incidence figures, as there is
Group (IRSG) and the National Wilm’s Tumor            a substantial gap between incident rates and rates
                                            CHILDHOOD CANCER                                           103

of referral of newly diagnosed paediatric cancer       are presented. A special section dealing with the
patients to member institutions of COG and par-        ethical aspects and unique considerations affect-
ticipation in clinical trials. Ross et al.2 analysed   ing the conduct of clinical trials in children is
21 026 incident paediatric cancer cases, diag-         also included. The final section is devoted to a
nosed from 1989–91, and compared observed              look into the future.
to expected numbers of cases seen at member
institutions of POG and CCG and found vastly                   HISTORY AND PERSPECTIVES
different ratios (observed/expected) depending on              ON IMPORTANT PAEDIATRIC
age and site, and to a much less extent, geo-                   CANCER CLINICAL TRIALS
graphic region. According to this survey, 92%
of children aged less than 15 years in the US
                                                       Statistically and clinically significant improve-
received their care at a CCG or POG institu-           ments have been achieved in all major forms
tion, thereby providing at least a mechanism           of childhood cancers through conduct of well-
approximating population-based studies. How-           organised single institution and cooperative group
ever, the ratio (O/E) for 15–19 year olds was          clinical trials which have resulted in sequen-
only 0.21, pointing to an adolescent gap in            tial and steady improvement in survival rates
access to national cancer clinical trials at qual-     since the 1960s when curative treatments were
ified institutions.                                     first devised. SEER data document that the over-
   As seen in Table 7.1, the Children’s Oncology       all childhood cancer mortality rates have con-
Group runs Phase III clinical trials in a wide         sistently declined throughout the 1975–95 time
variety of tumours, with accrual ranging from          period.1 Documentation of the overall progress
as few as 20 patients per year to over 1000 per        achieved by POG investigators has been reported,
year. The Children’s Oncology Group is also            demonstrating significant improvements in over-
heavily involved in correlative science, pilot         all survival (OS) and event-free survival (EFS)
studies of potential Phase III interventions, as       for 8 of 10 disease areas, in a sample of over 7000
well as standard Phase I (dose escalation) studies     children and adolescents treated between 1976
and Phase II (early efficacy) studies. The group        and 1989.4 Similar results have been achieved by
places special emphasis on translational research      CCG and by European national paediatric coop-
(biologic correlation studies) and cancer control      erative clinical trials organisations. There is also
(supportive care studies to limit long-term side       evidence that children and adolescents with acute
effects and epidemiologic studies to learn about       lymphocytic leukaemia (ALL), non-Hodgkin’s
the aetiology of childhood cancer). Due to the         lymphoma (NHL), Wilm’s tumour, medulloblas-
presumably genetic origin of most forms of             toma and rhabdomyosarcoma enjoy a significant
childhood cancer and the short lag time between        survival advantage when treated according to
symptoms and diagnosis, prevention trials and          well-defined protocols, compared to paediatric
screening trials are difficult to do in paediatric      patients not enrolled on protocols and treated out-
cancer, with neuroblastoma,3 which is based            side of paediatric cancer centres.5 Most probably
on urinary screening for elevated levels of            the inclusion benefit related to participation in
catecholamines, a notable exception.                   clinical trials is a result of a number of factors,
   This chapter is organised into several sections.    including the rigorous process of protocol devel-
In the first section, major accomplishments in          opment, incorporation of rapid pathology review
the area of childhood cancer treatment are dis-        and reference laboratories, defined staging prac-
cussed. In the following section, examples are         tices and procedures, on-study review of radio-
cited where translational research has affected        therapy port films, and close monitoring for toxi-
the design of paediatric cancer trials. In the suc-    city and efficacy. Some of the important advances
ceeding section, the typical methods of design-        achieved in treatment of paediatric cancers are
ing trials for the Children’s Oncology Group           listed in Table 7.2.
104                                   TEXTBOOK OF CLINICAL TRIALS

Table 7.2. Examples of important advances resulting    Hospital in Memphis who pioneered a ‘Total Ther-
from paediatric cancer clinical trials                 apy’ curative approach beginning in the 1960s. It
• Adjuvant chemotherapy improves survival from
                                                       is beyond the scope of this chapter to review the
  20% to 70% in non-metastatic osteosarcoma of         treatment advances achieved through clinical trials
  the extremity.50                                                                                 u
                                                       for ALL by the BFM (Berlin–Frankfurt–M¨ nster)
• Doxorubicin improves outcome when added to           Group, POG, CCG, the Dana Farber Consor-
  other chemotherapy for Ewing’s sarcoma51 and         tium, the Medical Research Council/UKALL, the
  the addition of ifosfamide and etoposide to
  vincristine, adriamycin, cyclophosphamide and        Dutch Childhood Leukaemia Study Group, the
  actinomycin results in greater benefit.52             French Acute Lymphoblastic Leukaemia Coopera-
• Radiation therapy does not improve survival for      tive Group (FRALLE) and the Italian Association
  patients receiving chemotherapy with Stage I and     of Paediatric Haematology–Oncology (AIEOP),
  II, Wilm’s tumour,53,54 Stage I                      but the interested reader may consult reviews
  rhabdomyosarcoma55 or localised non-Hodgkin’s
  lymphoma.56                                          summarising the spectacular progress achieved in
• Demonstration of improved event-free survival in     treatment of ALL.6
  high-risk neuroblastoma receiving myeloablative         The lymphomas, Hodgkin’s disease (HD) and
  therapy in conjunction with autologous bone          non-Hodgkin’s lymphomas (NHL), are the third
  marrow transplantation and subsequent treatment
  with 13-cis-retinoic acid compared to
                                                       most common form of paediatric malignancy,
  chemotherapy alone.57                                next in frequency behind leukaemias and tumours
• Attainment of 80% 4-year event-free survival rates   of the central nervous system. Currently 80–90%
  for standard risk B-precursor ALL.58                 of all children and adolescents with malignant
• Achievement of 78% EFS for patients with             lymphomas are curable with optimal multidis-
  loco-regional embryonal rhabdomyosarcoma
  through intensification of chemotherapy in            ciplinary management, based on immunopatho-
  Intergroup Rhabdomyosarcoma Study (IRS)-IV.59        logic classification, staging for determination
                                                       of disease extent, and design and selection of
                                                       risk-adapted therapies. Paediatric investigators at
   Success in treatment of the most common             Stanford, beginning in 1970, first pioneered com-
form of paediatric malignancy, acute lymphoblas-       bined modality treatment for children with HD
tic leukaemia (ALL), has been most gratifying.         and demonstrated that low-dose involved field
Indeed, a major reason for improvements in over-       radiotherapy combined with multiple cycles of
all survival for childhood cancer in general is due    chemotherapy (MOPP or MOPP/ABVD) resulted
to improvement in survival rates for ALL, which        in cure of 90% of paediatric patients.7 Similarly
accounts for roughly a third of paediatric cancer.1    outstanding rates of disease control with com-
With modern chemotherapy, 97–99% of children           bined modality management of paediatric HD
can be expected to attain complete remission, and      have since been reported by others, establishing
it is not inconceivable to predict that modifica-       the curability of HD in nearly all cases, such that
tions of the currently most successful protocols       the thrust of current trials in paediatric HD is
will boost long-term leukaemia-free survival rates     towards reduction of serious late effects of HD
to as high as 85–90%. Treatment success has            treatments, such as secondary malignancies, par-
been achieved through post-induction intensifi-         ticularly leukaemia, infertility, pulmonary fibrosis
cation/consolidation and re-induction treatments,      and restrictive lung disease, serious cardiac prob-
effective treatments (‘prophylaxis’) for subclinical   lems and premature death.
central nervous system leukaemia, and prolonged           The non-Hodgkin’s lymphomas occurring
anti-metabolite-based continuation treatments of       among children and adolescents are virtually
24–36 months duration. Advances have been              all high-grade, diffuse malignancies, differing
achieved by many single institutions and coopera-      markedly from the distribution of histologic types
tive groups treating childhood leukaemias, includ-     typically seen among older adults. Staging systems
ing investigators at St. Jude Children’s Research      in use for childhood and adult NHL also differ.8
                                             CHILDHOOD CANCER                                               105

Ninety percent of localised NHLs, regardless of          specifically for biologically defined, risk-adapted
histology, are readily cured by nine weeks of            subsets of patients. For example, the National
chemotherapy without radiation.9                         Wilms’ Tumor Study-5, a therapeutic trial and
   Progress in the treatment of paediatric solid         biology study, was designed to reduce treatment
tumours has been equally striking in the last            intensity for the subgroup(s) of patients with the
30 years as the progress in treating child-              most favourable prognosis and intensify treat-
hood leukaemias and lymphomas, and may be                ment for the patients with the least favourable
attributable to development of accurate diag-            prognosis, based on stage, histology (favourable
nostic methods and systems of disease staging            or unfavourable, anaplastic, rhabdoid and clear
and effective multimodal treatments combin-              cell types), tumour size and bilaterality, and to
ing surgery, chemotherapy and radiation. Cure            investigate the impact of loss of heterozygos-
rates for rhabdomyosarcoma have increased from           ity (LOH) of chromosome 16q and 1p on two-
approximately 25% in 1970 to greater than 75%            year relapse-free survival through collection of
currently, to 60–70% for non-metastatic bone             tumour and normal kidney tissue for DNA anal-
sarcomas, to over 80% for Wilm’s tumour, over            ysis and banking.
90% for retinoblastoma, over 90% for infants                Perhaps the best example of important trans-
and children with localised neuroblastoma, and           lational research that has led directly to thera-
to over half of all children with brain tumours.         peutic implications is in the collection of bone
   Aims of current trials are to increase or             marrow specimens for cytogenetic studies in
preserve high cure rates, decrease acute toxicity        childhood acute lymphocytic leukaemia (ALL).10
and long-term adverse sequelae of treatment,             While classical karyotype analysis is typically
decrease costs and improve the quality of life           informative in 60–70% of the patients, impor-
for children with readily curable cancers. Patients      tant genetic markers can now be identified by
with high risk or metastatic disease at diagnosis        probes, using FISH (fluorescence in situ hybridi-
or those who recur after front-line therapies            sation) or PCR (polymerase chain reaction) in
continue to pose challenges and should properly          virtually all patients. Translocations, such as the
benefit from pilot trials and Phase I or II studies       t(4;11),11 – 13 t(9;22)14 – 16 and t(1;19),17,18 confer
of new treatments.                                       an adverse prognosis and lead to targeting the
                                                         patients for more aggressive therapy. On the other
                                                         hand, patients with the cryptic t(12;21) genetic
 PROGNOSTIC FACTORS, TRANSLATIONAL                       lesion encoding the TEL-AML1 transcript,19 – 21
    RESEARCH AND THERAPEUTICALLY                         with hyperdiploid leukaemia identified by flow
         RELEVANT RISK GROUPS                            cytometric measurement of DNA index (typically
                                                         53+ chromosomes in their primary clone),22,23 or
Successful childhood cancer research is in large         with specific trisomies detected by FISH, such as
part dependent upon its translational research           4, 10 and 17,23,24 have a more favourable out-
programme. Over the past three decades, initial          come and can be targeted for less intensive treat-
diagnosis and classification of childhood cancer          ment. As an example of the latter, POG investi-
has become far more sophisticated, as laboratory         gators designed a trial (#9201) with less intense
scientists have collaborated closely with clinical       chemotherapy for ALL patients with lesser risk of
investigators. In addition, special biological and       relapse, defined by initial white blood cell counts
pharmacological studies, conducted during and            <50 000, age between 1 and 10 years, absence of
after treatment, offer tools to clinical investigators   CNS disease, and presence of one or both of the
that were never previously available. As a result,       following: DNA index >1.16, and/or trisomies of
paediatric oncologists, surgeons, pathologists and       chromosomes 4 and 10 by FISH.
collaborating statisticians have the opportunity            In addition to the well-recognised prognos-
and the obligation to design and stratify trials         tic importance of initial white blood cell count,
106                                  TEXTBOOK OF CLINICAL TRIALS

age at diagnosis, extramedullary disease and          assignments for the Intergroup Rhabdomyosar-
blast cell genetic features in B-precursor ALL        coma Study V (shown in Table 7.3) are based on
and their significance for stratification and trial     favourable prognostic factors identified in Stud-
design, the early response to therapy, presence       ies I–IV, conducted from 1972 through 1991,
of minimal residual disease (MRD), and pharma-        and include (1) undetectable distant metastases at
cologic and pharmacokinetic variables are also        diagnosis; (2) primary sites in the orbit and non-
predictive of outcome. Slow early response to         parameningeal head/neck and genitourinary non-
induction treatment is predictive of an adverse       bladder/prostate regions; (3) grossly complete
outcome and can be defined in several ways:            surgical removal of localised tumour at diagno-
slow clearance of circulating blast cells to one      sis; (4) embryonal/botryoid histology; (5) tumour
week of prednisone or multiagent induction, or        size ≤5 cm; and (6) age younger than 10 years
greater than 25% marrow blasts on day 7 (or           at diagnosis. Patients defined as shown into
day 14) of treatment. Quantitation of MRD by          low, intermediate and high risk are predicted to
immunologic methods or PCR assay of rear-             have an estimated three-year EFS rate of 88%,
ranged T-cell-receptor or immunoglobulin heavy-       55–76% and <30%, respectively.31
chain genes of leukaemic blasts as clonal markers        Similarly, significant advances in translational
of leukaemia in patients in clinical remission        research is neuroblastoma, which accounts for 8
has been shown to identify patients at elevated       to 10% of all childhood cancers, have resulted in
risk for relapse, a factor which (arguably) should    a refined risk-related approach to therapy based
be taken into account in assigning alternative        on the age of the patient, the stage of the tumour
treatment.25,26 Wide variability in absorption of     according to the International Neuroblastoma
orally administrated chemotherapy, such as 6-         Staging System (INSS), histopathologic features,
mercaptopurine, and inter-patient variability in      the number of N-myc copy numbers and the
systemic exposure to both methotrexate and 6-         ploidy of tumour cells (Table 7.4).
mercaptopurine are important determinants of             Because childhood cancer is rare, national ref-
outcome in ALL.27,28 Graham et al.29 uncovered        erence laboratories have been established to anal-
a pharmacologic interaction between methotrex-        yse and store samples from the membership of
ate and cytosine arabinoside when given simulta-      the Children’s Oncology Group as well as other
neously, and demonstrated a correlation between       large institutions and other international paedi-
host drug levels and adverse outcome. Individ-        atric clinical trials organisations. Such laborato-
ual variability in response to cancer treatment is    ries help the research programme in terms of sci-
surely related to genetic polymorphisms in drug-      entific expertise, quality control and correlative
metabolising enzymes, transporters, receptors and     science. Few institutions can afford to maintain
other drug targets, and suggests that these genetic   such laboratories solely for their own paediatric
differences may form a solid scientific basis for      cancer patients, and web-based informatics appli-
optimising therapies within the context of clinical   cations afford access to the most sophisticated
trials.30                                             on-line resources and information even in smaller
   Given the plethora of prognostic factors now       remote centres.
known for most paediatric malignancies, a prag-
matic and rational approach to clinical trials             STUDY DESIGN FOR CHILDHOOD
design and stratification consists of risk assign-                 CANCER TRIALS
ment by a combination of clinical and biological
factors identified through multivariate analysis                  PHASE I STUDY DESIGN
to be of prognostic significance. Treatment is
then tailored to risk status, commonly consider-      Because childhood cancer is rare and the response
ing variables such as patient age, extent of dis-     to conventional treatment good, most children
ease and tumour biology. For example, the risk        never experience recurrent disease and are thus
Table 7.3. Risk group assignments for intergroup Rhabdomyosarcoma Study Group study V

Risk (protocol)           Stage               Group                 Site         Size      Age      Histology        Metastasis      Nodes            Treatment
Low, subgroup A              1          I                  Favourable            a or b    <21          EMB               M0      N0               VA
(D9602)                      1          II                 Favourable            a or b    <21          EMB               M0      N0               VA + XRT
                             1          III                Orbit only            a or b    <21          EMB               M0      N0               VA + XRT
                             2          I                  Unfavourable          a         <21          EMB               M0      N0 or NX         VA
Low, subgroup B              1          II                 Favourable            a or b    <21          EMB               M0      N1               VAC + XRT
(D9602)                      1          III                Orbit only            a or b    <21          EMB               M0      N1               VAC + XRT
                             1          III                Favourable            a or b    <21          EMB               M0      N0 or N1 or NX   VAC + XRT
                             2          II                 Unfavourable          a         <21         EMB                M0      N0 or NX         VAC + XRT
                             3          I or II            Unfavourable          a         <21         EMB                M0      N1               VAC (+XRT, Gp II)
                             3          I or II            Unfavourable          b         <21         EMB                M0      N0 or N1 or NX   VAC (+XRT, Gp II)
Intermediate                 2          III                Unfavourable          a         <21         EMB                M0      N0 or NX         VAC ± Topo + XRT
(D9803)                      3          III                Unfavourable          a         <21         EMB                M0      N1               VAC ± Topo + XRT
                             3          III                Unfavourable          b         <21         EMB                M0      N0 or N1 or NX   VAC ± Topo + XRT
                        1 or 2 or 3     I or II or III     Favourable or         a or b    <21       ALV/UDS              M0      N0 or N1 or NX   VAC ± Topo + XRT
                             4          I or II or III     Favourable or         a or b    <10          EMB               M1      N0 or N1 or NX   VAC ± Topo + XRT
                                           or IV             unfavourable
                                                                                                                                                                       CHILDHOOD CANCER

High (D9802)                 4          IV                 Favourable or         a or b    ≥10          EMB               M1      N0 or N1 or NX   CPT-11, VAC + XRT
                             4          IV                 Favourable or         a or b    <21       ALV/UDS              M1      N0 or N1 or NX   CPT-11, VAC + XRT

Favourable = orbit/eyelid, head and neck (excluding parameningeal), genitourinary (not bladder or prostate) and biliary tract.
Unfavourable = bladder, prostate, extremity, parameningeal, trunk, retroperitoneal, pelvis, other.
a = tumour size ≤5 cm in diameter; b = tumour size >5 cm in diameter.
EMB = embryonal, botryoid, or spindle-cell rhabdomyosarcomas or ectomesenchymomas with embryonal RMS.
ALV = alveolar rhabdomyosarcomas or ectomesenchymomas with alveolar RMS, UDS = undifferentiated sarcomas.
N0 = regional nodes clinically not involved; N1 = regional nodes clinically involved; NX = node status unknown.
VAC = vincristine, actinomycin D, cyclophosphamide; XRT = radiotherapy; Topo = topotecan; Gp = Group; CPT-11 = irinotecan.

Source: Reproduced from Raney et al.31 (p. 218), with permission.
108                                             TEXTBOOK OF CLINICAL TRIALS

Table 7.4. International Neuroblastoma Staging System (INSS)

Stage 1:  Localized tumour continued to the area of origin; complete gross resection, with or without
          microscopic residual disease; identifiable ipsilateral and contralateral lymph node negative for
Stage 2A: Unilateral with incomplete gross resection; identifiable ipsilateral and contralateral lymph node
          negative for tumour.
Stage 2B: Unilateral with complete or incomplete gross resection; with ipsilateral lymph node positive for
          tumour; identifiable contralateral lymph node negative for tumour.
Stage 3: Tumour infiltrating across midline with or without regional lymph node involvement; or unilateral
          tumour with contralateral lymph node involvement; or midline tumour with bilateral lymph node
Stage 4: Dissemination of tumour to distant lymph nodes, bone marrow, liver or other organs except as
          defined in stage 4S.
Stage 4S: Localized primary tumour as defined in stage 1 or 2, with dissemination limited to liver, skin or
          bone marrow
                                Risk group and protocol assignment schema: POG and CCG

     INSS                                        N-myc                       Shimada                DNA                   Risk
     stage              Age (y)                  status                      histology              ploidy             group/study
    1                   0–21                 Any                           Any                      Any                Low
2A and 2B               <1                   Any                           Any                      Any                Low
                        ≥1–21                Nonamplifieda                  Any                      NA                 Low
                        ≥1–21                Amplifiedb                     Favourable               NA                 Low
                        ≥1–21                Amplified                      Unfavourable             NA                 High
        3               <1                   Nonamplified                   Any                      Any                Intermediate
                        <1                   Amplified                      Any                      Any                High
                        ≥1–21                Nonamplified                   Favourable               NA                 Intermediate
                        ≥1–21                Nonamplified                   Unfavourable             NA                 High
                        ≥1–21                Amplified                      Any                      NA                 High
        4               <1                   Nonamplified                   Any                      Any                Intermediate
                        <1                   Amplified                      Any                      Any                High
                        ≥1–21                Any                           Any                      NA                 High
       4S               <1                   Nonamplified                   Favourable               >1                 Low
                        <1                   Nonamplified                   Any                      1                  Intermediate
                        <1                   Nonamplified                   Unfavourable             Any                Intermediate
                        <1                   Amplified                      Any                      Any                High
    N-myc copy number ≤10.
    N-myc copy number >10.

POG, Pediatric Oncology Group; CCG, Children’s Cancer Group; INSS, International Neuroblastoma Staging System; NA, not applicable.

Source: Reproduced from Castleberry,60 (pp. 926, 930), with permission from Elsevier.

not eligible for trials of new agents. Phase I                            are accomplished as multi-institutional collab-
trials are designed to estimate the maximal tol-                          orations. Paediatric drug development requires
erated dose of a drug, to determine the nature                            separate Phase I studies (i.e., separate and dis-
and frequency of toxicities, and to define the                             tinct from studies done in adults) because pae-
drug pharmacokinetics. While eligibility varies,                          diatric patients may tolerate either higher or
patients have typically failed front-line therapy                         lower levels of drugs and may exhibit toxici-
and usually they will also have failed second-line                        ties unique to children. Separate trials warranting
therapy. Because of the small number of pae-                              emphasis may also reflect unique agents active
diatric patients eligible for Phase I trials, most                        in paediatric tumours, differing from agents that
                                            CHILDHOOD CANCER                                         109

are of the highest priority for cancers common         paediatric Phase I trials have been established.32
among adults.                                          A problem recently identified is the determination
   The basic design is to begin at about 80%           of MTDs in paediatric trials that are lower
of the adult maximal tolerated dose. Patients are      than those defined in adult patients, which may
entered in cohorts and treated at increasing doses.    relate to differences in the intensity of prior
At each level, three patients are typically accrued.   therapy between adult and paediatric patients
If there is no dose-limiting toxicity amongst the      entered onto Phase I trials. There is a well-
three patients, the dose is raised to the next         established association between prior therapy
level (usually a 20–30% escalation), in succes-        and reduced tolerance to myelotoxic drugs.
sive cohorts of patients with no intrapatient dose     If current paediatric Phase I trials in heavily
escalation. If two or all three of these initially     pretreated patients define MTDs that tend to be
accrued patients experience dose-limiting toxic-       lower than those determined in adult patients
ity (DLT), the maximum tolerated dose (MTD)            with minimal prior therapy, then application of
will have been deemed exceeded. Finally, if one        the paediatric MTD to less heavily pretreated
patient amongst the initial three patients experi-     paediatric patients, e.g., in Phase II trials, may
ences dose-limiting toxicity, an additional three      be problematic.
patients are accrued. If six patients are needed,
a dose escalation will occur if a total of one in                 PHASE II STUDY DESIGN
six (i.e. zero of the next three) has dose-limiting
toxicity. If two or more (i.e. one or more of          The specific purpose of a Phase II trial is to
the next three) experience dose-limiting toxic-        determine activity, i.e., to develop estimates of
ity, the maximal tolerated dose will be deemed         the response rate of patients with specific tumour
to have been exceeded. The MTD is defined               types to a particular drug or novel combination.
as the dose level immediately below the level          Eligible patients typically will have relapsed on
at which two patients in three to six experi-          a front-line therapy, and the prospect of a cure
ence DLT. The definition of dose-limiting toxicity      is unlikely. Typically, the dependent variable
can vary from study to study, but it generally         is an objective all or none response variable
falls into two categories: (a) Grade 3, 4 or 5         such as achievement of a complete or partial
non-haematologic toxicity other than (1) Grade         (>50%) response. Interim results are masked
3 nausea/vomiting; (2) Grade 3 transaminase            from the participants until the study closes to
elevation; and (3) Grade 3 fever/infection and         accrual and response information for all patients
(b) Grade 4 myelosupression, that lasts more           has been established. There are three types of
than 7 days, which requires transfusions twice in      Phase II trial designs that depend upon the
7 days, or causes a delay in therapy exceeding         study objectives.
14 days. While the study is temporarily closed
after accrual of each set of three patients in order                   Testing Activity
to assess patient-specific responses and toxicities,
a patient reservation system is used to obtain         The most common is ‘proving activity’. For
places when and if the study reopens. Phase I          these studies, a fixed objective response rate is
trials often require the evaluation of many dose       specified for activity (null hypothesis), and the
levels. At a given dose level, the probabilities of    goal is to reject the hypothesis in favour of
declaring that the MTD has been exceeded are           the alternate hypothesis that the response rate is
9.3%, (50%) and [83%], when the true probabil-         greater than this fixed figure. Generally, since the
ities of dose-limiting toxicities are respectively     number of Phase II agents that can be tested
0.1, (0.3) and [0.5].                                  is large in comparison to patient availability,
   Consensus guidelines established by American        sequential designs are preferred. However, as
and European investigators for the conduct of          Simon33 pointed out, it is rarely advantageous to
110                                  TEXTBOOK OF CLINICAL TRIALS

go beyond two stages. Two excellent references                       PHASE III DESIGN
with regard to Phase II design are Simon33 and
Shuster34 The designs of Simon33 stop at the first     These studies typically ask a randomised question
stage only if lack of activity is demonstrated.       about either survival or event-free survival (the
His argument is that patients should benefit from      time from study entry to the earliest of induction
active drugs. However, in paediatrics, due to         failure, relapse, second cancer, or death of any
the relative scarcity of patients with recurrent      cause). Intent-to-treat40 is the analysis of choice
disease, designs that stop early for either lack of   for efficacy, with other analysis done as sec-
activity or proven activity are preferred.            ondary supportive inference. For treatment ques-
                                                      tions where the randomised divergence is con-
                                                      siderably after study entry or where a significant
             Historical Comparison                    number of failures are expected to occur before
                                                      divergence, a delayed randomisation is typically
Another strategy for defining efficacy would be         done as close to the divergence point as possible.
to prove a response rate is superior to that          For these randomisations, the dependent variable
seen in an historical control study. The response     would be event-free survival from the randomi-
rate of the new study is statistically compared       sation date.
to that of the control therapy. Makuch and               Phase III studies are typically designed assum-
Simon35 have provided methods to determine            ing either proportional hazards or the cure model
the sample size requirements for these studies.       of Sposto and Sather.41 In either case, the designs
Chang et al.36 have extended this to two-stage        are group sequential in nature with planned
designs (i.e., a sequential approach that could       interim analyses. In the case of proportional haz-
save patient resources).                              ards, the O’Brien–Fleming method42 is used. The
                                                      reader is referred to Shuster43 for specific details.
       Randomised Phase II Comparison                 Nearly all Phase III childhood cancer trials are
                                                      run either as two-armed studies or as 2 × 2 fac-
Due to a limited availability of patients, it is      torial studies. It is rare that sufficient numbers of
exceedingly rare that a randomised comparison         paediatric cancer patients are available to conduct
of a new agent to a control is feasible in a          three-armed studies, except perhaps in ALL, the
paediatric Phase II study. However, such studies      most commonly occurring malignancy. The type
have been done. See McWilliams et al.37 for           of questions utilised in 2 × 2 factorial studies
an example from childhood neuroblastoma. As           must be such that the expectation is for no ‘quali-
above, two-stage or group sequential designs are      tative interaction’ between the two interventions.
the preferred method. The programme EAST38            A qualitative interaction between treatments A
can be used for designs that allow for both           and B would occur if a standard regimen plus A
early acceptance and early rejection of the null      is superior to the standard regimen alone, but the
hypothesis that the new treatment is equivalent       standard plus A plus B is inferior to the standard
to the control treatment.                             plus B. For example, if a study is to randomise
   In paediatric oncology, with limited patient       leukaemia patients to receive or not receive regi-
numbers, only one or two cooperative Phase II         men A, designed to have an impact on the CNS,
trials are conducted with each new agent, and         while at the same time to receive or not receive
all malignancies refractory to standard therapy       regimen B, designed to have an impact on mar-
are typically combined into a single paediatric       row remission, a factorial design would seem
Phase II trial, usually stratified by histology. Not   appropriate. Essentially, we can run two studies
surprisingly, Phase II trials of novel multiagent     for the price of one. If the two interventions have
regimens provide greater evidence of activity         much in common, this would be a contraindi-
than single agent Phase II trials and offer           cation for a factorial design. In contrast, if we
considerable possibility of therapeutic benefit.39     wished to ask if the same drug had an impact in
                                           CHILDHOOD CANCER                                           111

induction therapy (first intervention) and in main-                 ANCILLARY STUDIES
tenance therapy (second intervention), there is, at
least intuitively, the plausibility that the advan-   In paediatric cancer, there is considerable activity
tage of both interventions over just one may be       in translational research (see above). This can
zero or even harmful.                                 take the form of biologic studies, late effects, or
   Phase III studies done in cooperative groups       in controlling acute side effects. These studies
are required by the NCI to have a Data Safety         are designed on a case-by-case basis. Examples
and Monitoring Board which reviews the study at       include the conduct of case–control ‘tissue
a minimum of every six months for toxicity and        bank’ studies to establish a promising prognostic
at planned intervals for efficacy, until it releases   marker. Cases are defined as patients failing
the study to the study committee. The release         a protocol (typically a relapse) and controls
can occur no sooner than the earlier of (1) all       are long-term successes. These studies can be
subjects have completed the planned intervention      done using sequential designs, typically two-
                                                      stage designs. Other typical studies might look
or (2) the study was closed early and a new
                                                      at cognitive impairment (multivariate analysis
intervention is needed for patients on one or
                                                      of variance of neuropsychological variables),
both arms. Any release prior to the planned date
                                                      acute toxicity of a specified type (typical Chi-
of final analysis requires approval of the board.
                                                      square test), the prognostic significance of serial
Double-blind Phase III studies are rarely feasible
                                                      pharmacologically measured drug levels (time-
due to the toxic nature of cancer treatment.
                                                      dependent covariate in survival analysis), or
However, they are encouraged for studies of
                                                      exploratory analysis (e.g. microarrays).
supportive care, as long as the intervention is
given in a pill form, and has no major known side
effects requiring special medical monitoring.               ETHICAL AND OTHER SPECIAL
   Negative questions are often posed for paedi-       CONSIDERATIONS AFFECTING CONDUCT
atric cancer. For such studies, a very high cure        OF TRIALS IN CHILDREN WITH CANCER
rate of at least 85% has been shown possible on a
conventional regimen. The question posed is can       Children and adolescents constitute a special
we do ‘almost as well’ with reduced therapy? To       vulnerable population of research subjects, often
answer such questions with confidence requires         grouped with other special classes, like the
large numbers, and it is rare that even the entire    mentally retarded, mentally ill and prisoners.
patient resources of COG are sufficient to address     There are special federal protections which apply
this in a randomised manner. For example, if a        to all research involving children as subjects
disease has a historical 4-year remission rate of     which are covered by Subpart D of Part 46 of
90%, and an accrual rate of 200 patients per year,    Title 45 of the Code of Federal Regulations
a randomised study would take 6 years of accrual      (45 CFR 46), requiring that institutional review
(10-year duration) to have 95% power to detect        boards (IRBS) give consideration to the degree
a degradation to 85% under reduced therapy at         of risk, the benefit to child subjects, the nature
p = 0.20, one-sided. (Note that the typical values    of the knowledge to be gained, permission of
of type I error and power are reversed.) A single-    the parent or guardian, and the concurrence of
arm study would require 315 patients to ask the       the child subjects, known as assent. A child’s
same question of a fixed standard of 90% vs. a         capacity to give assent is conditioned by his or
reduction to 85% (nearly a 75% reduction in sam-      her developmental level.44,45
ple size). While the benefits of reduced therapy          Subsequent to the promulgation of the original
may be obvious, such studies carry considerable       rules, adopted in 1983 and modified in 1991,
risk and must be carefully monitored for early        there has been nearly continuous debate and
evidence that the reduction in therapy is unsafe      controversy surrounding safeguards for all human
and is associated with an inferior outcome.           subjects of research and for children especially.
112                                  TEXTBOOK OF CLINICAL TRIALS

The tragic death of an 18-year-old research           certain to increase paediatric clinical trials, partic-
subject in 1999 in a gene-transfer trial at           ularly drug trials. Federal NIH policies promul-
a major research university in which human            gated in 1998 were aimed at increasing the par-
subjects were not protected, adverse events had       ticipation of children in research so that adequate
not been reported and financial conflicts of            data would be developed to support the treatment
interest were involved, served to trigger several     for disorders affecting adults which also affect
new federal initiatives to further strengthen         children, and rules mandated that children (i.e.,
protections of human research subjects in clinical    individuals under age 21) must be included in
trials,46 including the imposition of sanctions on    all human subjects research unless there are sci-
investigators who fail to adhere to regulations. As   entific and ethical reasons not to include them.
this chapter goes to press, the federal Office for     The FDA rules and regulations48 require phar-
Protection from Research Risks (OPRR) has been        maceutical manufacturers to assess the safety
reorganised, expanded and renamed the Office           and effectiveness of new drugs and biologics in
for Human Research Protections (OHRP) and             paediatric patients and established powerful eco-
transferred to the Office of the Secretary, Health     nomic incentives for manufacturers (six-months’
and Human Services (HHS) and the National             extension of market exclusivity) on any drug
Biothetics Advisory Commission, at the request        for which FDA requested paediatric studies (see
of the President, has undertaken a sweeping           www.fda.gov/cder/cancer for further information
examination of the ethical and policy issues in       on regulatory aspects of paediatric oncology drug
the oversight of human research in the United         development).
                                                         In addition to ethical and regulatory issues
States (see www.bioethics.gov). As a result, the
                                                      which impact the conduct of paediatric trials,
ethical and regulatory framework within which
                                                      there are also practical problems associated with
paediatric cancer clinical trials are conducted,
                                                      clinical cancer research in children. Due to an
now and in the future, will continue to evolve,
                                                      understandably greater concern for long-term
and investigators must remain abreast.
                                                      adverse consequences of treatment in a popula-
   Specific ethical issues impacting statisticians
                                                      tion of patients, the majority of whom are likely
involved in collaborative research include ensur-     to be cured and alive for decades at risk for late
ing confidentiality, data and safety monitoring,       effects, it is absolutely essential that long-term
and problems and pitfalls in interpretation of        follow-up and serial surveillance of survivors is
interim analyses and planning studies to answer       built into the studies. While follow-up is essen-
negative questions.47 A negative question, e.g.,      tial, it is also exceedingly difficult and expensive
what is the minimum therapy needed to produce         to maintain, as children and adolescents grow up,
cure?, has particular relevance for paediatric can-   go away to school, leave home, marry, change
cer trials which are (often) aimed at reduction of    name, etc. The frequency and severity of late
the acute or delayed effects of cancer treatment      effects also tend to progress with time off treat-
on the growing child.                                 ment, making follow-up beyond 15 or 20 or
   Notwithstanding the strict ethical guidelines      30 years critical and identification of risk factors
and regulations surrounding research in children,     for the development of these late consequences
there is substantial and even increasing pressure     of treatment essential. For example, Lipshultz
to enroll children in clinical trials as a result     et al.49 studied 120 survivors of childhood ALL
of other federal policies and recent legislation,     or osteogenic sarcoma who had been treated with
including the Food and Drug Administration’s          doxorubicin a mean of 8.1 years earlier (range
(FDA’s) 1998 paediatric rule, the paediatric pro-     2–14 years) and compared their cardiac func-
visions of the FDA Modernization Act (FDAMA)          tion to a control population, and evaluated the
of 1997, and the sweeping Children’s Health Act       impact of gender, age at diagnosis, length of
of 2000 (PL 106–310), the sum of which is             time since completion of therapy, and dosage and
                                            CHILDHOOD CANCER                                             113

cumulative dose of doxorubicin on cardiac sta-         agents, many of which will likely be orphan drugs
tus. Calculating sex-specific standardised scores       for orphan diseases.
or z scores (expressed as the number of standard          With advances in translational research, the
deviations above or below the value for the nor-       pie (universe of childhood cancer patients) will
mal controls) for cardiac contractility, wall thick-   be divided into smaller but more homogeneous
ness and afterload, the results of univariate and      slices than ever before. International collabora-
multivariate analysis showed that female sex and       tion will probably be required in a substantial
higher cumulative dose of doxorubicin were asso-       segment of cancer types in order to obtain suf-
ciated with depressed contractility, that there was    ficient patient numbers to conduct randomised
an association between younger age at diagnosis        trials. Enlightened partnerships between industry
and reduced left ventricular wall thickness and        and academia, with the assistance of the FDA and
increased afterload, and that the prevalence and       NCI, will be needed for efficient development of
severity of abnormalities increased with longer        new agents.
follow-up.49 Such studies typify the challenge of         Finally, the skill sets necessary to conduct
methodologic and statistical issues in the study       paediatric cancer research are expanding. Tradi-
of late effects of childhood cancer, the greatest      tionally the field involved paediatric haematolo-
challenge being data collection.                       gist/oncologists, surgeons, radiation oncologists,
                                                       pathologists, nurses, clinical research associates,
                                                       pharmacologists, epidemiologists and biostatisti-
        A LOOK INTO THE FUTURE                         cians. Today, diagnostic imagers, bench scien-
    OF CHILDHOOD CANCER RESEARCH                       tists, geneticists, pharmacists, clinical psychol-
                                                       ogists, health economists and others also play
Despite the progress of the last half century there    significant roles in the research. In the future,
remain a number of challenges in childhood can-        other fields of expertise will surely need to be
cer. The focus of research in certain patient sub-     added to the team. The cooperation of a multi-
sets with very high cure rates will be on quality      disciplinary team and prompt referral of patients
of life endpoints. For example, retinoblastoma is      to paediatric cancer centres participating in clini-
curable in nearly 100% of cases, so preservation       cal trials will be critical to achieving future goals
of sight and reduction of second malignancies          of refining and improving therapy.
(not survival) are now considered to be the pri-
mary goals and endpoints, and trials avoiding
enucleation and eliminating external beam ther-
apy are now the norm.
   One would hope that future therapies for child-      1. National Cancer Institute, SEER Program. Cancer
                                                           Incidence and Survival among Children and Ado-
hood cancer will be developed which would be               lescents: United States SEER Program 1975–1995.
more rational, less empirical and less toxic, rely-        NIH Publ. No. 99–4649. Bethesda, MD: National
ing more on strategies for growth control (e.g.,           Cancer Institute (1999).
anti-angiogenesis) and regulation of gene expres-       2. Ross JA, Severson RK, Pollock BH, Robison LL.
sion and cell proliferation, and/or induction of           Childhood cancer in the United States. A geo-
                                                           graphic analysis of cases from the Pediatric Coop-
apoptotic pathways or blocking of anti-apoptotic           erative Clinical Trials Groups. Cancer (1996) 77:
signals, than on cytotoxic or ablative treatments.         201–7.
Assuming that deregulated and/or mutated cellu-         3. Woods WG, Tuchman M, Robison LL et al. A
lar proto-oncogenes or loss of tumour suppressor           population-based study of the usefulness of
genes are the proximate cause(s) of most forms             screening for neuroblastoma. Lancet (1996) 348:
of childhood cancer, then the genes and/or their        4. Pediatric Oncology Group. Progress against child-
protein products will very likely be the targets           hood cancer: the Pediatric Oncology Group expe-
for the next generation of paediatric anti-cancer          rience. Pediatrics (1992) 89(4): 597–600.
114                                      TEXTBOOK OF CLINICAL TRIALS

 5. Murphy SB. The national impact of clinical coop-             of contemporary therapies: a report from the
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    Pediat Oncol (1995) 24: 279–80.                              527–35.
 6. Pui CH. Childhood Leukemias. Cambridge: Cam-           19.   Shurtleff SA, Buijs A, Behm FG et al. TEL/AML1
    bridge University Press (1999).                              fusion resulting from a cryptic t(12;21) is the
 7. Donaldson SS, Link MP. Combined modality                     most common genetic lesion in pediatric ALL and
    treatment with low-dose radiation and MOPP                   defines a subgroup of patients with an excellent
    chemotherapy for children with Hodgkin’s                     prognosis. Leukemia (1995) 9: 1985–9.
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 9. Link M, Shuster J, Donaldson S, Berard CW,                   Group study. Blood (1997) 89: 1143–6.
    Murphy SB. Treatment of children and young             21.   Raimondi SC, Shurtleff SA, Downing JR et al.
    adults with early-stage non-Hodgkin’s lymphoma.              12p abnormalities and the TEL gene (ETV6) in
    New Engl J Med (1997) 337(18): 1259–66.                      childhood acute lymphoblastic leukemia. Blood
10. Shuster JJ, Carroll AJ, Look TA et al. Manage-               (1997) 90: 4559–66.
    ment of cytogenetic data in multi-center leukemia      22.   Trueworthy R, Shuster J, Look T et al. Ploidy
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    40: 269–77.                                                  treatment outcome in B-progenitor cell acute
11. Pui CH, Frankel LS, Carroll AJ et al. Clinical               lymphoblastic leukemia of childhood: a Pediatric
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13. Heerema NA, Sather HN, Ge J et al. Cytogenetic               of leukemic cell chromosomes 4 and 10 identifies
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15. Uckun FM, Nachman JB, Sather HN et al. Poor                  ative Group. N Engl J Med (1998) 339: 591–8.
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16. Arico M, Valsecchi MG, Camitta B et al. Out-           27.   Evans WE, Crom WR, Abromowitch M et al.
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17. Crist WM, Carroll AJ, Shuster JJ et al. Poor prog-           New Engl J Med (1986) 314: 471–7.
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18. Uckun FM, Sensel MG, Sather HN et al. Clinical         29.   Graham ML, Shuster JJ, Kamen BA et al.
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      translating functional genomics into rational ther-     47. Shuster J et al. Ethical issues in cooperative
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31.   Raney RB, Anderson JR, Barr FG et al. Rhab-                 II. Specific issues. Am J Ped Hematol/Oncol
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      the first two decades of life: a selective review        48. Hirschfeld S et al. Pediatric oncology: regulatory
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                                                                  factors for late cardiotoxic effects of doxorubicin
32.   Smith MD, Ho P, Ungerleider R et al. The con-
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33.   Simon R. Optimal two-stage designs for phase II         50. Link MP, Goorin AM, Miser AW, Green AA,
      clinical trials. Contr Clin Trials (1989) 10: 1–10.         Pratt CB, Belasco JB, Pritchard J et al. The effect
34.   Shuster JJ. Optimal two-stage designs for single            of adjuvant chemotherapy on relapse-free survival
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35.   Makuch R, Simon R. Sample size considerations           51. Smith M. The impact of doxorubicin dose inten-
      for non-randomized comparitive studies. J Chron             sity on survival of patients with Ewing’s sarcoma.
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36.   Chang M, Shuster J, Kepner J. Group sequential          52. Grier HE, Krailo MD, Tarbell NJ et al. The addi-
      designs for phase II trials. Contr Clin Trials (1999)       tion of ifosfamide and etoposide to standard
      20: 353–64.                                                 chemotherapy in Ewing’s sarcoma/primitive neur-
37.   McWilliams N, Hayesm F, Green A et al. Cyclo-               oectodermal tumor of bone: a Children’s Cancer
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      Cambridge, MA: Cytel Software Corp. (1992).             54. D’Angio G, Evans A, Breslow N, Beckwith B,
39.   Weitman S, Ochoa S, Sullivan J et al. Pediatric             Bishop H, Feigl P et al. The treatment of Wilms’
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40.   Armitage P. Controversies and achievements in               intergoup rhabdomyosarcoma study – 1. Cancer
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41.   Sposto R, Sather H. Determining the duration of
                                                              56. Link M, Donaldson S, Berard C, Shuster J, Mur-
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      J Chronic Dis (1985) 38: 683–90.                            phy SB. Results of treatment of childhood local-
42.   O’Brien PC, Fleming TR. A multiple testing pro-             ized non-Hodgkin’s lymphoma with combination
      cedure for clinical trials. Biometrics (1979) 35:           chemotherapy with or without radiotherapy. New
      549–56.                                                     Engl J Med (1990) 322: 1169–74.
43.   Shuster J. Power and sample size for phase              57. Matthay KK, Villablanca JG, Seeger RC, Stram
      III clinical trials of survival. Chapter 7. In:             DO, Harris RE, Ramsay NK, Swift P et al. Treat-
      Crowley J, ed., Handbook of Statistics in Clinical          ment of high-risk neuroblastoma with inten-
      Oncology. New York: Marcel Dekker (2001).                   sive chemotherapy, radiotherapy, autologous bone
44.   Jonsen AR. Research involving children: recom-              marrow transplantation, and 13-cis retinoic acid.
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      131–6.                                                      Link M, Murphy SB et al. Uniform approach to
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59. Baker KS, Anderson JR, Link MP, Grier HE et al.      60. Castleberry R. Biology and treatment of neurob-
    Benefit of intensified therapy for patients with           lastoma. Ped Clin North Am (1997) 44: 919–37.
                                Gastrointestinal Cancers
                                           Mayo Clinic, Rochester, MN 55905, USA

                    INTRODUCTION                                        fallen substantially. For example, in 1930, gastric
                                                                        cancer was the most common cancer diagnosis.
Cancers of the gastrointestinal tract account for                       By 1994, gastric cancer had fallen to 12th in
approximately 20% of all new cancer cases in                            incidence among cancers. In contrast, the rates
the United States, and the same proportion of                           of colon and rectal cancer have remained very
cancer-related deaths. In this discussion we will                       stable. Incidence rates for GI cancers also vary
use a broad definition of GI cancer, including                           greatly worldwide: gastric cancer is tenfold more
any cancer of a digestive organ. In this def-                           prevalent in Asia than in the US.
inition we include cancers of the oesophagus,                              One common feature in all GI cancers is
gastro-oesophageal junction, stomach, pancreas,                         the prognostic importance of staging. The TNM
gallbladder, bile duct, liver, small and large intes-                   system has been widely adopted to describe the
tine, rectum and anus. Incident cancers of the                          patient’s disease status at the time of detection,
oesophagus, stomach, pancreas, liver, large intes-                      and has great relevance to the choice of therapy
tine and rectum all exceed 10 000 a year in the                         and eventual outcome in all GI cancers. The
United States. In addition to the high prevalence                       importance of early detection is clear, and some
and the large number of cancer sites within the                         GI cancers are sufficiently frequent and amenable
GI tract, the prognosis of patients with GI cancers                     to detection to allow cost-effective screening.
varies greatly. For example, patients with can-                            In this chapter we will review, for the major
cers of the large intestine, when discovered early                      sites of the GI tract, the important clinical trials
in the course of disease, have 5-year survival                          that have been conducted. Whenever possible,
rates exceeding 90%. In contrast, the prognosis                         we will highlight the methodological and design
for patients with pancreatic cancer is very poor,                       issues of these trials, in an effort to provide
with a 5-year survival rate of less than 5% across                      insight into their results. We will describe,
all stages.                                                             through this review, how the current standard
   Incidence rates for GI cancers show a similar                        treatments in each disease site have evolved, as
diversity. In the past 50 years, the incidence rates                    well as presenting some of the most pressing
for liver and gastric cancers in the US have                            issues for future research.

Textbook of Clinical Trials. Edited by D. Machin, S. Day and S. Green
 2004 John Wiley & Sons, Ltd ISBN: 0-471-98787-5
118                                 TEXTBOOK OF CLINICAL TRIALS

           OESOPHAGEAL CANCER                        advantage in disease-free survival in the treated
                                                     group. In smaller trials, Le Prise et al.6 and Urba
Oesophageal cancer is an area where contro-          et al.7 reached the same conclusion based on
versy as to the appropriate and optimal ther-        86 and 100 randomised patients, respectively.
apy exists in almost every aspect. In patients       In contrast, Walsh et al.,8 in a trial of 113
with localised disease (stage 1–3), the roles of     patients, found a striking survival advantage for
surgery, radiotherapy and chemotherapy, alone or     the combined modality pre-operative approach,
in combination, have all been both advocated and     with a median survival of 16 months in the
questioned. In advanced disease, it seems clear      multimodality arm compared to 11 months in
that chemotherapy regimes have provided some         the surgery alone arm (p = 0.01). However,
degree of progress, albeit limited.                  the Walsh study has been criticised for several
                                                     factors, including the small sample size, poorer
                                                     than expected survival for the surgery alone
                                                     control group, and the fact that the study was
In the past two decades, a large number of           stopped early at an unplanned interim analysis.
randomised clinical trials, involving thousands      In an effort to resolve this controversy, a large
of patients, have investigated the contributions     multicentre randomised trial was mounted in
of radiotherapy or chemotherapy, both alone          the US, with an accrual goal of 500 patients.
and in combination, in the pre-operative and         Unfortunately, accrual to the trial was very slow,
post-operative settings or as definitive therapy      and the trial was closed early, far short of its
without surgery. Pre-operative radiotherapy, as a    accrual goal. Currently, the combined modality
single modality, has been shown in two relatively    pre-operative approach has been widely adopted,
small randomised trials to provide no additional     despite the conflicting evidence of benefit.
benefit compared to surgery. These two trials,           Additional controversy exists in this setting
reported by Launois et al.1 and Gignoux et al.,2     as to whether surgery itself is beneficial. The
randomised 124 and 208 patients, respectively.       Radiation Therapy Oncology Group (RTOG) has
Chemotherapy as a single modality added to           conducted two randomised trials that have not
surgery was investigated in 440 patients by          included surgery as part of the treatment. Her-
Kelsen et al.3 and shown to have no advantage        skovic et al.9 randomised 129 patients to radi-
over surgery alone. The larger sample size of        ation alone versus combined chemoradiotherapy.
this study lends credence to this result. The two    The study was stopped early (planned sample size
modalities have also been compared to each other     of 150 patients) when the first planned interim
as single agents,4 and no difference in patient      analysis showed a significant survival advantage
outcomes were observed. Based on these results       to the combined modality group. The RTOG
it seems clear that single modality therapy has      then followed that study with a study comparing
limited if any impact on patient outcome.            two doses of radiotherapy, both combined with
   Recently, interest has focused on combined        chemotherapy.10 This study was also stopped
radiochemotherapy regimens in the pre-operative      early, in this case due to a lack of any additional
setting. The results in this regard have been        benefit in the high-dose radiation arm. No tri-
conflicting. Four studies have been conducted,        als to date have compared a surgical approach to
three with negative results and one with a           a non-surgical approach, such a trial would sci-
positive conclusion. Bosset et al.5 randomised       entifically be highly desirable but the practical
297 patients to pre-operative chemoradiation         feasibility of such a trial is questionable.
followed by surgery versus surgery alone, and           Based on these results, it is clear that there
found no evidence of a difference in overall         is no consensus as to a ‘standard of care’
survival (a relative risk for survival between the   for patients with localised oesophageal cancer,
two arms of 1.0), though they did observe an         and that there is a great need for additional
                                        GASTROINTESTINAL CANCERS                                       119

clinical trials. Historically, trials in this setting   conclusion that the most important surgical prin-
have tended to be small and underpowered for            ciple is achievement, when possible, of a patho-
detecting moderate effects on outcome. Larger,          logically negative resection (an R0 resection).
more definitive trials should be conducted.              However, patients have improved post-operative
                                                        quality of life if some of the stomach is retained,
              ADVANCED DISEASE                          and most surgeons resect only as much of the
Trials in advanced oesophageal cancer have              stomach as is needed to achieve pathologically
been plentiful, though attention in this setting        free margins. The rich lymphatic networks of
has focused more on Phase II trials than ran-           the stomach can sometimes result in apparently
domised Phase III trials. A multitude of agents         clear margins, yet residual intralymphatic disease
have been investigated, alone and in combina-           may be present in ‘skip areas’. This has impli-
tion. It is clear that progress has been made;          cations regarding post-operative treatment, and
over the last 20 years median survival for              suggests a potential role for adjuvant radiation
advanced oesophageal cancer has increased from          to the tumour bed and regional structures.
3 months to 6–9 months or greater. The empha-              Many surgeons, particularly those in Japan,
sis on Phase II trials, in an attempt to find a          advocate extended lymph node dissections as
promising new approach, is certainly appropriate        a means to improve outcome due to the cen-
given the modest results available from current         tral location of the stomach with many lymph
chemotherapies.                                         node-bearing areas at risk for metastatic spread.
                                                        In a landmark study the Dutch Gastric Cancer
                                                        Group employed a single Japanese surgeon to
               GASTRIC CANCER                           train participating Dutch surgeons to perform the
                                                        classical Japanese extended lymphadenectomy.12
While the incidence of gastric cancer has declined      These investigators randomised 711 eligible
in the United States over several decades, 21 600       patients to resection of the primary tumour with
new diagnoses and 12 400 deaths were still              clear gastric margins and either standard (D1)
expected in 2002.11 The nearly 40% cure rate            or extended lymphadenectomy (D2). Three-year
that these numbers imply likely results from            survival rates were 56% and 58% respectively for
a better natural history than oesophageal or            the two cohorts, suggesting no advantage to more
pancreatic cancer, early detection via endoscopy,
                                                        aggressive surgery. The British Medical Research
improvements in surgery, and the post-operative
                                                        Council conducted a similar, albeit smaller (400
use of chemotherapy with radiation for patients
                                                        patients) trial that confirmed this finding.13
with resected disease. While gastric cancer is
                                                           The adjuvant therapy of gastric cancer, mainly
unusual among GI primary sites because of the
                                                        using 5-FU based regimens, has been a mat-
large number of antineoplastic agents that show
                                                        ter of investigation for many years. Many ran-
some activity (as measured by tumour response
                                                        domised trials of chemotherapy versus surgery
rate), in the advanced disease setting even the most
                                                        alone have been reported and these individual
active combination chemotherapy regimens result
                                                        trials have generally been negative. A meta-
in remissions that generally last for only a few
                                                        analysis of 21 randomised controlled trials con-
months and median survivals of less than one year.
                                                        ducted worldwide, that included 3962 patients
                                                        with 1840 allocated to surgery alone and 2122
                                                        allocated to adjuvant chemotherapy, did show a
The ideal operation for gastric cancer, includ-         modest potential benefit for treatment.14 The odds
ing the issues of limited versus total gastrectomy      ratio (OR) in favour of chemotherapy was 0.84
and extended versus more limited lymph node             overall, but the principal benefit was confined to
dissection, has been a matter of controversy. Tri-      patients enrolled in trials done in Asia (n = 888
als done in the 1980s and 1990s have led to the         patients, OR 0.58) as opposed to Western patients
120                                 TEXTBOOK OF CLINICAL TRIALS

(n = 3074, OR 0.96). This finding lends some          with supportive care alone is around three
support to the possibility of a geographically or    months. One or more agents from virtually all
ethnicity based difference in the natural history    classes of chemotherapy drugs have demonstra-
of this disease, a finding supported by some epi-     ble activity, and median survivals approaching
demiologic evidence. Studies of post-operative       one year have been reported with several com-
radiation versus surgery alone have not shown        bination chemotherapy regimens. One example
any advantages, although interpretation of the       representative of modern Phase III trials ran-
limited data addressing this issue is problematic.   domised patients to epirubicin, cisplatin and 5-FU
   Adjuvant radiation and chemotherapy used          (ECF) versus 5-FU, doxorubicin and methotrex-
in combination has recently been shown to be         ate (FAMtx).16 The overall response rate was
advantageous in North American patients. In a        45% compared to 21% (p = 0.0002) and the
603 patient study, patients were randomised to       overall survival was 8.9 months compared to
either surgery alone or to surgery followed by       5.7 months (p = 0.0009) for ECF over FAMtx.
combined modality therapy.15 In the treatment        Despite the intensive nature of these two reg-
arm patients were given 5-FU plus leucovorin         imens, and other combinations tested to date,
before and after 4500 cGY to the gastric bed         the beneficial effects in terms of improved
(with radiosensitising 5-FU + leucovorin admin-      patient longevity have been modest. Earlier
istered for four consecutive days at the beginning   detection, improvements in the management of
and three days near the end of the radiation).       local regional disease, and the testing of new
Adjuvant chemoradiotherapy led to a significant       agents seem to provide the best avenues towards
median survival advantage of 36 compared to          better outcomes.
27 months (p = 0.005) and a reduction in local
regional relapse rate to 67% compared to 82%.
In addition to these outcome improvements, two                   PANCREATIC CANCER
important patterns of care findings were noted.
The trial recommended but did not demand at          Pancreas cancer has a very poor prognosis. It
least a D1 resection and noted that a D2 resec-      affects approximately 27 000 new patients each
tion was preferred. However, when operative          year in the US, and is fatal in approximately
reports were analysed, only 10% of patients had      95% of cases. As in all GI cancers, therapy
D2 resections, 36% D1 resections, with the bal-      includes surgery, radiotherapy and chemotherapy,
ance having less aggressive surgery. Secondly,       depending on the disease stage.
pretreatment radiation field review by a single
radiation oncologist indicated that 35% of sub-
                                                                  LOCALISED DISEASE
mitted treatment plans contained major or minor
deviations from the protocol, indicating a need      In the setting of resectable or locally advanced
for education of surgeons and radiation oncol-       disease, both radiotherapy and chemotherapy, and
ogists as to the preferred procedures in these       the combination, have been tested extensively.
settings. Some readers have raised the possibility   Studies conducted prior to the mid-1990s tended
that the chemotherapy and radiation were benefi-      to be small and underpowered, which has led to
cial mainly because of suboptimal surgery in this    a variety of conflicting results.
cohort of patients.                                     In locally advanced disease, the Gastrointesti-
                                                     nal Tumor Study Group (GITSG) randomised
             ADVANCED DISEASE                        227 patients to three arms: radiotherapy alone,
                                                     or radiotherapy at two different dose levels
Palliative therapy does make a meaningful dif-       given with chemotherapy (5-FU).17 Accrual to
ference to many patients with advanced dis-          the radiotherapy alone arm was stopped early due
ease in gastric cancer, whose median survival        to poor results. Two studies have investigated the
                                       GASTROINTESTINAL CANCERS                                       121

need for chemoradiotherapy versus chemotherapy         justified by the occasional tumour response that
alone, with conflicting results. Klaassen et al.,18     was observed. Single agent therapy with 5-FU
in a two-arm randomised study of 191 patients,         has been used as the control arm for multiple
found no advantage for combined therapy ver-           randomised trials, with the assumption that 5-FU
sus chemotherapy alone, while GITSG19 reported         was at worst a toxic placebo, thus if a new
that overall survival was improved with the addi-      experimental regimen were shown superior to
tion of radiation to chemotherapy in a two-arm         5-FU, it would indeed have improved efficacy
study of 43 patients. The small sample sizes of        when compared to no treatment. Burris et al.21
all these trials make definitive conclusions diffi-      reported a Phase III randomised trial with 126
cult, but there is little evidence to support a role   patients that showed an improved overall survival
for radiation alone in this setting.                   for gemcitabine compared to 5-FU alone (median
   In the setting of a complete surgical resec-        survivals of 5.7 versus 4.4 months respectively,
tion, several small randomised studies have sug-       p = 0.003). The Burris trial established gemc-
gested a benefit to post-operative chemotherapy         itabine as a new standard of care in this setting.
or chemoradiotherapy. None of these trials             Ongoing and future trials will likely use gemc-
enrolled greater than 114 patients, limiting the       itabine as a base, comparing gemcitabine alone
ability to draw conclusions. The recent report         to a multi-drug chemotherapy regimen including
by Neoptolemos et al.20 provided much more             gemcitabine.
conclusive evidence in this regard. In this               A recently completed trial in pancreatic cancer
study, 541 eligible patients were randomised to        can be used to illustrate the need for careful con-
receive post-operative chemotherapy (6 months          sideration of an agent prior to Phase III testing.
of post-surgical treatment), chemoradiotherapy (a      Due in large part to the dismal prognosis and lim-
10-day course of radiotherapy accompanied by           ited treatment options available for patients with
chemotherapy), both or neither (the design was         pancreatic cancer, pressure has been applied to
not a true 2 × 2 factorial because clinicians were     rapidly introduce novel agents into Phase III tri-
allowed to choose to participate in either one or      als. The goal is to seek to speed the process of
both randomisations). In this study, there was no      testing a new agent by avoiding the Phase II stage
benefit to the chemoradiotherapy, while a clear         of testing. Such was the case in a randomised
benefit was observed for the chemotherapy group         Phase III trial reported by Moore et al.,22 where a
compared to the no treatment group (median sur-        novel agent (a matrix metalloproteinase inhibitor
vivals of 19.7 versus 14.0 months). Interestingly,     (MMPI)) was tested against gemcitabine in 277
the authors of that study did not conclude that        patients. In this trial the MMPI had significantly
a no treatment arm was inappropriate for future        inferior outcome compared to gemcitabine. The
trials, in fact they are currently sponsoring a        trial was carefully and appropriately designed to
three-arm trial in 990 patients of two different       allow early stopping if the results were extreme,
chemotherapy approaches (5-FU with folinic acid        which in this case they were. A Phase II trial may
or gemcitabine) versus surgery alone. This trial       have identified the lack of efficacy of this agent
has been criticised for including patients with        prior to its large-scale testing.
involved margins after surgery and also primaries
arising in the ampulla and bile ducts.
                                                                   COLORECTAL CANCER
                                                       Colorectal cancer is the most common malig-
Chemotherapy has been considered the standard          nancy in the GI tract. Not surprisingly, it is also
of care in the US for advanced pancreatic cancer,      the GI cancer that has been the most extensively
despite the lack of any randomised trial demon-        investigated in clinical trials.
strating a survival benefit for chemotherapy ver-          Likely as the direct result of these intensive
sus no treatment. The use of chemotherapy was          research efforts, considerable progress has been
122                                    TEXTBOOK OF CLINICAL TRIALS

made in many facets of colorectal cancer,               effect. Nonetheless, the existing data do not
including chemoprevention, early detection and          support a major role for this agent in colorectal
treatment.                                              cancer chemoprevention.
                                                           Antioxidant vitamins such as the retinoids,
             CHEMOPREVENTION                            carotenoids, ascorbic acid and alpha-tocopherol
Cancer chemoprevention can be defined as the             may prevent carcinogen formation by neutral-
use of nutritional or pharmaceutical agents to          ising free radicals within the intestinal lumen.
prevent, inhibit or reverse carcinogenesis at a         Although somewhat inconsistent, the prepon-
pre-invasive stage of disease. Candidate agents         derance of data from case–control and cohort
are often identified through a combination of            studies support an inverse association between
epidemiological and laboratory-based research.          antioxidant vitamin intake and colorectal can-
Since most subjects enrolled onto chemopre-             cer risk. Four colorectal cancer chemopreven-
vention trials are generally healthy (except for        tion trials have investigated antioxidant vitamins
their increased cancer risk), minimal toxicity          at different doses and in various combinations.
represents an important criterion for select-           One relatively small study found that recur-
ing candidate agents. Colorectal adenomas are           rent adenomas were less common among sub-
commonly employed as intermediate endpoint              jects treated with vitamin A (30 000 IU per
biomarkers to facilitate more rapid comple-             day), vitamin C (1 g per day) and vitamin E
tion of colorectal cancer chemoprevention trials.       (70 mg per day) over a mean intervention period
To date, several colorectal cancer chemopre-            of 17.8 months.28 Another three-year chemopre-
vention agents have been investigated, includ-          vention trial reported a 69% reduction in the
ing fibre, antioxidant vitamins, calcium and             number of recurrent colorectal polyps among sub-
nonsteroidal anti-inflammatory drugs (NSAIDs).           jects randomised to receive multiple antioxidants
Selective cyclooxygenase-2 enzyme inhibitors,           (beta-carotene, selenium, vitamin C, vitamin E)
which may have a better safety profile than tradi-       plus calcium versus placebo compounds.29 Con-
tional NSAIDs, have received considerable atten-        versely, two larger trials of vitamin C and vita-
tion in this context as well. Further discussion        min E yielded unremarkable results.30,31 Thus,
regarding the current status of these agents is pro-    definitive evidence for a protective benefit from
vided below.                                            antioxidant vitamins on colorectal cancer risk
   Dietary fibre represents a heterogeneous mix-         remains to be demonstrated.
ture of complex materials derived primarily from           Calcium may serve as a colorectal cancer
plant cell walls. Extensive observational data          chemoprevention agent through at least two
collected over more than three decades suggest          mechanisms: functionally removing toxic bile
that fibre might help to prevent colorectal neo-         acids from the faecal stream and decreasing cellu-
plasia by diluting or adsorbing faecal carcino-         lar proliferation in the large bowel mucosa. Data
gens, reducing colonic transit time, altering bile      compiled from 24 observational studies yielded
acid metabolism, or increasing short-chain fatty        a summary risk estimate of 0.86 (95% CI =
acid production. However, high fibre interven-           0.74–0.98) for colorectal cancer among sub-
tions have not been associated with a reduced           jects with high versus low calcium intakes.32 In
risk for recurrent colorectal adenomas in five           addition to encouraging data from the relatively
clinical trials.23 – 27 In fact, one small randomised   small clinical trial of multiple antioxidants plus
study observed a higher adenoma recurrence rate         calcium mentioned above,29 the Calcium Polyp
among subjects in the active fibre intervention          Prevention Study found that treatment with cal-
group.25 It remains possible that administration of     cium carbonate at 3 g per day for 4 years was
dietary fibre at an earlier point in tumourigenesis      associated with a statistically significant 15%
(for example, prior to first adenoma formation)          reduction in recurrent colorectal adenoma risk,
might have a more appreciable anti-carcinogenic         as compared to placebo.33 Further data regarding
                                     GASTROINTESTINAL CANCERS                                       123

the chemopreventive potential of calcium (and        subjects with familial adenomatous polyposis.37
vitamin D) are being collected from the large        Additional COX-2 inhibitor trials are ongoing to
Women’s Health Initiative Clinical Trial,34 which    confirm the initial findings and to evaluate the
should help to clarify whether or not application    effect of these agents on sporadic colorectal can-
of this agent to average-risk subjects has measur-   cer risk.
able value.                                             A number of other candidate agents, includ-
   NSAIDs are a structurally diverse class of        ing oestrogen compounds, ursodeoxycholic acid,
pharmaceutical agents that appear to reduce          difluoromethylornithine and Bowman–Birk in-
proliferation, delay cell cycle progression and      hibitor, have shown promising results in cell cul-
induce apoptosis in epithelially-lined tissues.      ture experiments, animal model systems and/or
Extensive data from rodent models suggest that       observational studies. Further data regarding
NSAID administration can reduce gastrointesti-       these (and other) potential colorectal cancer
nal tumour incidence and/or multiplicity by up       chemopreventive agents are anticipated in the
to 80%. In human populations, regular NSAID          near future as new Phase I, II and III clinical
use has been associated with decreased col-          trials are organised and completed.
orectal cancer risk in numerous observational
studies. Despite a consistent demonstration of                     EARLY DETECTION
probable benefit, NSAIDs have not been rig-
orously evaluated in colorectal cancer chemo-        Due to a variety of factors, colorectal cancers
prevention trials until recently. The Physicians’    are very amenable to early detection. First, the
Health Study (n = 22 071 subjects), which was        biology of colorectal carcinogenesis is becom-
a randomised, double-blind, placebo-controlled       ing increasingly well understood, as evidenced
trial of aspirin 325 mg every other day to prevent   by continued expansion of knowledge regard-
cardiovascular disease, did analyse colorectal       ing the molecular events associated with different
cancer incidence rates as a secondary endpoint.      stages in the adenoma–carcinoma sequence. This
After a mean follow-up period of 5 years, no         relatively slow process typically requires sev-
statistically significant difference was observed     eral years to progress from normal mucosa to
between the active and placebo groups (RR =          advanced neoplasia, which affords a clear oppor-
1.15; 95% CI = 0.80–1.65).35 Extension of the        tunity for detecting lesions at an asymptomatic
follow-up period to 12 years did not apprecia-       stage. Second, there are a variety of possible
bly alter the risk estimate (RR = 1.03; 95% CI =     screening methods that range from non-invasive
0.83–1.28).36 However, certain limitations of the    stool tests or imaging studies to invasive endo-
Physicians’ Health Study trial design, such as       scopic evaluations. Third, due to the high inci-
the relatively low aspirin dose and lack of uni-     dence of colon cancer, such screening may be
form colorectal cancer surveillance guidelines,      cost-effective in terms of screening costs versus
may have hindered its ability to detect a protec-    years of life saved. Fourth, the high incidence of
tive association.                                    colon cancer provides a motivation for many indi-
   The chemopreventive effects of traditional        viduals to seek out screening. Based on these and
NSAIDs are thought to result primarily from          other considerations, several randomised trials of
inhibition of cyclooxygenase-2 (COX-2). Selec-       various screening methods have been conducted.
tive COX-2 inhibitors like celecoxib and rofe-          With respect to faecal occult blood testing,
coxib are therefore being aggressively pursued as    three large clinical trials have shown that regular
potential colorectal cancer prevention agents. In    screening may reduce colorectal cancer mortal-
the first trial to be reported, celecoxib 400 mg      ity by 13–33%.38 – 40 In two trials from Europe,
twice per day was associated with statistically      subjects (n = 61 933 and n = 150 251) were ran-
significant reductions in both the mean num-          domised to undergo screening every other year
ber and total burden of colorectal polyps among      versus usual care. In the Minnesota Colon Cancer
124                                 TEXTBOOK OF CLINICAL TRIALS

Study, subjects (n = 46 551) were randomised         the absence of symptoms or other known risk
to annual screening, biennial screening or usual     factors). However, screening colonoscopy has not
care. Follow-up in these studies ranged from         yet been investigated in a randomised clinical
11–18 years. Interestingly, only one trial found     trial, with the exception of one ongoing feasi-
that programmatic screening was associated with      bility study.46 Two novel methods of colorectal
a statistically significant reduction in colorectal   cancer screening, CT colonography and DNA-
cancer incidence.40 These data suggest that pre-     based stool assays, are currently being tested in
invasive adenomas (arguably the most relevant        population-based clinical trials as well. Results
screening target) are poorly detected by faecal      from these studies are anticipated in the near
occult blood testing. Thus, despite the inclusion    future and may necessitate further modification
of faecal occult blood testing in widely endorsed    of current early detection algorithms.
colorectal cancer screening guidelines,41,42 fur-
ther pursuit of more sensitive and specific stool             TREATMENT: COLON CANCER
biomarkers is needed.
   Direct examination of the distal colorectum by                   Localised Disease
flexible sigmoidoscopy represents another option
for colorectal cancer screening. However, this       Surgery is the primary modality for the treat-
procedure is at least moderately invasive and        ment of localised colon cancer. Depending on
may be associated with transient discomfort. As      disease stage, surgery alone produces 5-year sur-
such, adherence to recommendations for initial       vival rates of 50% to greater than 90%. As
and repeat flexible sigmoidoscopies was recently      opposed to gastric and rectal cancer, however,
evaluated in the Prostate, Lung, Colorectal and      the surgical technique for colon cancer resec-
Ovarian (PLCO) Cancer Screening Trial. Among         tion has been the subject of limited investigation
subjects randomised to the screening intervention    in randomised clinical trials. One large surgical
arm (n = 17 713), 83% completed the baseline         trial recently completed accrual of approximately
flexible sigmoidoscopy. Additionally, 87% of          900 patients. In this study, patients were ran-
subjects who were eligible for repeat testing        domised to either the standard ‘open’ colectomy
after three years complied with the follow-up        or a ‘minimally invasive’ laproscopically assisted
evaluation.43 At present, the effects of flexible     colectomy.47 The trial’s primary endpoint was
sigmoidoscopy screening on colorectal cancer         cancer recurrence, and it was designed to demon-
incidence in the PLCO trial cohort remain            strate equivalence of the two approaches. The
unknown. An even larger flexible sigmoidoscopy        trial also included extensive quality of life and
screening trial is underway at 14 centres in         cost-effectiveness assessments.
the United Kingdom and Wales (n = 170 432               The value of adjuvant treatment for patients
randomised subjects).44 When available, data         with stage 3 colon cancer (cancer able to be
from these two trials should be highly informative   completely resected, but with positive lymph
regarding the utility of flexible sigmoidoscopy       nodes in the resection specimen) is well accepted.
screening to reduce colorectal cancer incidence      The first trial conducted with a positive result was
rates in the general population.                     conducted by the North Central Treatment group,
   Colonoscopy is currently the gold standard        initiated in 1978.48 This was a three-arm trial,
for structural evaluation of the large intes-        with a sample size of approximately 135 patients
tine. Cost-effectiveness models suggest that         per arm, comparing no post-surgical treatment to
one-time screening colonoscopy between ages          adjuvant treatment with either levamisole alone
50–54 years may be a rationale colorectal cancer     or 5-FU plus levamisole. The initial results of
prevention approach.45 Existing early detection      this trial indicated a moderate but statistically
guidelines support a slightly more conserva-         significant benefit for the 5-FU plus levamisole
tive strategy (i.e. colonoscopy every 10 years, in   arm compared to control. Given the novelty of
                                      GASTROINTESTINAL CANCERS                                        125

this result, in a decision that likely would never    infusion. Based on promising results in the
be made in the current day, the investigative         advanced disease setting (as discussed below),
team decided to embark on a larger, confirmatory       multiple clinical trials have been conducted using
trial prior to the release of the results to the      regimens based on a long-term infusion with
oncology community. This confirmatory trial,           5-FU. Intergroup trial 0153 directly compared
known as Intergroup trial 0035, enrolled over         a bolus to an infusional 5-FU based regimen
1200 patients to the same three arms as the           in a randomised Phase III trial of 1078 patients
initial trial. Intergroup 0035 clearly demonstrated   (terminated early at an interim analysis–original
improved overall survival in patients treated with    planned sample size of 1800 patients).56 In this
adjuvant 5-FU and levamisole.49 These findings         trial no difference in efficacy was observed
lead in part to the 1990 consensus statement          between the arms, although the toxicity profile
from the National Cancer Institute that patients      did differ substantially. Based on these results,
with stage 3 colon cancer who are unable to           two recent Phase III randomised trials in the
enter a clinical trial should be offered adjuvant     United States have used control arms of 6 months
treatment with 5-FU plus levamisole unless there      of bolus 5-FU plus leucovorin. However in
are contraindications.50                              Europe, regimens using short-term 24–48 hour
   A number of clinical trials were in progress       5-FU infusions are more popular.
at the time of the publication of the beneficial          Future efforts in the adjuvant treatment of stage
results from the use of adjuvant 5-FU plus            3 colon cancer will likely be directed in two
levamisole. Several of these trials included a        areas – first, to improving the treatment options
no post-surgical treatment control arm, and thus
                                                      available, and second, and relatedly, to tailoring
these trials were closed prior to reaching their
                                                      therapy to the individual patient. In the treatment
accrual goals due to ethical reasons. Included in
                                                      area, for the time being, new studies will ran-
this list of trials that were closed prematurely
                                                      domise patients to treatments based on adding a
were five Phase III randomised trials testing
                                                      new treatment to a 5-FU and leucovorin regimen.
5-FU plus leucovorin versus no post-surgical
                                                      For example, the two recent large Phase III trials
treatment control. The results from three of these
trials were pooled for analysis;51 the other two      in the United States compared 5-FU and leucov-
were reported separately.52,53 In each of these       orin to either a 5-FU, leucovorin and irinotecan
analyses, adjuvant 5-FU plus leucovorin showed        (trial C89803) or 5-FU, leucovorin and oxali-
a survival advantage compared to control. In          platin (trial C-06). In somewhat of a leap of faith,
subsequent studies, throughout the 1990s, various     the trial currently being planned by the US Gas-
investigative groups conducted trials comparing       trointestinal Intergroup will compare 5-FU, leu-
various different schedules and combinations          covorin and irinotecan to 5-FU, leucovorin and
of 5-FU combined with either leucovorin or            oxaliplatin. This leap is necessitated by the new
levamisole. None of these trials demonstrated a       realities of conducting trials in the adjuvant colon
statistically significant improvement in survival      setting – namely, that patient outcome has been
between study arms, although through such trials      sufficiently improved that significant follow-up
it did become clear that 6 months of 5-FU plus        is required in order to obtain sufficient events to
leucovorin was at least as effective as 12 months     power a study. Both the C89803 and C-06 trials
of 5-FU plus levamisole.54,55 As a result, the        will require a minimum of three years of follow-
current standard of care in the United States (as     up prior to any formal analysis. The options for
of 2002) for stage 3 colon cancer is 6 months of      conducting a follow-up study are thus to wait at
5-FU plus leucovorin.                                 least three years, or to push ahead, assuming that
   In the discussion in the preceding paragraph,      at least one of the experimental regimens will
all of the regimens discussed were based on           prove superior to the current standard. A dis-
the delivery of 5-FU as a short-term bolus            cussion of the second area, tailoring therapy to
126                                   TEXTBOOK OF CLINICAL TRIALS

the individual patient, will be deferred until the     Mamounas et al.,59 pooled data from four ran-
next section.                                          domised trials conducted by the NSABP. In none
   One additional insight into the conduct of clin-    of these four trials was there a direct randomised
ical trials in GI cancers may be gained by exam-       comparison between treatment and control. In
ining the steady increase in the sample sizes that     their analysis, the authors estimated the magni-
has occurred in stage 3 colon clinical trials over     tude of the difference in outcome between the two
the past two decades. In trials conduced in the        study arms in each of the four studies. They then
early 1980s, sample sizes of 100–200 per arm           compared whether this difference in outcome dif-
were typical,48,52 with some exceptions (such as       fered by patient stage. The authors concluded that
the NSABP C-01 trial, with approximately 380           the treatment effect within each study was similar
patients per arm).57 With such a sample size, the      between stage 2 and stage 3 patients, and since
study provided adequate power to detect only a         it had been previously demonstrated that treat-
relatively large effect. Fortunately, 5-FU, when       ment is beneficial in stage 3 patients, they con-
combined with either levamisole or leucovorin,         cluded that treatment is also beneficial in stage
did provide a rather large effect, with a reduction    2 patients.
in the hazard of death by approximately 25%.58            The second investigation60 used a more direct
However, the likelihood of a subsequent treat-         approach. In this analysis, the study team pooled
ment advance by such a magnitude is unlikely,          the data from stage 2 patients who had partic-
and smaller advances may indeed be clinically          ipated in five randomised trials of 5-FU plus
relevant. Therefore, more modern trials in stage 3     leucovorin versus control. They found no statis-
disease have included sample sizes of 1600 (trial      tically significant benefit of treatment, based on
C89803), 2400 (trial C-06) and 4900 patients for       a pooled sample size of just over 1000 patients.
a four-arm trial (the QUASAR trial).54 As ther-        Due to the excellent outcome of stage 2 patients,
apy continues to improve, the sample size neces-       with an approximately 80% 5-year survival in
sary to detect further incremental advances will       untreated patients, even this pooled sample size
continue to grow. One possible strategy for prac-      had poor power to detect a small but possi-
tically conducting such large trials is discussed in   bly important improvement in patient outcome
the next section.                                      (only 60% power to detect an 85% 5-year sur-
   As opposed to the adjuvant treatment of stage       vival in treated patients). Thus, the benefit of
3 disease, the benefit of adjuvant treatment for        5-FU based adjuvant therapy in stage 2 disease
stage 2 (node negative) disease is unclear. In         remains unclear, and further pooled analyses will
many previous trials, patients with stage 2 disease    likely be necessary. A large randomised trial of
have been pooled together with stage 3 patients.       a monoclonal antibody in the setting of stage 2
The sample size for such trials has typically been     disease has recently completed accrual of over
based on an analysis pooling the data from both        1700 patients (trial C9581); the results of this
patient groups. For a variety of reasons, patients     trial should help clarify the appropriate treatment
with stage 3 disease have typically constituted        for patients with stage 2 disease.
a majority of the enrollment to such trials, thus
each individual trial has been underpowered to                         Advanced Disease
detect a moderate benefit of treatment in stage
2 patients. Due to the limited sample size in          It is likely that more clinical trials have been
each trial, two attempts have been made to pool        conducted in advanced colon cancer than in any
data from several trials in order to gain a suffi-      other GI disease site. This is due to the high
cient sample size to draw a definitive conclusion       incidence of the cancer, and the fact that it is to at
regarding the value of adjuvant therapy in stage 2     least some degree sensitive to chemotherapeutic
disease. However, the two analyses have reported       agents. Trials in advanced colon cancer typically
differing conclusions. One analysis, reported by       include patients with advanced rectal cancer, as
                                      GASTROINTESTINAL CANCERS                                        127

the response to chemotherapy has not been shown          At almost the same time as the introduction
to depend on the precise site of the patient’s        of oral 5-FU based agents for advanced colorec-
disease within the colorectum.                        tal cancer, new chemotherapeutic agents have
   The drug 5-FU has been the mainstay of treat-      been added to 5-FU with promising results. Based
ment for colorectal cancer for over 40 years.         on results with the agent irinotecan in patients
From 1950–1990, a multitude of trials were con-       who had failed a 5-FU based regimen,66,67 tri-
ducted in an effort to improve the efficacy of         als with irinotecan were performed in the setting
5-FU based regimens, by changing methods of           of patients with previously untreated advanced
administration, combining it with various supple-     disease. As reported by Saltz et al.68 and Douil-
mental agents (such as leucovorin or levamisole),     lard et al.,69 irinotecan, when added to 5-FU and
or changing the dose and schedule. Regarding          leucovorin, resulted in improved time to progres-
the timing of administration, the clear result of     sion and overall survival when compared to 5-
multiple studies is that, among regimens where        FU and leucovorin alone in first-line treatment
5-FU is delivered as a bolus injection, the partic-   of advanced disease. These two relatively large
ulars of the administration have a definite impact     trials (683 and 387 patients, respectively) estab-
on toxicity, some impact on tumour response,          lished a new standard of care in this setting. In
but little impact on patient survival. The addi-      the Saltz trial irinotecan was added to a bolus
tion of leucovorin to 5-FU has been demon-            5-FU schedule, while the Douillard trial added
strated in a meta-analysis to provide increased       irinotecan to an infusional 5-FU regimen, thus
efficacy in terms of response rate compared to         the optimal method in which to give 5-FU with
5-FU alone.61 In another meta-analysis, a sched-      the new agent remained unclear. Recently, the
ule where the 5-FU is delivered by a continuous       drug oxaliplatin has shown promising activity
infusion has been shown to provide an advantage       when combined with 5-FU and leucovorin in sev-
in both toxicity and overall survival compared to     eral studies,70,71 with reported median survivals
bolus schedules.62,63 However, the improvement        equaling or exceeding 18 months.
in median survival was modest at 0.8 months,             The proven efficacy of irinotecan as second-
thus many practitioners (at least in the United       line therapy in patients who fail 5-FU based
States) have continued to administer the bolus 5-     therapy has complicated the design of first-
FU based regimens based on perceived benefits          line advanced disease trials. Traditionally, overall
of patient and physician convenience.                 survival has been used as the primary endpoint
   After 40 years of testing variations on a 5-FU     for such studies, and extending the patient’s
theme, two more recent developments have added        longevity remains the ultimate goal. However,
excitement to the advanced colorectal cancer          given that there are second- and even third-line
clinical trials arena. The first is the introduction   therapies with proven benefit, the relative merits
of oral 5-FU based regimens. The oral method of       of overall survival as the primary outcome for
delivery offers clear benefits in terms of patient     a trial warrant a reconsideration. Consider the
preference. However, an oral approach would not       design used in the Saltz trial,68 where irinotecan
likely be accepted if it did not provide at least     plus 5-FU and leucovorin was compared to 5-
equivalent efficacy to an IV approach. Therefore,      FU and leucovorin. In this trial, patients who
two large equivalence trials have been conducted      progressed on the 5-FU and leucovorin arm
comparing an oral to an IV regimen. These two         were able to receive irinotecan off study, as it
trials, one reported by Hoff et al.64 and the other   was approved for the second-line indication. The
by van Cutsem et al.,65 enrolled 605 and 602          availability of this effective second-line agent
patients respectively, and were formally designed     provided at least the theoretical possibility that
to test the equivalence of the oral regimen to the    the two primary study arms could show no
IV approach. In both cases, formal equivalence        difference in terms of overall survival, even
was declared.                                         though irinotecan was beneficial to patients on
128                                   TEXTBOOK OF CLINICAL TRIALS

both arms of the study. For this reason, time          be optimised by using continuous infusion 5-FU
to tumour progression was specified as the              based therapy as opposed to bolus. All patients
primary endpoint for the trial. In retrospect,         in this study received radiation. This study of
the addition of irinotecan as a component of           680 patients concluded that (1) semustine is not
the initial treatment resulted in both improved        necessary, and (2) infusional 5-FU based ther-
time to progression and overall survival, making       apy during the radiotherapy provides a survival
the result clear. However, these factors must be       advantage compared to bolus therapy.73
taken into consideration for future trials, where at      Two studies conducted by the National Sur-
minimum data on the use of second- and third-          gical Breast and Bowel Project (NSABP) have
line therapy should be collected.                      questioned the value of radiation in the post-
                                                       operative setting. In the Krook and O’Connell
        TREATMENT: RECTAL CANCER                       studies mentioned above, all patients received
                                                       radiation, and the studies focused on the rela-
Rectal cancer is second to colon cancer among          tive benefit of different chemotherapy regimens.
GI malignancies in the number of new cases             In contrast, NSABP study R-01 tested three arms
per year. When the initial diagnosis for rectal        in a randomised manner in 574 patients: no post-
cancer is as advanced disease, i.e. not surgically     surgical treatment, post-operative radiation and
completely resectable, its primary treatment is in     post-operative chemotherapy. A survival benefit
the same manner as for advanced colon cancer.          was observed for the chemotherapy arm com-
However, the optimal adjuvant treatment for            pared to the no treatment arm, but this advan-
rectal cancer is the issue of considerable study.      tage was not observed in the radiation alone
Questions abound as to the importance of surgical      arm.74 The NSABP followed this study with a
technique, the value of radiation therapy, the         two-arm randomised trial of 741 patients com-
optimal chemotherapy regimen and the timing of         paring chemotherapy alone to chemotherapy plus
therapy, either pre- or post-resection.                radiation.75 The results of this trial showed no
                                                       improvement in overall survival for the combined
           Surgery/Adjuvant Therapy                    modality arm, although there was a statistically
                                                       significant improvement in the rate of local recur-
Prior to 1990, external beam radiotherapy in the       rence associated with radiation. Despite these two
post-operative setting was considered by many as       consistent results, radiation continues to be com-
the standard of care in the United States, based       monly used in the post-operative treatment of
primarily on an observed benefit in lowering the        stage 2 and 3 rectal cancer.
risk of local recurrence. In particular, radiation        Increasingly, practitioners are turning to deliv-
as a single agent added to surgery had never           ering radiotherapy for rectal cancer in the pre-
been shown to improve overall survival com-            operative setting. There are several theoretical
pared to surgery alone. In a randomised study of       advantages to the pre-operative approach. Per-
204 patients, Krook et al.72 demonstrated a bene-      haps most importantly, from the patient’s per-
fit in overall survival of post-operative combined      spective, pre-operative therapy may shrink the
therapy with radiation and 5-FU and semus-             tumour sufficiently to allow a sphincter-sparing
tine compared to radiation alone. The 1990 NIH         resection. Pre-operative radiotherapy has been
consensus statement concluded that ‘Combined           shown to improve outcome compared to no treat-
postoperative chemotherapy and radiation ther-         ment in a large randomised trial of the Swedish
apy improves local control and survival in stage II    Rectal Cancer Trial group. This trial randomised
and III patients and is recommended’.50 In a sub-      1168 patients to a two-arm trial of a short
sequent study conducted by the US GI Intergroup,       course (25 Gy in 1 week) of pre-operative radia-
two questions were asked in a 2 × 2 factorial          tion compared to no pre-operative treatment, and
design: is semustine necessary, and can therapy        showed a statistically significant improvement in
                                     GASTROINTESTINAL CANCERS                                       129

both local recurrence rate and overall survival.76   radiation therapy have been shown to reduce the
In the United States, the standard pre-operative     local recurrence rate and improve overall survival
regimen is to deliver the 5-week post-operative      based on large randomised trials. It is also clear
course of 50.4 Gy pre-operatively. The efficacy       that considerable work remains to define the opti-
of this approach has never been established in       mal timings and combinations of the different
a randomised trial. A comparison of these two        treatment modalities.
pre-operative approaches is clearly warranted.
   Regardless of the specifics of the pre-operative
                                                         SELECTED METHODOLOGIC ISSUES
approach, a burning question concerns whether
                                                                 WITH EXAMPLES
the pre- or post-operative approach provides the
best outcome. Two randomised trials have been
attempted in the United States, and both were        The number and variety of large Phase III
closed early far short of their accrual goals due    randomised trials that have been conducted in GI
to poor accrual. However, an ongoing trial in        cancers brings to light a number of clinical trials
Europe has been more successful, with accrual of     methodology issues that have direct relevance to
over 600 patients to one of the two approaches.77    the conduct and conclusions that can be drawn
The 50.4 Gy long course radiation is being used      from such trials. In this section we will highlight
in both arms, and both arms are receiving the        three such issues: subgroup analysis, the study of
same chemotherapy regimen in combination with        prognostic and predictive factors, and monitoring
the radiation.                                       of clinical trials for safety.
   In addition to the controversies present in
chemotherapy and radiation therapy, there is                     SUBGROUP ANALYSIS
considerable interest in the optimal surgical
management of this disease. In particular, the       Studies are often conducted in multiple possible
surgical approach of total mesorectal excision       heterogeneous groups of patients in order to
(TME) has been promoted as an important              achieve a necessary sample size, or to complete
surgical advance. Based on case-series and other     a trial more quickly. The conduct subgroup
historical data, proponents of TME have claimed      analyses, that is, to examine the result of a
significant reductions in local recurrence rates      trial separately in different groups of randomised
and improved overall survival compared to            patients, is extremely important. In fact, such
standard surgery.78 However, TME has never           analyses can help demonstrate the robustness of
been tested against non-TME surgery in a             a result: if a study finding can be shown to be
randomised trial, and such a trial is unlikely to    consistent in different patient groups, such as
ever be conducted. In a large randomised trial of    patients of different ages, or patients enrolled
1861 patients conducted by the Dutch Colorectal      from different countries, then the overall result
Cancer Group, pre-operative radiation was shown      cannot be explained by an extreme result in
to reduce the rate of local recurrence compared      one subset of patients. Additionally, subgroup
to no radiation when all patients received TME       analyses are important in generating hypotheses
surgery.79 In this early report, with a median       for future study. However, caution must be
follow-up of 2 years in living patients, there was   exercised when examining the results of subset
no improvement in overall survival for patients      analyses, particularly if they were not pre-
receiving radiation.                                 specified in advance.
   In summary, it is clear that rectal cancer is        One example of a subgroup analysis of great
an area where randomised clinical trials have        controversy in the setting of GI cancers is
made several important contributions to improv-      whether post-surgical adjuvant treatment is ben-
ing patient outcomes. Post-operative chemother-      eficial for patients with stage 2 colon cancer,
apy and chemoradiotherapy, and pre-operative         as discussed previously. Historically, most trials
130                                  TEXTBOOK OF CLINICAL TRIALS

in adjuvant colon cancer have included patients       treatment benefit in both subgroups of patients;
with both stage 2 and 3 disease. The majority of      the absence of a significant interaction implies
patients in such trials have been stage 3 patients,   that there is no evidence that the benefit of treat-
and subset analyses within these trials have con-     ment differs by patient subgroup.
sistently shown 5-FU based chemotherapy to be            Two adjuvant rectal trials conducted by the
beneficial in this group. However, because the         NSABP, trials R-0174 and R-02,75 can be used
majority of patients in such trials have not been     to demonstrate a different feature of subgroup
stage 2, and because the prognosis for the stage      analyses. The first trial, R-01, demonstrated a
2 patients is overall more favourable, with fewer     significant benefit in terms of overall survival
patient deaths and thus less statistical power,       for the addition of chemotherapy following
the individual studies have not shown consistent      resection compared to no post-surgical treatment.
results in the subset of B2 patients. As mentioned    However, in subgroup analyses, this benefit
above, two pooled analyse have been conducted,        seemed to be limited to the male patients,
with conflicting results. Both analyses are to be      which could not be explained. The NSABP is
commended for obtaining and using the individ-        to be commended for treating this finding as
ual patient data from each of the included trials,    hypothesis generating, and testing the hypothesis
and for having very complete follow-up for the        in their next study R-02. In study R-02, the
studies used. However, both analyses could be         randomisation scheme differed for men and
criticised for other methodologic issues. The first,   women, with females being randomised to two
by the NSABP investigators,59 pooled data from        arms and males to four arms. The results of R-
multiple trials with different treatment arms, none   02 did not demonstrate the need for different
of which compared directly a no treatment arm         treatment for the two genders, which put the
to what would be considered a standard treat-         issue to rest after being tested as appropriate in
ment by current standards. The second, by the         a randomised trial. This experience demonstrates
IMPACT investigators,60 did pool results from         the value of confirming a finding that results from
randomised trials of no post-surgical treatment to    a subgroup analysis prior to accepting the result
therapy with 5-FU and leucovorin, the current US      into clinical practice.
standard of care. However, these investigators did
not include data from two large trials testing 5-FU            TUMOUR MARKER STUDIES
and levamisole versus control, which despite hav-     A second area of considerable interest and debate
ing the 5-FU modulated by a different agent did       in the GI cancer community regards the use
indeed test a very similar question, with 5-FU and    of putative prognostic and predictive markers to
levamisole shown in large randomised trials to        guide the choice of therapy for an individual
give results indistinguishable from 5-FU and leu-     patient. Hundreds if not thousands of studies have
covorin. Additionally, the IMPACT investigators       been done on markers based on immunohisto-
used a less powerful analysis than might be pos-      chemistry, flow cytometry, chromosomal markers
sible. The original trials included in the IMPACT     such as allelic loss and microsatellite instability,
analysis included patients with both stage 2 and      pathologic features, and many others. Unfortu-
3 cancers. In these trials, treatment was proven      nately, few if any of these markers have made
beneficial overall. Therefore, the most relevant       their way into clinical practice. The reasons for
question is whether the effect of treatment dif-      this lack of progress are many,80 we will focus
fered between the stage 2 patients and the stage 3    here on three that are directly related to the
patients. This question could be tested by obtain-    later stages of clinical trials: analyses confined
ing all of the data from the trials, examining        to patient subgroups, inadequate sample size and
the degree of benefit overall, and then testing        improper design.
for a stage by treatment interaction. This is the        In any report investigating tumour markers
most statistically powerful method for testing the    based on patients from clinical trials, the rate
                                       GASTROINTESTINAL CANCERS                                        131

of sample collection is an important issue. In         several Phase III trials that are in development
the case of retrospective trials conducted on tis-     in the US.
sue obtained from a clinical trial, often tissue is
available on only a subset of the patients who                     SAFETY MONITORING
entered the initial trial. In these retrospective
marker studies, comparisons are frequently made        As a final clinical trials methodologic issue,
between characteristics such as baseline demo-         we consider the process of monitoring patient
graphics and/or tumour stage for the patients          safety in clinical trials. Clinical trials have
whose tumours were used in the marker study            been conducted for many years, and detailed
and those whose tissues were not used. How-            and effective methods have been developed for
ever, even if the characteristics for the patients     ensuring the safety of participants. One of the
who were used in the analysis and those who            fundamental tenants of clinical trials is the
were not appear similar, the results of such stud-     progression of an agent or regimen through
ies could still be biased. Such an example has         a series of trials, starting in small, typically
been described by Pajak et al.,81 who reported on      single-centre Phase I studies, on to somewhat
a study originally conducted by Grignon et al.82       larger, possibly multi-centre Phase II trials, then
In their study, in patients with advanced prostate     on to Phase III trials. The sequential nature of
adenocarcinoma, Grignon et al. studied the rela-       such trials, among other features, allows for
tionship between tumour p53 status and progno-         considerable experience with an agent or drug
sis in 129 of 456 patients entered onto a trial        combination prior to a large, multi-centre trial.
conducted by the Radiation Therapy Oncology            The recent pressure towards developing and
Group (RTOG study 86-10). When reanalysed              testing agents more rapidly, although beneficial
by Pajak et al., it was shown that the distribu-       in many ways, does challenge this established
tion of treatment received and combined Glea-          mechanism for establishing the safety of an agent.
son Score of patients who had p53 assessed             More Phase I/II, Phase II/III, or even Phase I/III
was identical to those who did not have p53            trials are being conducted, the result of which
assessed. However, the survival of those patients      is that agents or combinations are being pushed
who had a p53 determination performed on their         into the multi-centre setting more rapidly that in
tumour, and were thus included in the study, was       the past. This warrants an examination of why
significantly worse than those not included in          caution is warranted as agents are taken from
the study.                                             Phase I testing to larger trials.
   This example demonstrates the possible pitfalls        Phase I trials have a successful history as the
of performing marker studies on patient subsets.       first step in testing new cancer therapies. How-
Despite such examples, the approach of collect-        ever, several factors must be considered as a
ing a set of patients with tissue available, testing   new agent or combination of agents is taken
a possible prognostic or predictive marker, and        from a Phase I trial to a Phase II or Phase III
reporting the results continues to be the method       trial. These factors relate to possible differences
by which most markers are examined. The rea-           between patients entered onto Phase I trials and
sons for this are many: expediency, ethical issues     those entered on later trials. First, Phase I tri-
of mandatory tissue submission, and policies of        als often include patients with any type of solid
informed consent and institutional review boards.      tumour. This speeds the completion of the trial,
It does raise the issue of whether for future          and is justified because in many cases the tolera-
prospective studies, tissue submission should be       bility of an agent is not related to the location of
mandatory prior to patient entry on a therapeu-        the patient’s primary tumour. However, in some
tic clinical trial. Such a discussion raises ethical   instances the tolerability of an agent may dif-
and legal issues that are beyond the scope of          fer in patients with different tumour types. Sec-
this work, but such discussions are ongoing for        ond, Phase I trials are frequently conducted at
132                                   TEXTBOOK OF CLINICAL TRIALS

highly specialised cancer centres, where medical       report was prompted by the finding of an
personnel experienced with detailed monitoring         unexpected number of early deaths on two GI
and rapid intervention reduce the consequences         cancer trials, one in advanced colorectal cancer
of and future risk for toxicity whenever possi-        and the other in adjuvant cancer. In one of the
ble. In contrast, Phase II and III trials are often    trials in the review, 23 patients were reported
conducted in the community setting, where the          to have died within 60 days of initiation of
clinical staff may be using a new agent or com-        therapy. When these 23 events were reported
bination of agents for the first time.                  to the group operations office for this trial,
   A final reason for caution is that patients are      only 10 were deemed to have been related to
enrolled onto Phase I trials only after failing all    treatment. However, upon independent review,
standard therapies. This has several implications.     16 of the 23 events were deemed treatment-
Patients enrolled on Phase I trials have typically     related or treatment-induced.
been previously exposed to cytotoxic agents, thus         Several conclusions can be drawn regard-
they may be physically or emotionally more             ing toxicity in clinical trials. First, as the pace
robust and tolerate a new therapy better than a        of drug development continues to quicken, it
patient in the first-line setting. Additionally, only   is likely that there will continue to be agents
patients that have tolerated their initial therapy     pushed into large trials prior to full and exten-
acceptably are likely to choose enrollment, or         sive Phase I and II testing. Second, effective
be considered candidates, for a Phase I trial. A       systems must be established to monitor toxic-
final issue with respect to patients who have           ity in trials of all phases. Third, an independent
been previously treated is that patients and their     assessment of the attribution of an event may
physicians may have a sense of the rate of disease     be beneficial, as local investigators may be hes-
progression such that patients with the most           itant to attribute a poor event to a treatment.
virulent disease are often not even considered for     In addition, new metrics (such as 60-day all-
enrollment in a Phase I trial.                         cause mortality85 ) and new terminology (such
   In part due to the combination of these various     as treatment-induced, treatment-exacerbated and
factors, study sponsors, including the National        treatment-unrelated deaths84 ) may be helpful in
Cancer Institute, have developed sophisticated         standardising the reporting of adverse events in
systems to aid in the timely identification of          clinical trials.
toxicity problems in ongoing studies. Despite
these systems, gaps remain. For example for               CASE STUDY: 5-FU PLUS LEUCOVORIN
agents that are commercially available, expedited                 IN COLON CANCER
reporting of severe but expected events may not
be required. If such an event were occurring at        As is clear, the history of clinical trials in GI
a greater frequency than expected, and expedited       cancer is long and has been very successful. As
reporting was not required, a multi-centre trial       an example illustrating several facets of both
may not detect such an incidence for weeks or          the past history of GI clinical trials and issues
months due to the nature of the process of data        that will likely be faced again in future studies,
collection, editing, entry and analysis. This has      here we present a case study of the development,
led some groups to propose supplements to the          establishment and replacement of what was once
standard systems to collect data on all severe         the US standard of care for advanced colorectal
events in a timely manner.83                           cancer and, as of 2002, remains the standard for
   Even when data is reported in a timely manner,      adjuvant stage 3 colon cancer, the ‘Mayo Clinic’
care must be taken in interpreting the data            bolus regimen of 5-FU and leucovorin delivered
received. As an example, consider the experience       for 5 consecutive days every 4 or 5 weeks.
in two large Phase III randomised trials reported         The activity of fluorinated pyrimidines in the
on by Rothenberg et al.84 The Rothenberg et al.        treatment of GI cancers has been reviewed
                                        GASTROINTESTINAL CANCERS                                        133

extensively. 5-Fluorouracil (5-FU) is the most          explore the efficacy of 5-FU and leucovorin in
ubiquitous of the fluorinated pyrimidines, which         inhibiting tumour growth.
at least in part exert their antineoplastic effect by      Early investigators studying the biochemical
inhibiting the activity of the enzyme thymidylate       modulation of 5-FU with leucovorin in the treat-
synthase (TS), which in turn interferes with DNA        ment of colorectal and gastric cancers included
synthesis in dividing cells. Often agents designed      Machover and colleagues.94,95 The Machover
to improve the efficacy of fluorinated pyrimidines        regimen consisted of administering high-dose
are combined with these agents in an effort             leucovorin at 200 mg/m2 /d prior to 5-FU at a
to preferentially sensitise tumour cells relative       dose of 370 mg/m2 /d, with both drugs given
to host cells to the agent(s). Leucovorin is an         consecutively for 5 days. With this dose of
agent commonly used in such a setting. The              leucovorin, the blood level is approximately
Mayo regimen of 5-FU and leucovorin is thus a           10–20 µmol/L.96 In large part to lower the cost
combination of an active chemotherapy agent, 5-         of the regimen (leucovorin was very expensive
FU, with a ‘biochemical modulator’ leucovorin.          at the time), the ‘Mayo’ regimen was devised to
   Prior to the early 1980s, 5-FU was primarily         use the identical 5-FU schedule to the Machover
administered as a single agent. Administered            regimen, but to use low-dose leucovorin at a dose
in this fashion, it was associated with limited         of 20 mg/m2 /d, which resulted in blood levels of
activity and moderate toxicity. Response rates          1–2 µmol/L.
for metastatic colorectal cancer were low, in the          This regimen was first tested as part of a ran-
neighbourhood of 10%, and these responses were          domised Phase II study in advanced unresectable
short-lived, lasting on average a few months.61         colorectal cancer.97 Three of the treatment arms
   Based on pre-clinical laboratory studies,86 – 88     are relevant for this discussion: (1) 5-FU as a sin-
the addition of leucovorin to cell culture with one     gle agent administered at a dose of 500 mg/m2 /d
of the metabolites of 5-FU, fluorodeoxuridylate          by IV bolus for 5 consecutive days every
monophosphate (FdUMP), resulted in enhanced             5 weeks; (2) the Machover regimen repeated at
binding to and inhibition of TS as compared             4 weeks, 8 weeks and every 5 weeks thereafter;
to the binding when FdUMP was used alone.               and (3) the Mayo regimen repeated at the same
This improved inhibition of thymidylate synthase        frequency as the Machover regimen. In this trial,
resulted in inhibited DNA synthesis and resulted        provision was made in the protocol to escalate
in enhanced tumour shrinkage. Depending on the          the 5-FU dose on any treatment arm if there was
model systems, optimal concentration of leucov-         no observed myelosuppression or significant non-
orin ranged from leucovorin 1–20 mmol/L.89 – 93         haematologic toxicity during the previous treat-
These studies supported the use of leucovorin           ment course. When the toxicity was analysed
doses ranging from 10 to 600 mg/m2 in clini-            after treatment of the first 100 patients, the start-
cal trials where leucovorin was added to 5-FU           ing dose of 5-FU for the Mayo regimen was
in an effort to improve on 5-FU’s single agent          increased to 425 mg/m2 /d in order to produce
activity. While such laboratory studies provided        definite but tolerable toxicity that was of simi-
basic information on the modulation of 5-FU             lar magnitude between the six treatment arms.98
using leucovorin, the applicability of these results    The original combination of low-dose leucovorin
to humans with colorectal cancer was unclear.           with 370 mg/m2 /d of 5-FU for 5 consecutive
Based on clinical experience, individuals with          days was empiric; no formal Phase I trial of this
colorectal cancer clearly exhibit significant het-       regimen had ever been performed. In the 208 eli-
erogeneity in their response to treatment. The          gible patients entered on the three study arms of
sequence of administration of 5-FU and leucov-          interest, the overall response rates were 10% for
orin, the optimal concentration of leucovorin, and      5-FU alone, 26% for the Machover regimen, and
the appropriate interval of 5-FU and leucovorin         43% for the Mayo regimen. Both leucovorin reg-
administration all were variables to be studied to      imens demonstrated significant improvement in
134                                   TEXTBOOK OF CLINICAL TRIALS

response rate and overall survival compared to         were similar between the Mayo and RPMI 5-FU
5-FU alone.                                            plus leucovorin programmes, and the 5-FU plus
   Concurrent to the previously mentioned study,       both leucovorin and levamisole regimen.55 Based
investigators at the Roswell Park Memorial             on the essentially identical activity profiles of
Cancer Institute (RPMI) began testing a reg-           these regimens, the choice between the two 5-
imen of leucovorin 500 mg/m2 /d with 5-FU              FU and leucovorin regimens (Mayo and RPMI)
600 mg/m2 /d given for 6 consecutive weeks fol-        has been based on issues related to schedule
lowed by a 2-week rest period.99 In a small study,     (some patients preferred weekly therapy over
the RPMI regimen was shown to significantly             five consecutive days of treatment), cost (at the
improve the tumour response rate compared to           time of these studies leucovorin was expensive),
single agent 5-FU. Shortly thereafter, the RPMI        toxicity profile and clinician’s preference.
and Mayo regimens were compared in a ran-                 From the late 1980s until the year 2000,
domised trial of 366 patients.100 In this trial, the   the Mayo regimen of 5-FU and leucovorin was
objective response rates and overall survival was      regarded as the standard of care for advanced
similar between the two arms. The toxicity profile      colon cancer. As discussed previously, in the late
of the two regimens did differ, but no clear win-      1990s and early 2000s, several randomised tri-
ner was identified. Based largely on cost consid-       als were conducted in both the US and Europe in
erations, investigators from the Mayo Clinic and       which infusion-based 5-FU regimens or regimens
the North Central Cancer Treatment group chose         that combine 5-FU with CPT-11 or oxaliplatin
to pursue the Mayo regimen for future testing.         have demonstrated improved patient outcomes
   The activity seen with the combination of           compared to those seen with the Mayo regi-
leucovorin and 5-FU in the advanced disease            men. In addition, the oral agent capecitabine
setting naturally led to the evaluation of several     has been approved as an alternative to IV 5-FU
of these regimens in the adjuvant treatment of         in advanced disease. Thus it appears that in
patients with stage 2 and 3 colon cancer. In           the advanced disease setting, the Mayo 5-FU
a study that was suspended after accrual of            + leucovorin regimen has been replaced as the
317 patients (based on the results of a large          standard of care, indeed a welcome advance.
trial that demonstrated 5-FU plus levamisole was       In the adjuvant setting, no randomised trial has
an effective treatment in this setting49 ), patients   been completed that demonstrates improved over-
with resected stage 2 or 3 colon cancer were           all survival for a multiple drug combination, or
randomised to the Mayo 5-FU plus leucovorin            equivalence for an oral regimen, although trials in
regimen for 6 months or to a no treatment control      both areas have completed accrual and are await-
arm.53 The 5-year survival for treated patients        ing results. Increased toxicity has clearly been
was 74%, compared to 63% in the control group          demonstrated for multiple drug combinations in
(p = 0.02). This result established the efficacy        the adjuvant setting,84 demonstrating the value of
of the Mayo 5-FU plus leucovorin regimen in            waiting for the results from these definitive tri-
the adjuvant setting.                                  als before adopting a promising new therapy as
   Following this small study, a large trial was       a standard of care in the community.
conducted to test four different combinations
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                                   Haematologic Cancers
                         CHARLES A. SCHIFFER1 AND STEPHEN L. GEORGE2
          Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA
      Department of Biostatistics and Bioinformatics, Duke University Medical Centre, Durham, NC 27710, USA

                    INTRODUCTION                                        of haematopoietic growth factors, stem cell
                                                                        transplantation in first remission and modula-
                                                                        tion of various mechanisms of intrinsic drug
The story of therapeutic research for acute
                                                                        resistance.1 – 7 Some of these trials have, in fact,
myeloid leukaemia (AML) is one of mixed
                                                                        changed the standard care of the disease but
success. AML has been studied extensively both
                                                                        most have unfortunately been negative in that
in the clinic and in the laboratory, in part because
                                                                        the newer approaches failed to improve remission
of the accessibility of cells for in vitro testing, and
                                                                        rates and overall survival. Intensive treatment
has served as a model for the elucidation of many
of the principles of anti-neoplastic therapy and                        regimens have improved outcome in younger
translational research in infectious disease and                        patients, but clinical trials in patients 60 years
transfusion medicine supportive care. Complete                          and older by the Cancer and Leukemia Group B
remission after initial therapy is achieved in                          (CALGB) and others have shown remarkably
about two-thirds of patients, a significant fraction                     consistent poor results, with complete remis-
of whom can be cured with additional post-                              sion (CR) rates of around 50%, and only 10%
remission treatment. Unfortunately, however, the                        of patients surviving four years.1,8,9 Indeed, it
great majority of patients eventually relapse and                       is arguable that the prognosis of older patients
succumb to complications of the disease and                             with AML has not changed in the last 15 years.
its treatment. The incidence of AML spans the                           Therefore, it is imperative that new therapies are
entire age spectrum but is most common in adults                        evaluated in as efficient a fashion as possible.
greater than 60 years of age and the prognosis is                       There are a number of issues which can serve
particularly poor in these individuals.                                 as impediments to new drug development, some
   Large numbers of randomised trials have                              of which are idiosyncratic to AML. This chapter
been performed in patients with AML includ-                             will review some of these problems and sug-
ing comparative evaluations of different doses                          gest and discuss some of the statistical issues in
and types of chemotherapeutic agents, the use                           trial design.

Textbook of Clinical Trials. Edited by D. Machin, S. Day and S. Green
 2004 John Wiley & Sons, Ltd ISBN: 0-471-98787-5
142                                  TEXTBOOK OF CLINICAL TRIALS

                BACKGROUND                            cured of their leukaemia; however, less than 10%
                                                      of patients greater than 60 years of age remain in
AML occurs as a consequence of an acquired            long-term remission.1,6,8,9 Multiple randomised
mutation in a haematopoietic stem cell which          trials evaluating high-dose therapy with either
results in a failure of normal maturation and dif-    autologous or allogeneic stem cell rescue have
ferentiation of myeloid cells and an accumulation     produced results similar to those achieved with
of juvenile leukaemia cells or ‘blasts’. By mecha-    chemotherapy alone, although the causes of treat-
nisms which are not well understood, the expan-       ment failure vary somewhat, with lower rates
sion of this malignant clone suppresses normal        of relapse with transplant approaches offset by
blood cell formation and patients usually present     higher treatment associated mortality.6 In addi-
with symptoms related to absence of normal            tion, transplant approaches are generally suitable
blood cells including weakness and fatigue due to     only for younger patients.
anaemia, infection because of decreased number           AML is also an extremely heterogeneous dis-
of normal white blood cells, and bleeding because     order biologically. Multiple subtypes can be
of marked decreases in the number of platelets.       identified by cytogenetic or molecular studies
Because this is a systemic disease, initial treat-    of the leukaemia cells. Some of these sub-
ment is with chemotherapy, generally including        types (predominantly found in younger patients)
an anthracycline and cytarabine (ara-c), adminis-     have an excellent prognosis with cure rates of
tered for three and seven days respectively. This     approximately 60%, whereas other subtypes, gen-
induces a period of low blood counts for three        erally characterised by chromosome loss and
to four weeks at which time the patient is at risk    duplication, have almost no patients cured with
for bleeding and infection and invariably requires    chemotherapy alone.11 The latter is much more
transfusions of red blood cells, platelets and        common in older patients, particularly those in
the use of systemic antibiotics. Should therapy       whom AML developed as a progression of a
be successful, a complete remission is obtained       prior bone marrow disorder either of a myelo-
which is defined as normal blood counts and bone       proliferative nature or more commonly following
marrow with no evidence of leukaemia.10 It is         a myelodysplastic syndrome.
known that small amounts of leukaemia remain,            Cytogenetic and molecular characterisation of
which cannot be detected morphologically with         the type of AML can be critical as evidenced
the microscope, because without further therapy,      by the remarkable results achieved in recent
leukaemia invariably relapses, generally within       years in acute progranulocytic leukaemia (APL),
six months. Remission rates are approximately         a subgroup representing about 10% of patients
75% in younger patients but are only 50% in           with AML, predominantly in younger adults
older patients (greater than 60 years of age).        and children.12 All patients with APL have a
   There have been major improvements in infec-       balanced translocation between chromosomes 15
tious disease and transfusion supportive care so      and 17, resulting in a mutation of the gene
that, today, the major cause of initial treatment     coding for the retinoic acid nuclear receptor.
failure is drug-resistant leukaemia (i.e. persis-     By complex mechanisms, this confers unique
tence of leukaemia after treatment). Randomised       sensitivity to an oral retinoid, all-trans retinoic
trials comparing different types of anthracyclines,   acid (ATRA), which has appreciably fewer side
different doses and schedules of administration       effects than traditional chemotherapy. A series
of ara-c, and the use of growth factors for sup-      of randomised trials have elucidated the optimal
portive care, have not improved these induction       means of combining ATRA with chemotherapy
results. With appropriate post-remission therapy,     such that more than 70% of patients with
approximately 35% of patients less than 50 years      this previously devastating leukaemia can be
of age remain disease-free after three years, with    cured.13 Interestingly, APL also has a unique
almost all of these patients being functionally       sensitivity to arsenical compounds. It is hoped
                                         HAEMATOLOGIC CANCERS                                        143

that similar strategies with different compounds         However, there are a number of both practical
can be discovered for other AML variants with          and biologic issues complicating the conduct of
discrete activating mutations, as has recently also    such trials:
been achieved in patients with chronic myeloid
leukaemia (CML) with the use of the tyrosine           • Evaluation of post-remission manipulations
kinase inhibitor imatinib mesylate (STI571),             is made more difficult by the low com-
which specifically targets the abnormal enzyme            plete response rate, so that less than 50%
produced by the bcr/abl mutation characteristic          of patients initially entered on trial are eli-
of CML.14                                                gible for post-remission treatment. In addi-
   Some studies have suggested differential res-         tion, many such patients are not candidates
ponsiveness of AML subtypes to different types           for intensive therapy because of compromised
of chemotherapy. In particular, patients with            organ function from toxicities encountered dur-
more favourable balanced translocations seem             ing induction, and because many older patients
to benefit from high-dose ara-c-based consoli-            do not recover fully normal blood counts even
dation therapy. In contrast, patients with poor          after a significant anti-leukaemic response dur-
prognosis chromosomal changes do not bene-               ing induction.
fit from these more intensive chemotherapeutic          • In addition, many older individuals decline
approaches,15 although a fraction may be cured           post-remission treatment, preferring to spend
with the graft versus leukaemia effect induced           their remaining time outside of the hospital,
by allogeneic stem cell transplantation. Stem cell       as far from aggressive medical ministrations
transplant is currently not a possibility for older      as possible.
patients. Because of this, many treatment coop-
erative groups have devised different therapeutic      Thus, randomised studies of new therapies intro-
approaches for older and younger patients, with        duced post-remission need larger numbers of
manipulations of stem cell transplantation being       patients to account for this drop-off in patients
evaluated in the latter group.                         as the study progresses. This represents a major
                                                       issue since only a small fraction of such patients
                                                       are captured for clinical trials.
     IMPROVING THERAPY FOR OLDER                          Furthermore:
                                                       • AML in older individuals is extremely hetero-
Rates of complete remission are much lower and           geneous. Some therapies might be appropriate
remission duration more abbreviated in patients          only for certain AML subtypes and positive
greater than the age of 60 years as a consequence        effects can be missed when tested in the over-
of more intrinsic drug resistance and more base-         all AML population. This may be particularly
line organ dysfunction than are encountered in           true for newer targeted therapies.
younger individuals. New therapeutic approaches        • A focus on patients with highly resistant
should focus both on increasing remission rates          disease represents a particularly high hurdle
as well as on prolonging remission and enhanc-           for new therapies and treatments. Modest, but
ing the cure fraction of such patients. Many AML         nonetheless important, benefits which could
studies have focused on older patients because           be of value to other patient groups could be
of the large numbers of such patients available          missed by studying only patients in very poor
for studies as well as the feeling that the overall      prognostic groups.
results of therapy are so poor that it would be pos-
sible to identify truly active agents very rapidly       These problems are particularly relevant, be-
because differences with historical or randomised      cause there is no shortage of new agents which
controls would be obvious.                             could and should be evaluated in AML. In
144                                   TEXTBOOK OF CLINICAL TRIALS

addition to a continued supply of cytotoxic            on Phase II data alone which showed benefit in
drugs, there will be large numbers of anti-            patients with resistant disease and otherwise few
angiogenesis compounds, immune modulators,             therapeutic options.
signal transduction inhibitors (either with specific
or more generic enzymatic targets), as well as
                                                              STATISTICAL ISSUES IN DESIGN
new and less acutely toxic approaches to stem cell
                                                                     AND ANALYSIS
transplant. Many of the non-cytotoxic therapeutic
approaches also have the allure of oral treatment
with potentially much less toxicity.                   Because of the nature of AML and its treat-
   If an agent can be safely added to the              ment, several statistical issues in the design and
usual dose of conventional therapy, it might           analysis of clinical trials need special attention.
be most efficient to utilise the new therapy in         Four of these are discussed: factorial designs,
both induction and consolidation, thereby perhaps      outcome measures, competing risks and statisti-
maximising the chance to detect anti-leukaemic         cal modelling.
activity. Possible study designs for trials of new
post-remission therapies are shown in Table 9.1,                     FACTORIAL DESIGNS
where conventional therapy might refer to a
                                                       The treatment phases for AML are conventionally
few courses of low-dose ara-c which results in
                                                       divided into an initial phase of induction therapy
a median remission duration of approximately
                                                       and, for those achieving a complete remission
eight months and less than 10% long-term
                                                       during this phase, a post-remission or mainte-
disease-free survival.9 This is slightly better than
                                                       nance therapy phase. The post-remission phase
observation without treatment which produces
                                                       is sometimes further divided into earlier consol-
very few if any long-term disease-free survivors
                                                       idation therapy and later maintenance therapy,
and shorter CR durations. The choice among
                                                       but for our purposes here, two phases are suf-
the various randomised approaches might be
                                                       ficient. It is natural to design studies to compare
influenced by the unique features of the agent
                                                       therapies in each of these two phases, leading to
being tested. Also, given the very poor results
                                                       factorial designs, in which patients are randomly
observed with standard therapy, it could be
                                                       assigned to one of two or more induction thera-
argued that a straightforward Phase II trial in        pies (the first factor) and then to one of two or
which the new agent is evaluated alone could           more maintenance therapies (the second factor).
have merit, although the usual problems with           With two possible treatment assignments in each
historical controls and patient selection would be     phase, this is a 2 × 2 factorial design, a common
issues. However, a number of anti-cancer agents        and well-known statistical design. Much has been
have been approved by the FDA in recent years          written about this design applied in the clinical
under an accelerated approval mechanism, based         trials setting.16 The twist in the current situation is
                                                       that the second randomisation is applicable only
                                                       for patients who respond to the induction ther-
Table 9.1. Possible study designs evaluating new
agents in post-remission therapy
                                                       apy. As noted above, in the case of older AML
                                                       patients, only about 50% of all patients entered
Phase II studies                                       on study may respond and, thus, be eligible and
New agent alone                                        medically suitable for the second randomisation.
Randomised Phase III studies                              It is typical to separate the objectives of such
Observation vs. new agent                              studies into a comparison of induction regi-
Conventional vs. new agent                             mens with respect to response rates and, sep-
Conventional vs. conventional + new agent              arately, a comparison of maintenance regimens
Conventional followed by observation vs. new agent
New agent in both induction and consolidation          with respect to the length of remission, disease-
                                                       free survival or overall survival. For example,
                                         HAEMATOLOGIC CANCERS                                         145

CALGB 8923 was a randomised clinical trial               attention is focused on identifying activity of
of this type involving AML patients at least             an agent, no matter how small. Achievement of
60 years old.2,9 The induction phase involved a          a complete response is sine qua non for long-
randomisation between GM-CSF, a haematopoi-              term control of disease. However, the CR rate
etic growth factor, and placebo following initial        is a very imperfect surrogate for more mean-
chemotherapy. The hypothesis was that the GM-            ingful clinical outcome measures described
CSF would reduce infectious complications and            below, and has been defined differently by dif-
perhaps increase the response rate. Responding           ferent leukaemia treatment groups, and should
patients were to be randomised to receive one            never be used as a substitute for them, espe-
of two post-remission regimens, cytarabine alone         cially in Phase III clinical trials. The primary
or a combination of cytarabine and mitoxantrone.         role for the CR rate is as a measure of clinical
Overall, 388 participants were randomised to the         activity in Phase II trials.
induction therapies; 205 (53%) achieved a CR,          • Event-free survival (EFS) – this is the time
but only 169 (44%) were randomised in the post-          from the start of study until a failure to
remission phase.                                         respond, relapse (for those achieving a CR)
   One of the problems with the usual approach to        or death, whichever occurs first. This outcome
these designs is that there is no direct estimation      measure is a good measure of the overall
or testing of the four possible treatment poli-          control of disease from the start of therapy
cies implied in the design. The policies are             and combines the effects of induction and
defined by selecting one of two induction ther-           post-remission therapies. In a Phase III trial,
apies followed by one of two post-remission              all randomised patients contribute to any
therapies, if a response is obtained and the             analysis of EFS under the usual intent-to-
patient consents to continue. One paper deals            treat approach.18 Standard techniques for time-
directly with this issue, making efficient use of         to-event data (survival methods) are used in
data from all patients.17 There are also method-         design and analysis for EFS, and for the other
ologic issues about when the randomisation to            time-to-event endpoints defined next.19
the post-remission therapy should be done. For         • Disease-free [or relapse-free] survival (DFS) –
example, if both randomisations are done at the          this is a standard outcome measure in trials
time of study entry with a planned intent to             of adjuvant therapy for solid tumours, but in
treat analysis, then the inevitable (and antici-         AML trials, DFS refers to the survival time
pated) large patient drop-out can substantially          spent free of disease. Thus, DFS is applicable
complicate evaluation of the second therapeutic          only to patients who achieve a CR. It is defined
manoeuvre.                                               as the time from achieving a CR to relapse
                                                         or death, whichever occurs first. Since patients
            OUTCOME MEASURES                             who fail to achieve a CR are excluded, this
                                                         measure is unsuitable as an overall assessment
There are various choices for outcome measures           of therapy. However, it is useful for compar-
in clinical trials involving AML patients. The           ing two or more post-remission therapies as
primary ones are:                                        long as it is recognised that the distribution of
                                                         DFS is not representative of the result to be
• Response rate – the proportion of patients who         expected for all patients.
  achieve an initial clinical response to the induc-   • Length of remission (LR) – the length of
  tion therapy is referred to as the response rate.      remission is ordinarily defined as the time
  In older AML patients, as in all leukaemia             from achieving CR to the time of relapse, with
  patients, the critical category is the complete        deaths in remission counted as censored obser-
  response (CR) rate, although partial responses         vations. This measure suffers from the same
  are sometimes included in Phase II trials where        problems as DFS and, in addition, the usual
146                                  TEXTBOOK OF CLINICAL TRIALS

  Kaplan–Meier estimation is no longer valid          which treats other risks as independent censoring
  (see discussion below on competing risks).          mechanisms, are inherently flawed. One way to
• Overall survival (OS) – the time from the start     properly account for the dependence is through
  of study to death is an obviously critical out-     the use of the cumulative incidence curve, a
  come measure for any generally fatal disease        topic that has been extensively explored in recent
  like AML in older adults. It has the virtue of      years.23
  being unambiguously defined and captures a
  result of obvious significance. However, there                    STATISTICAL MODELS
  are often difficulties in interpretation, partic-
  ularly if multiple therapies are given, or if       Statistical models are heavily used in AML
  patients cross over to the alternative therapy      trials. The usual time-to-event measures (EFS,
  after relapse. Nevertheless, the importance of      DFS, OS) are often handled non-parametrically
  overall survival is so fundamental that it should   in the primary analysis (e.g., Kaplan–Meier
  always be analysed, even if it is not used as the   estimates, logrank tests, etc.), but the semi-
  primary outcome measure.                            parametric proportional hazards regression model
• Other outcome measures – there are some             is surely the most commonly used method to
  other measures occasionally used in AML             adjust for covariates in the analysis.19 In addition,
  studies, particularly measures of quality of life   because of the nature of AML, increasing interest
  (QOL).20 Some attempt to measure survival           is being focused on so-called cure models,
  or related time to event measures adjusted for      in which it is hypothesised that an unknown
  quality of life. For example, the Q-TWiST           fraction (c) of patients are cured (or at least
  method discounts survival time spent with an        will have long-term control of disease) and
  unacceptable level of adverse symptoms due          the rest (1 − c) are not.24 Interest then focuses
  to treatment.21 Such methods attempt to quan-       on estimating c, comparing the cure rates of
  tify the generally accepted notion that sim-        various treatments, identifying factors predictive
  ply prolonging survival is not a sufficient          of c, and identifying prognostic factors for the
  objective. Improved quality of life is equally      time-to-failure in the patients not cured. In
  important.                                          older patients with AML, this model has not
                                                      been used as much due to the obviously low
                                                      value of c, but it has been important in other
              COMPETING RISKS
For some purposes in designing and analysing tri-
als of therapy for older AML patients, it is infor-                       SUMMARY
mative to use the techniques of competing risks
analysis.22 That is, rather than using a composite
                                                      Acute myeloid leukaemia in the older patient
measure such as EFS, one can break this measure
                                                      is a common and important disease which is
into its constituent parts by considering the time
                                                      relatively resistant to current therapies. Careful
to each outcome separately. The term ‘compet-
                                                      consideration of the particular characteristics of
ing risks’ refers to various risks of failure, each
                                                      this disorder is required when designing clinical
competing with the others. This terminology orig-
                                                      trials. There will be a large number of compounds
inally arose in the context of analysing various
                                                      available for evaluation in upcoming years and
causes of death, but it is applicable more gener-
                                                      it is desirable that such studies be conducted
ally. The fundamental problem from a statistical
                                                      using the most efficient and informative designs
perspective is that the risks cannot be assumed
                                                      to rapidly identify therapies which lengthen
to be operating independently from each other.
                                                      survival and increase the fraction of patients who
Thus, methods which assume such independence,
                                                      are cured.
such as the Kaplan–Meier life table analysis,
                                         HAEMATOLOGIC CANCERS                                             147

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                                     P.-Y. LIU1 AND VERNON K. SONDAK2
                         Fred Hutchinson Cancer Research Centre, Seattle, WA 98109 1024, USA
                 University of Michigan Comprehensive Cancer Centre, Ann Arbor, MI 48109 0932, USA

                    INTRODUCTION                                        and death from melanoma. Clinically localised
                                                                        melanomas are grouped into three prognostic
Randomised Phase III clinical trials are the                            categories based on the thickness of the pri-
gold standard for medical decision making,                              mary tumour as measured by the pathologist
particularly in terms of adjuvant therapies where                       using a micrometer built into the microscope eye-
a modest incremental benefit is sought. However,                         piece (Breslow’s thickness). Melanomas less than
there is sometimes marked disagreement among                            1.0 mm in thickness have an overall excellent
clinicians in their interpretation of Phase III trial                   prognosis with relatively minimal intervention
results. Nowhere is this more evident than in                           and are considered ‘low-risk’ lesions. Melanomas
the arena of adjuvant therapy of resected ‘high-                        between 1.0 and 3.9 mm are considered to be
risk’ melanoma. In this chapter, we will review                         intermediate risk, while melanomas 4.0 mm or
the results of several key randomised trials and                        greater are considered ‘high-risk’ tumours. The
attempt to reconcile at times conflicting clinical                       presence of ulceration of the primary tumour
interpretations.                                                        increases the risk of metastasis and death within
                                                                        any given thickness category.1
                                                                           The thickness is highly predictive of the risk
                     BACKGROUND                                         of regional lymph node metastasis, with nodal
                                                                        involvement in <5% of melanomas that are
A basic familiarity with malignant melanoma is                          <1.0 mm versus >30% in melanomas ≥4.0 mm.
required in order to understand the statistical and                     Intermediate-thickness melanomas have an inter-
clinical issues presented herein.                                       mediate risk of nodal spread, on the order of 20%.
   The prognosis of localised cutaneous melanoma                        The prognostic significance of the presence of
is based on several well-defined factors. Patho-                         nodal metastasis far outweighs the significance of
logic analysis of the primary tumour can predict                        tumour thickness: a thin or intermediate-thickness
the likelihood of regional and distant metastasis                       melanoma with nodal metastases generally has

Textbook of Clinical Trials. Edited by D. Machin, S. Day and S. Green
 2004 John Wiley & Sons, Ltd ISBN: 0-471-98787-5
150                                  TEXTBOOK OF CLINICAL TRIALS

a worse prognosis than a thick melanoma with          from reactive nodes, but is still not able to identify
negative nodes. Once nodal metastasis has been        microscopic foci of melanoma in normal nodes.4
documented, the number of involved nodes is the       Currently, neither PET nor CT are routinely rec-
strongest predictor of subsequent outcome, along      ommended for clinical staging.
with the manner of detection of the metastasis.          For patients with low-risk melanomas, i.e.,
Melanoma in clinically enlarged nodes portends        those that are <1 mm in Breslow’s depth and
a worse prognosis than melanoma in clinically         have no evidence of ulceration or significant
normal nodes.1                                        regression, clinical staging by physical exami-
   The mainstay of treatment for localised or         nation is standard practice. Currently, surgical
regionally metastatic melanoma is surgery. Ade-       staging is used in the majority of patients with
quate wide excision of the primary tumour site        higher-risk lesions. For any patient with clinically
(generally taking a margin of 1 to 2 cm of nor-       evident nodal involvement, a complete therapeu-
mal skin around the visible edge of the melanoma      tic lymph node dissection is associated with cure
or biopsy scar) is highly efficacious in controlling   in about 20% to 40% of patients.
disease at the primary site.2,3
   Three main options are available for stag-              SURGICAL STAGING BY COMPLETE
ing regional nodes in patients with cutaneous            (ELECTIVE) LYMPH NODE DISSECTION
melanoma: clinical staging, surgical staging by
complete (elective) lymph node dissection, and        Elective removal of clinically normal regional
surgical staging by sentinel lymph node biopsy.       nodes identifies evidence of metastasis about 20%
                                                      of the time, and is clearly a more accurate deter-
              CLINICAL STAGING                        minant of nodal status than clinical staging. Ret-
                                                      rospective reviews suggested a survival advan-
Physical examination is the mainstay of clini-        tage for elective node dissection compared to
cal staging of the regional nodes. Any palpa-         clinical staging with subsequent therapeutic node
ble lymph nodes that are ≥1 cm in maximum             dissection at the time of nodal recurrence.5 To
diameter or very hard or fixed to adjacent struc-      date, however, no prospective study has demon-
tures must be considered highly suspicious for        strated an overall survival advantage for elective
metastatic involvement. Unfortunately, both the       node dissection.3,6 Although the lack of a demon-
specificity and sensitivity of physical examina-       strated benefit is not the same as the demonstra-
tion for detecting melanoma nodal metastases are      tion of no benefit, elective dissection of clinically
low. In muscular or obese patients, even rela-        normal nodes is not considered standard practice
tively large lymph node metastases can be missed      for cutaneous melanoma at the present time. It
on physical examination. Lymph nodes may be           is clear, however, that elective node dissection
enlarged after a biopsy procedure due to reactive     results in durable regional disease control in the
hyperplasia without containing metastasis. Most       vast majority of patients, and failures within the
importantly, metastatic involvement of normal-        dissected nodal basin are quite uncommon.
sized lymph nodes cannot be identified by phys-
ical examination.                                      SURGICAL STAGING BY SENTINEL LYMPH
   Radiologic studies–computed tomography (CT)                    NODE BIOPSY
and positron emission tomography (PET)–are also
available to clinically stage the regional nodes.     Sentinel lymph node biopsy is based on the
CT shares many of the deficiencies of physical         concept that lymphatic fluid from an area of
examination: enlarged nodes may not be malig-         skin drains specifically to an initial node or
nant, and normal-sized nodes harbouring metas-        nodes (‘sentinel nodes’) prior to disseminating
tases will be deemed normal. PET is more sensitive    to other nodes in the same or nearby basins.
than CT for differentiating melanoma-containing       Morton et al. described a reliable method for
                                               MELANOMA                                             151

identification and removal of the sentinel node        while others will relapse regardless of adjunc-
draining the site of a cutaneous melanoma.7 They      tive measures. Currently there are no predictive
showed conclusively that the pathologic status of     methods to distinguish one group of patients
the sentinel node accurately determines whether       from another, therefore it is necessary to treat
melanoma cells have metastasised to that spe-         all patients in hopes of gaining an incremental
cific lymph node basin.8 An important aspect           benefit for a select few. Hence, in addition to
of sentinel node biopsy is a detailed histologic      the overall level of efficacy, clinicians evaluate
examination of the sentinel lymph nodes. Gen-         toxicity, convenience, cost-effectiveness and the
erally, this examination is more thorough than        prospects of post-relapse salvage therapy when
is practical to perform on the larger number          deciding whether to employ adjuvant therapy.
of nodes obtained during elective node dissec-        Virtually all of these factors can be determined
tion. This more detailed pathologic analysis, com-    accurately only in randomised trials.
bined with the ability to identify sentinel nodes        In 1995, high-dose interferon-α2b (IFN-α2b)
that are outside the defined boundaries of a           was approved by the United States Food and
regional basin, makes sentinel node biopsy the        Drug Administration, based on the positive
most sensitive and specific test for nodal metas-      results of a single, randomised Phase III clinical
tasis currently available. The prognostic value of    trial, E1684. The FDA’s decision was considered
sentinel node status has been demonstrated in         controversial at the time. Subsequent randomised
multiple studies. In published multivariate anal-     trials involving the same basic interferon regimen
yses, histologic status of the sentinel nodes is      have not only failed to put this controversy to
the most powerful predictor of disease-specific        rest, but have in fact enhanced it.
survival.9 Overall, 5-year disease-specific sur-
vival is >80% for patients with negative sentinel
                                                      ADJUVANT INTERFERON CLINICAL TRIALS
nodes, compared to about 50% for patients with
one or more positive sentinel nodes. Importantly,
patients with positive sentinel nodes go on to                             E1684
elective complete lymph node dissection. Among        Eastern Cooperative Oncology Group (ECOG)
patients with negative sentinel nodes, only 4%        trial E1684, with 280 eligible patients with thick
or fewer ultimately experience a clinically evi-      primary (≥4.00 mm) or node-positive melanoma
dent relapse within the nodal basin. Thus, sentinel   who were randomly assigned after surgery to
node biopsy matches the excellent regional con-       observation or post-operative adjuvant treat-
trol achieved by elective node dissection while       ment with IFN-α2b for one year, demonstrated
subjecting fewer patients to the morbidity of the     statistically-significant improvements in relapse-
complete node dissection procedure.                   free and overall survival for patients randomised
                                                      to the interferon arm. IFN-α2b therapy increased
   ADJUVANT THERAPY FOR MELANOMA                      the median relapse-free survival by 9 months
                                                      (1.72 years for IFN-α2b patients versus 0.98 years
The development of effective adjuvant therapy         for observation patients) and produced a relative
has been a long-standing goal of melanoma             42% improvement in the 5-year relapse-free sur-
researchers, and the subject of over 100 ran-         vival rate (37% for IFN-α2b patients versus 26%
domised clinical trials involving a host of dif-      for observation patients). In addition, IFN-α2b
ferent agents.10 Adjuvant therapy is the systemic     therapy significantly increased median overall sur-
or regional administration of drugs or radiation      vival by 1 year (3.82 years for IFN-α2b patients
to patients after apparently successful surgery,      versus 2.78 years for observation patients) and
in an effort to minimise the risk of subsequent       produced a 24% relative improvement in the
recurrence. Although many patients are cured by       5-year overall survival rate (46% for IFN-α2b
surgery, some benefit from adjuvant treatment          patients versus 37% for observation patients).11
152                                   TEXTBOOK OF CLINICAL TRIALS

Side effects were common and frequently severe,                CLINICAL CONSIDERATIONS
but even when adjusted for time with toxicity, the
results favoured adjuvant IFN-α2b therapy.12
                                                             RELAPSE-FREE SURVIVAL VERSUS
                                                                  OVERALL SURVIVAL
                                                       It has been the authors’ experience that clinicians
A subsequent Intergroup adjuvant therapy trial,        tend to view clinical trial results as dichotomous,
E1690, also compared the high-dose IFN-α2b to          that is, ‘positive’ or ‘negative’. Moreover, par-
observation after complete resection of all known      ticularly for adjuvant therapy trials, the accep-
disease.13 This was a three-arm trial involving        tance of a clinical trial as ‘positive’ is often
608 eligible patients. The eligibility criteria were   restricted to trials demonstrating a statistically
the same as for E1684, except for the fact that        significant benefit in overall survival. From this
elective node dissection was not required for          perspective, there seems to be an obvious discrep-
patients entered onto E1690 with thick primary         ancy among the two observation-controlled trials:
melanomas and clinically negative nodes. Results       E1684 demonstrated seemingly striking benefits
of this trial confirmed the relapse-free survival       from the high-dose interferon regimen in both
advantage seen in E1684 but with no survival           relapse-free and overall survival, whereas E1690
advantage observed.                                    validated only the relapse-free survival benefit
                                                       with no survival difference. However, the impor-
                      E1694                            tance of relapse-free survival may be worth closer
                                                       examination in the current setting.
In light of the discordant survival results in            Statistically it is commonly known that, com-
E1684 and E1690, the initial results of another        pared to overall survival, disease relapse is a less
Intergroup trial, E1694, have received intense         objective endpoint because it depends on the def-
scrutiny. This trial compared one year of high-        inition of relapse as well as the frequency and
dose interferon not to an observation control          method of detection. Defining relapse is less of
as in the two earlier studies, but rather to two       an issue in the adjuvant setting since patients
years of a ganglioside vaccine called GMK.             enter the study with no detectable disease and
This was the largest of the three trials, with         thereafter any new disease found is considered
774 eligible patients between two study arms.          a relapse. In a well-conducted clinical trial the
For the first time, staging of the lymph nodes          interval and method of disease assessment are
by sentinel node biopsy was performed in a             specified in the protocol and generally complied
significant fraction of patients. Gangliosides are      with by trialists, thereby rendering relapse-free
carbohydrate antigens found on the surface of          survival a more reliable endpoint than in other
melanoma cells, as well as normal cells of neural      situations. From the purely clinical viewpoint,
crest origin and tumour cells of other types. A        patients have made clear that they are willing
pilot randomised trial suggested a relapse-free        to accept even toxic adjuvant therapies that pro-
survival benefit in patients who were treated           vide improvements in relapse-free survival, even
with purified ganglioside GM2 (the specific              if they do not result in any prolongation of over-
ganglioside in the GMK vaccine) plus BCG               all survival. This observation has been directly
compared to those treated with BCG alone.14 In         validated in melanoma patients,16 and represents
May 2000, the E1694 trial’s independent Data           the perception that time spent without signs or
Safety Monitoring Committee concluded that the         symptoms of recurrent cancer is inherently of
high-dose interferon arm was associated with           value even in the absence of prolongation of total
highly significantly improved relapse-free and          lifespan. In addition, relapse-free survival often
overall survival, and mandated that the study          represents a truer reflection of the biologic activ-
results be disclosed early.15                          ity of an adjuvant therapy since randomised trials
                                                 MELANOMA                                               153

rarely include rigorous controls on post-relapse        arm received subsequent interferon-α-containing
salvage therapy. The confounding effect of such         regimens (31% vs. 15%) and/or biochemotherapy
treatment on overall survival is unknown and            (17% vs. 6%).
not assessable.                                            While there is some evidence of differential
                                                        post-relapse treatment received, concluding that
RECONCILING THE STUDY RESULTS BASED                     the lack of interferon survival benefit observed
    ON CLINICAL CONSIDERATIONS                          in E1690 is due to these differences is not
                                                        justified. Making this conclusion presupposes
Two of the three randomised Phase III trials of         survival efficacy from these salvage therapies,
high-dose interferon, E1684 and E1690, demon-           which cannot be substantiated with currently
strate a relapse-free survival advantage. The third     available data. In addition, comparing outcomes
trial, E1694, also shows a relapse-free survival        by post-relapse treatment groups provides little
benefit but with GMK vaccine and not obser-              useful information because patients were not
vation as the control treatment. The implication        randomised to salvage treatment strategies upon
of this design difference is discussed in detail        relapse. As is inherent in observational data,
below. Nevertheless, many consider there is uni-        unknown patient selection factors cannot be
formity of evidence that high-dose interferon has       accounted for by analysis techniques and their
biologic activity in at least delaying relapse after    impact can easily remain even after adjusting
surgical therapy. This fact alone, combined with        for known prognostic factors. Therefore, although
the lack of proven alternatives, is enough for          available data appear compatible with the notion
many patients to choose interferon therapy in the       that initial observation after surgery followed by
absence of consensus regarding the overall sur-         high-dose interferon in case of resectable relapse
vival benefit.                                           presents an alternative strategy to routine use of
   Crossover to interferon therapy upon relapse         adjuvant high-dose interferon, this study offers
might have partially affected the outcome of at         no proof for the conjecture. The conservative
least one study. The original trial, E1684, was         conclusion is that salvage treatment difference
unlikely to have been affected by crossover for         is a possible confounding factor that limits the
two reasons. Surgical staging of the regional           confidence regarding the lack of overall survival
nodes by complete (elective or therapeutic) node        benefit of high-dose interferon from study E1690.
dissection was required. Hence, few patients
were likely to experience regional relapse or
other resectable recurrence, where secondary                   STATISTICAL CONSIDERATIONS
resection and delayed adjuvant interferon could
be employed. Most relapses occurred in non-             Although clinical factors clearly impact on the
resectable distant sites. In recent medical practice,   interpretation of the three trials, our main goal is
interferon is rarely employed for the treatment of      to examine the statistical aspects of these trials
measurable metastatic disease.                          to determine the extent to which they actually
   In contrast, the E1690 trial required only clin-     present ‘conflicting’ information. We focus first
ical staging of the regional nodes, and surgery         on E1684 and E1690.
was not required for patients with thick primary
tumours and clinically negative nodes. Among                STATISTICAL TESTS EMPLOYED AND
all relapsed patients (n = 114 in the high-dose                PRESENTATION OF RESULTS
interferon arm and n = 121 in the observation
control arm), 54% on high-dose interferon and           One source of confusion could be due to the fact
45% on observation experienced regional recur-          that one-sided p-values were presented for E1684
rence only. Retrospective data collection indi-         but two-sided p-values were presented for E1690.
cated more patients relapsing on the observation        Since all comparisons involved were one-sided
154                                   TEXTBOOK OF CLINICAL TRIALS

in nature (i.e., is high-dose interferon superior to   contributed to an exaggerated impression of the
observation after surgery), we use all one-sided       overall survival benefit from E1684.
p-values (p1 ) in this discussion. In addition,
all hazard ratios are expressed as observation                      TRIAL SIZE, OVERALL RESULTS
arm versus treatment arm ratios. Thus, a hazard                         AND OTHER ASPECTS
ratio >1 indicates an excess of hazard in the
observation arm, or treatment advantage.               To interpret the combined results E1684 and
   Another possible source of confusion could          E1690, it is useful to compare the study param-
be the fact that, in E1684, statistically signifi-      eters and overall results. Tables 10.1–10.3 are
cant p-values for relapse-free and overall sur-        extracted mainly from Ref. 13. Since there was
vival differences by the stratified logrank test        not a low-dose interferon arm in E1684, only
(adjusted for disease burden and presentation at       the high-dose interferon and observation arms of
initial diagnosis versus recurrent nodal disease       E1690 are included in the tables. Due to the
status) were reported (Table 2 of Ref. 11). But        limitations of data availability, all randomised
when Cox regression analysis was performed,            patients regardless of eligibility determination are
further adjusting for age, time from diagnosis to      presented for consistency.
randomisation and ulceration status of the pri-           The tables indicate that when E1690 results
mary tumour, a significant interferon over obser-       became available, the study had 50% more
vation benefit was presented only for those with        patients than E1684, reflecting wider participa-
nodal disease (Table 4 of Ref. 11). The haz-           tion from the US Melanoma Intergroup. The
ard ratio was 1.64 for relapse-free survival and       patient enrollment periods were non-overlapping.
                                                       Although the updated data for E1684 had longer
1.49 for overall survival with p1 = 0.01 in both
                                                       follow-up at the time of E1690 publication, more
cases. However, these hazard ratios (presented
in their reciprocals as interferon over observa-
tion ratios, 0.61 and 0.67, in actuality) were         Table 10.1. E1684 and E1690 study characteristics
labelled ‘Treatment with IFN’ without reference        Study                          E1684                  E1690∗
to the positive nodal disease subset. An interac-
tion term between the interferon treatment and         Participating               ECOG                ECOG, SWOG,
the thick primary, no nodal disease patient cat-         groups                                          CALGB,
egory was actually included in the Cox mod-            Patient accrual             1984–1990           1991–1995
els and the results were presented in the same           period
table with the label ‘CS1/PS1 + IFN’. The haz-         N (all                      286                 427
ard ratios were 0.36 and 0.34 respectively for           randomised)
relapse-free survival and overall survival. These      Median                      6.9                 4.3
interaction hazard ratios translated into observa-       (years)
tion over interferon hazard ratios of 0.60 and 0.50    Event count: RFS            197                 241
for relapse-free and overall survival in patients      Event count: OS             175                 190
with thick primary tumours and pathologically          ∗
                                                           High-dose interferon and observation arms only.
negative nodes, reflecting the occurrence that
interferon-treated patients fared worse than the
observation patients in this subset. For the readers   Table 10.2. E1684 and E1690 patient disease stage
who did not appreciate these details of the Cox
modelling, the hazard ratios for the nodal disease     Disease          T4      T1-4 N+ T1-4 N+     N+
subset could have been over-interpreted as the         stage            N0       (occult) (overt) Recurrent
Cox model treatment effects for the study as a
                                                       E1684           11%         12%            14%           63%
whole, which were not presented in the original        E1690           26%         11%            12%           50%
publication. Such misinterpretation might have
                                                           MELANOMA                                             155

Table 10.3. E1684 and E1690 results                             other) with a one-sided p-value of 0.0125 for
                                                                each comparison to maintain an overall one-sided
                   Hazard                                       type I error rate of 0.025 for the study. When
Study               ratio              95% CI      p-Value∗
                                                                the results were presented, however, one-sided p-
Relapse-free survival                                           values less than 0.025 were treated as statistically
E1684∗∗        1.43                 (1.08, 1.89)    0.002       significant for each comparison, representing a
E1690          1.28                 (1.0, 1.65)     0.03
                                                                study-wide, one-sided type I error rate of 0.05 or
Overall survival                                                a two-sided error rate of 0.10. Also, per design
E1684∗∗        1.32                 (0.98, 1.77)    0.03        the study was sized so that the power for each
E1690          1.0                  (0.75, 1.33)    0.50
                                                                individual comparison was 0.83. In other words,
    One-sided p-value by stratified logrank test.                the type II error rate for each comparison was
    Ref. 21.                                                    0.17 for an approximate study-wide type II error
                                                                rate of 0.34. Should the true magnitude of benefit
events were analysed for E1690 from the larger                  from both interferon regimens be the same, the
sample size and the fact that few events occurred               power to detect both effects in the same study
after 5 years. The main known patient char-                     was close to 0.66. With the inflated type I error
acteristic difference was in the distribution of                rate in the end, the overall power would increase
disease stage. There were more node-negative                    somewhat but would likely remain less than ade-
patients (26% vs. 11%) and fewer recurrent dis-                 quate for detecting reasonable effects from both
ease patients (63% vs. 50%) in E1690, repre-                    treatment arms. Hence, the question about the
senting a somewhat more favourable prognosis.                   low-dose interferon regimen’s treatment effect
It may be worth pointing out that, among those                  was essentially unanswered in this study, yet clin-
with nodal disease, there did not appear to be sur-             icians seem to have uniformly concluded that
vival differences between newly diagnosed and                   low-dose interferon is inactive in E1690.
recurrent disease patients. The more favourable
relapse and survival experiences of the obser-                           WHAT DOES E1694 TELL US?
vation patients in E1690 compared to those in
E1684 (5-year relapse-free survival of 35% vs.                  E1694 was designed to detect a GMK vaccine
26% and overall survival of 54% vs. 37%) remain                 benefit over interferon as the contemporary
largely unexplained by known factors. Regard-                   treatment standard. As is often practiced with
ing the treatment outcome, the magnitude of the                 superiority designs, the trial would be stopped
interferon benefit was smaller in E1690 than                     at planned interim analyses if the hypothesised
in E1684 for both relapse-free survival (hazard                 vaccine benefit could be definitively ruled out.
ratio 1.43 vs. 1.28) and overall survival (haz-                 This provision was incorporated in the study
ard ratio 1.32 vs. 1.00). The larger event counts               design in the following manner. Instead of
in E1690 resulted in narrower confidence inter-                  the typical, highly stringent interim p-value
vals. As offered by the authors as one plausible                requirements, the GMK vaccine needed only
conclusion,13 the combined evidence from these                  to be inferior to interferon at a fixed, one-
two trials seems to indicate that, for node posi-               sided p-value of 0.05 for relapse-free survival
tive and thick primary, node-negative melanoma                  in order to consider study termination at interim
patients, treatment of high-dose interferon pro-                analyses. Such evidence might not establish the
longs relapse-free survival. Survival benefit, if it             vaccine inferiority but would certainly rule out
exists, may be more limited.                                    its superiority.
   It is worth pointing out that E1690 was                         Considering the substantially more favourable
designed with not one but two primary compar-                   vaccine toxicity profile, a more appropriate trial
isons, comparing high-dose interferon and low-                  design might have sought to demonstrate the
dose interferon to observation (but not to each                 equivalence of the two agents in their efficacy
156                                  TEXTBOOK OF CLINICAL TRIALS

rather than the superiority of the vaccine. In fact   reconcile a trend in favour of antibody respon-
the Data and Safety Monitoring Committee in           ders with speculations of a deleterious effect of
this case seemed to have followed the equiva-         the vaccine resulting from production of ‘block-
lence principle and disclosed the study results       ing’ antibodies. However, it is known that effects
only when there was decisive evidence that the        of prognostic factors such as disease stage can
GMK vaccine was inferior to high-dose inter-          easily overwhelm any treatment effects.
feron in both relapse-free survival (p1 = 0.0015)
and overall survival (p1 = 0.009).15 Because no         DID ANY SUBSET OF PATIENTS BENEFIT
observation control arm was incorporated in the              MORE FROM INTERFERON?
study design, the clinical interpretation of E1694
in this respect is subject to debate. Obviously,      The predominant subcategories of high-risk
if it were known that the GMK vaccine had             melanoma patients are those having thick primary
some level of clinical efficacy, the finding that       tumours with clinically or pathologically nega-
high-dose interferon was significantly better in       tive nodes and those having documented involve-
both disease-free and overall survival would be       ment of the nodes. Among the node-positive
of great clinical significance and would substan-      patients, subsets include those with 1, 2 to 3 and
tiate the benefits identified in the initial E1684      ≥4 nodes; patients with clinically evident ver-
trial. Without this knowledge, some have main-        sus microscopic nodal involvement; and patients
tained the possibility of a deleterious vaccine       found to have nodal involvement at the time of
effect and insisted that the study cannot be used     initial presentation versus those developing recur-
to give information on the non-design comparison      rent disease in the nodes.
of interferon versus observation.                        The initial findings of E1684 indicated that the
   Unfortunately, no credible evidence exists that    subset of patients with thick primary tumours and
the GMK vaccine is either beneficial or delete-        pathologically negative nodes had no benefit, and
rious. It is likely that the GMK vaccine acted        perhaps even a detrimental effect, from adjuvant
essentially as placebo and the study provided         interferon.11 The veracity of this finding was
further validation that high-dose interferon was      called into question from the outset, because
efficacious over no treatment in both relapse-free     of the small number of node-negative patients
and overall survival. But we do not know this         (a total of 31 out of 280 eligible patients, or
for certain. As the dramatic survival difference      11%) and an imbalance in a major prognostic
between E1684 and E1690 observation patients          factor (ulceration of the primary tumour) biasing
amply illustrates,13 comparison of patient out-       the results in favour of the observation arm.
comes in the GMK vaccine arm to historical            In contrast, subset analysis of the results of
controls in the other two trials offers few clues     trial E1690 found that the relapse-free survival
to the efficacy of the vaccine.                        benefit for patients with thick primary tumours
   Data were presented that, among the vaccine-       and clinically negative nodes (making up 25% of
treated patients, those displaying antibody respon-   the eligible patient population) was identical to
ses had a trend towards favourable outcomes           that for the study population as a whole.13 Subset
Ref. 17. Even assuming that the analyses cor-         analysis of E1694 showed the greatest interferon
rected for the inherent responder versus non-         over vaccine benefit for the subset of thick, node-
responder bias,20 the results still cannot be used    negative patients.15
to establish a causal relationship between vaccine       Indeed, in each of the three clinical trials,
response and favourable outcome. As pointed out       subset analysis indicated a different group as
in numerous publications, response to treatment       obtaining the most benefit from high-dose inter-
could simply serve as a selection mechanism           feron: the subset with one single positive node
wherein responders represented a better progno-       in E1684; the subset with two to three positive
sis group. One may contend that it is difficult to     nodes in E1690; and the node-negative subset
                                                 MELANOMA                                                157

in E1694. The authors properly suggested that,          of a far more homogeneous patient population
taken together, there was no indication of prefer-      than any prior clinical trial, potentially enhancing
ential treatment effect in any one subset.15 These      the scientific validity. Of note, this group now
results exemplify the lack of reliability of sub-       constitutes by far the largest fraction of ‘high-
set results, a phenomenon previously discussed in       risk’ melanoma patients being seen and treated
regard to other melanoma clinical trials.18 With-       in the United States today, yet less than 10%
out appropriate study size for adequate power           of participants in the three prior trials combined
within subsets, and control for inflated type            were from this category. Unfortunately, this trial
errors stemming from multiple testing, post hoc         is likely to be small compared to the most recent
subset analyses suffer both high false-positive         Intergroup trials and, regardless of the results, it
and high false-negative rates.                          will not directly address the role of interferon in
                                                        all of the other high-risk categories.
                                                           It is now nearly 20 years since the design
                 CONCLUSIONS                            of clinical trial E1684, and 8 years since the
                                                        FDA’s approval of high-dose interferon-α for
Three randomised trials evaluating high-dose            the adjuvant therapy of high-risk melanoma, and
interferon, involving over 1600 patients, have          we may never fully know to what extent this
been conducted, yet its treatment benefit remains        toxic and inconvenient regimen improves overall
controversial. The combined evidence indicates          survival. The implications of that statement are
that, for high-risk melanoma patients, treatment        profound, and the burden they place on clinical
of high-dose interferon prolongs relapse-free           trialists is clear: design and analyse our trials
survival. Survival benefit is less certain. There        carefully to have the greatest probability of a
is no credible evidence to suggest that interferon      clear and unambiguous result.
exerts a differential effect in different subsets of
‘high-risk’ patients.
   There are many reasons why high-dose inter-
feron has not been uniformly embraced by physi-
cians and patients around the world, even though         1. Balch CM, Soong SJ, Gershenwald JE, et al. Pro-
it is the only adjuvant therapy yet shown to have           gnostic factors analysis of 17,600 melanoma
                                                            patients: validation of the American Joint Com-
any sustained impact on relapse-free survival.              mittee on Cancer melanoma staging system. J Clin
When the three trials are looked at in the light            Oncol (2001) 19: 3622–34.
of statistical principles, what seem to be glaring       2. Veronesi U, Cascinelli N. Narrow excision (1-
differences are more plausibly regarded as under-           cm margin): a safe procedure for thin cutaneous
standable variations reflecting trial design and             melanoma. Arch Surg (1991) 126: 438–41.
                                                         3. Balch CM, Soong S, Ross MI, et al. Long-term
analysis, combined with the fluctuations inher-              results of a multi-institutional randomized trial
ent in human clinical trials conducted over time            comparing prognostic factors and surgical results
in similar yet subtly different patient populations.        for intermediate thickness melanomas (1.0 to
   While it is easy to conclude that further                4.0 mm). Intergroup Melanoma Surgical Trial.
research is necessary to determine if high-dose             Ann Surg Oncol (2000) 7: 87–97.
                                                         4. Wagner JD, Schauwecker D, Davidson D, et al.
interferon α-2b improves overall survival, there is         Prospective study of fluorodeoxyglucose-positron
in fact little chance that definitive further research       emission tomography imaging of lymph node
will take place. Only one current clinical trial,           basins in melanoma patients undergoing sentinel
the Sunbelt Melanoma Trial, is comparing one                node biopsy. J Clin Oncol (1999) 17: 1508–15.
year of high-dose interferon to a control group.         5. Balch CM. The role of elective lymph node
                                                            dissection in melanoma: rationale, results, and
This study includes only patients with a single             controversies. J Clin Oncol (1988) 6: 163–72.
positive sentinel node identified at the time of          6. Cascinelli N, Morabito A, Santinami M, MacKie
initial presentation.19 As such, it is comprised            RM, Belli F. Immediate or delayed dissection
158                                       TEXTBOOK OF CLINICAL TRIALS

      of regional nodes in patients with melanoma of        14. Livingston PO, Wong GYC, Adluri S, et al. Im-
      the trunk: a randomised trial. WHO Melanoma               proved survival in stage III melanoma patients
      Programme. Lancet (1998) 351(9105): 793–6.                with GM2 antibodies: a randomized trial of
 7.   Morton D, Wen D, Wong J, et al. Technical details         adjuvant vaccination with GM2 ganglioside. J Clin
      of intraoperative lymphatic mapping for early             Oncol (1994) 12: 1036–44.
      stage melanoma. Arch Surg (1992) 127: 392–9.          15. Kirkwood JM, Ibrahim JG, Sosman JA, et al.
 8.   Morton DL, Thompson JF, Essner R, et al. Vali-            High-dose interferon alfa-2b significantly prolongs
      dation of the accuracy of intraoperative lymphatic        relapse-free and overall survival compared with
      mapping and sentinel lymphadenectomy for early-           the GM2-KLH/QS-21 vaccine in patients with
      stage melanoma: a multicenter trial. Multicen-            resected stage IIB–III melanoma: results of
      ter Selective Lymphadenectomy Trial Group. Ann            Intergroup trial E1694/S9512/C509801. J Clin
      Surg (1999) 230: 453–65.                                  Oncol (2001) 19: 2370–80.
 9.   Gershenwald JE, Thompson W, Mansfield PF,              16. Kilbridge KL, Weeks JC, Sober AJ, et al. Patient
      et al. Multi-institutional melanoma lymphatic             preferences for adjuvant interferon alfa-2b treat-
      mapping experience: the prognostic value of               ment. J Clin Oncol (2001) 19: 812–23.
      sentinel lymph node status in 612 stage I or          17. Kirkwood JM, Ibrahim J, Lawson DH, et al.
      II melanoma patients. J Clin Oncol (1999) 17:             High-dose interferon alfa-2b does not diminish
      976–83.                                                   antibody response to GM2 vaccination in
10.   Sondak VK, Wolfe JA. Adjuvant therapy for                 patients with resected melanoma: results of the
      melanoma. Curr Opin Oncol (1997) 9: 189–204.              multicenter Eastern Cooperative Oncology Group
11.   Kirkwood JM, Strawderman MH, Ernstoff MS,                 phase II trial E2696. J Clin Oncol (2001) 19:
      et al. Interferon alfa-2b adjuvant therapy of high-       1430–6.
      risk resected cutaneous melanoma: the Eastern         18. Sondak VK. Multi-institutional melanoma vac-
      Cooperative Oncology Group trial EST 1684. J              cine trial [Letter]. Ann Surg Oncol (1996) 3:
      Clin Oncol (1996) 14: 7–17.                               588–9.
12.   Cole BF, Gelber RD, Kirkwood JM, et al. Qua-          19. McMasters KM, Sondak VK, Lotze MT, Ross
      lity-of-life – adjusted survival analysis of inter-       MI. Recent advances in melanoma staging and
      feron alfa-2b adjuvant treatment of high-risk             therapy. Ann Surg Oncol (1999) 6: 467–75.
      resected cutaneous melanoma: an Eastern Cooper-       20. Anderson JR, Cain KC, Gelber RD. Analysis of
      ative Oncology Group study. J Clin Oncol (1996)           survival by tumor response. J Clin Oncol (1983)
      14: 2666–73.                                              1: 710–19.
13.   Kirkwood JM, Ibrahim JG, Sondak VK, et al.            21. Kirkwood JM, Manola J, Ibrahim J, et al. A pooled
      High- and low-dose interferon alfa-2b in high-risk        analysis of ECOG and Intergroup trials of adjuvant
      melanoma: first analysis of Intergroup trial E1690/        high-dose interferon for melanoma. Accepted for
      S9111/C9190. J Clin Oncol (2000) 18: 2444–54.             publication in Clinical Cancer Research (2004).
                                      Respiratory Cancers
                              JOAN H. SCHILLER1 AND KYUNGMANN KIM2
          Departments of 1 Medicine and 2 Biostatistics and Medical Informatics, University of Wisconsin,
                                            Madison, WI 53792, USA

                    INTRODUCTION                                        late 1970s, the incidence of lung cancer is still ris-
                                                                        ing because of long latency and a steady increase
Carcinoma of the lung and bronchus is estimated                         in smoking among the female population.
to account for almost 13% of all new cancer                                With the litigation and subsequent settlement
cases, but to be responsible for about 157 200                          between the tobacco industry and the state gov-
deaths in the United States in 2003.1 This                              ernments in the US, the marketing effort of the
represents more than 28% of all deaths due to                           US tobacco industry has shifted to the emerging
cancer, exceeding the number of deaths due to the                       markets in Asia and Eastern Europe. As a conse-
next four leading cancers, colon, breast, prostate                      quence, the smoking-related public health problem
and pancreas, all combined.                                             is predicted to pose a serious threat to the national
   The incidence of the disease continues to rise,                      security in a country such as China, in which smok-
particularly in women and blacks, and thus is likely                    ing has increased dramatically in recent years.
to present a significant public health problem for                          The best investment for prevention of smoking-
years to come. Cigarette smoking is attributed as                       related cancer incidence and death, as well as
the cause of 80% to 90% of lung cancer cases, with                      other diseases such as cardiovascular and other
the risk for lung cancer among smokers being 20                         pulmonary diseases, appears to be in smoking
to 30 times that among non-smokers. Other risk                          cessation and prevention of taking up the smok-
factors include exposure to asbestos and radon.                         ing habit among teenagers and females.
Asbestos exposure, known to cause malignant
mesothelioma, increases the risk for lung cancer,                                       CLASSIFICATIONS
especially among smokers. There are limited data
on molecular and genetic profile as a risk factor,                       Lung cancer consists of four major histological
and familial predisposition to lung cancer. Diet’s                      types: adenocarcinoma, squamous cell carcinoma,
role in lung cancer is even less obvious.                               large-cell carcinoma and small-cell carcinoma.
   Despite the significant reduction in smoking,                         Because of the unique biological features of small-
especially among the male population since the                          cell lung cancer (SCLC), its staging and treatment

Textbook of Clinical Trials. Edited by D. Machin, S. Day and S. Green
 2004 John Wiley & Sons, Ltd ISBN: 0-471-98787-5
160                                    TEXTBOOK OF CLINICAL TRIALS

differ radically from the other three types of lung         the TNM staging.2 It is this classification that
cancer, which are collectively called non-small-            forms the basis for management and treatment of
cell lung cancer (NSCLC).                                   patients with NSCLC.
   Besides histological classification, lung can-               A staging system entirely different from that
cer is also classified according to the Tumour,              for NSCLC is used for patients with small-cell
Node and Metastasis (TNM) staging and the                   carcinoma of the lung. Small-cell lung cancer
International Staging Classification. The TNM                is clinically categorised into two stages: limited
staging system is applied primarily to NSCLC                and extensive. Limited-stage SCLC is defined
and consists of three components, each accord-              as tumours confined to one hemithorax and its
ing to primary tumour (T), nodal involvement                regional lymph nodes that can be encompassed
(N) and distant metastasis (M) as summarised                in a tolerable irradiation field. Extensive-stage
in Table 11.1. The International Staging Classi-            SCLC is defined as any extent of disease beyond
fication summarised in Table 11.2 is based on                that classification.

Table 11.1. TNM staging

Primary tumour (T)
TX    Tumour proven by the presence of malignant cells in bronchopulmonary secretions but not visualised
        roentgenographically or bronchoscopically, or any tumour that cannot be assessed as in a retreatment
T0    No evidence of primary tumour
Tis   Carcinoma in situ
T1    A tumour that is 3.0 cm or less in greatest dimension, surrounded by lung or visceral pleura, and without
        evidence of invasion proximal to a lobar bronchus at bronchoscopy
T2    A tumour more than 3.0 cm in greatest dimension, or a tumour of any size that either invades the visceral
        pleura or has associated atelectasis or obstructive pneumonitis extending to the hilar region. At
        bronchoscopy, the proximal extent of demonstrable tumour must be within a lobar bronchus or at least
        2.0 cm distal to the carina. Any associated atelectasis or obstructive pneumonitis must involve less than
        an entire lung
T3    A tumour of any size with direct extension into the chest wall (including superior sulcus tumours),
        diaphragm, or the mediastinal pleura or pericardium without involving the heart, great vessels, trachea,
        oesophagus or vertebral body, or a tumour in the main bronchus within 2 cm of the carina without
        involving the carina
T4    A tumour of any size with invasion of the mediastinum or involving the heart, great vessels, trachea,
        oesophagus, vertebral body for carina or presence of malignant pleural effusion; a satellite nodule
        within the same lobe

Nodal involvement (N)
NX    Regional lymph nodes cannot be assessed
N0    No demonstrable metastasis to regional lymph nodes
N1    Metastasis to lymph nodes in the peribronchial or the ipsilateral hilar region, or both, including direct
N2    Metastasis to ipsilateral mediastinal lymph nodes and subcarinal lymph nodes
N3    Metastasis to contralateral mediastinal lymph nodes, contralateral hilar lymph nodes, ipsilateral or
        contralateral scalene or supraclavicular lymph nodes

Distant metastasis (M)
M0    No distant metastasis
M1    Distant metastasis, including pulmonary nodule not in the same lobe as the primary tumour
                                           RESPIRATORY CANCERS                                         161

Table 11.2. International Staging Classification for     First, it has a more rapid clinical course and
lung cancer                                             natural history, with the rapid development of
                                                        metastases, symptoms and eventually death. Left
                              Five-year survival (%)
                                                        untreated, the median survival time is typically
                              Clinical Pathological     12–15 weeks for patients with local disease and
Stage      TNM subset          stage      stage         6–9 weeks for those with advanced disease.
IA      T1, N0, M0              61          67          Second, it exhibits features of neuroendocrine
IB      T2, N0, M0              38          57          differentiation in many patients, which may
IIA     T1, N1, M0              34          55          be distinguishable histopathologically and is
IIB     T2, N1, M0; T3, N0,     24          39          associated with paraneoplastic syndromes. Third,
IIIA    T3, N1, M0; T1–3,        9          25          unlike NSCLC, SCLC is exquisitely sensitive to
          N2, M0                                        both chemotherapy and radiotherapy, although
IIIB    T4, any N, M0; any      13          23          resistant disease often develops.
          T, N3, M0                                        Due to sensitivity of patients with SCLC to
IV      Any T, any N, M1         1           –          chemotherapy, it can pose challenges in design
                                                        of clinical trials for drug development as will be
                                                        discussed in some detail.

In the year 2002, 1 284 900 new cases of invasive           CLINICAL TRIALS IN LUNG CANCER
cancer were expected in the United States,
excluding carcinoma in situ of any site except          Clinical trials have resulted in significant seminal
the urinary bladder and also excluding basal and        trials which have led to changes in the man-
squamous cell cancers of the skin. Lung cancer          agement of these patients. Those seminal studies
is estimated to account for 13% (169 400 cases)         in screening, chemoprevention and treatment are
of all new cancer cases, 14% (90 200) in males          outlined.
and 12% (79 200) in females.
   The annual age-adjusted incidence rate of lung           SCREENING AND EARLY DETECTION
cancer in the male population has been in a
steady decline since its peak in the early 1980s.       Three US randomised screening studies failed to
However, that in the female population appears          detect an impact of screening high-risk patients
to be still increasing, although the rate of increase   with chest radiographs or sputum cytology on
has slowed in the late 1990s.                           mortality, although earlier stage cancers were
                                                        detected in the screened groups.3 – 5 These studies
                   PROGNOSIS                            have been criticised for a number of potential
                                                        methodological and statistical problems, such as
Prognosis for patients diagnosed with lung cancer       over-diagnosis and analysing data by survival
is dismal, with less than 15% surviving longer          rather than mortality.6
than 5 years from the time of diagnosis, and it            Recently, several clinical studies have demon-
is highly dependent on stage of the disease as          strated that early stage lung cancers can be
indicated in Table 11.2.                                detected with the use of spiral CT that would
                                                        not have been detected by routine chest X-ray.7
       SALIENT FEATURES OF SMALL-CELL                   Spiral CT is a CT scan which does not evaluate
                LUNG CANCER                             the mediastinum and thus does not use contrast or
                                                        require the presence of a radiologist, employs low
Small-cell lung cancer, which makes up a quarter        doses of radiation and can be completed within
to a third of all lung cancer at diagnosis, differs     one patient ‘breath’. Because it can be done
from NSCLC in a number of important ways.               rapidly and does not require a radiologist to be
162                                   TEXTBOOK OF CLINICAL TRIALS

present, it is being used in some centres to screen    The selenium group had fewer total carcino-
for lung cancers in high-risk populations. How-        mas, including lung cancer with a relative risk
ever, it has not been determined whether there         of 0.54 and a 95% confidence interval of (0.30
is a survival benefit with this technique.6,7 Given     to 0.98) (p = 0.04).11 This has formed the basis
the availability of this scanning technique in the     for an intergroup chemoprevention trial which is
community, it is imperative that clinical trials be    now ongoing.
completed to determine if the early detection of
small tumours results in improved survival that
                                                            Stage II and ‘Non-Bulky’ IIIA Disease
is not a result of lead time or length bias.
                                                       Treatment of locally advanced NSCLC is one
       TREATMENT: NON-SMALL-CELL                       of the most controversial issues in the manage-
             LUNG CANCER                               ment of lung cancer. Treatment options include
Treatment of NSCLC is dependent primarily on           surgery for less-advanced disease, or radiother-
stage of disease at the time of diagnosis and stage,   apy, either of which has been given with or
in turn, is dependent upon the size of the tumour      without chemotherapy for control of micrometas-
(T), location of nodal involvement (N), if any, and    tases. Interpretation of the results of clinical tri-
presence or absence of distant metastases (M). The     als involving patients with locally advanced dis-
current TNM staging classification is shown in          ease has been clouded by a number of issues,
Table 11.1 and the stage grouping in Table 11.2.       including changing diagnostic techniques, differ-
                                                       ent staging systems and heterogeneous patient
                                                       populations that may have disease that ranges
                 Stage I Disease
                                                       from ‘non-bulky’ stage IIIA (clinical N1 nodes,
A lobectomy is the treatment of choice for stage I     with N2 nodes discovered only at the time of
NSCLC, with cure rates of 60–80% reported.             surgery or mediastinoscopy), to ‘bulky’ N2 nodes
Within stage I, patients with T2, N0 disease do        (enlarged adenopathy clearly visible on chest
not fare as well as those with T1, N0 cancers.         X-ray films, or multiple nodal level involvement),
In approximately 20% of patients with medical          to clearly inoperable stage IIIB disease.
contraindications to surgery but with adequate
pulmonary function, high-dose radiotherapy will        Post-operative Thoracic Radiotherapy: The
result in cure. No role of adjuvant chemotherapy       treatment for stage II and selected IIIA NSCLC
for stage I NSCLC has been identified.                  patients is surgical resection. However, many
                                                       of these patients will relapse, prompting numer-
Chemoprevention: Patients with a resected stage        ous trials evaluating the role of post-operative
I NSCLC are at high risk of approximately 1%           radiotherapy or chemotherapy. A meta-analysis
per year for the development of second lung            examining the role of post-operative radiother-
cancers, prompting a number of ongoing clini-          apy (PORT) found that patients randomised to
cal trials looking at the role of chemoprevention.     receive PORT actually had an inferior survival
Surprisingly, several randomised studies have          to those randomised to observation alone.12 In
demonstrated that the use of vitamin A or one          a meta-analysis of 2128 patients in nine clini-
of its derivatives at best, does not prevent lung      cal trials of post-operative radiotherapy, a 7%
cancer in smokers and at worst, may increase           survival decrement from radiation was identi-
the risk of developing it.8 – 10 Preliminary stud-     fied. However, this particular analysis included
ies have suggested that selenium may reduce the        a number of trials from the 1960s and 1970s
incidence of lung cancer and total cancer mortal-      when staging was highly inaccurate and relatively
ity. In a multi-centre, double-blind, randomised,      outmoded radiation therapy technologies were
placebo-controlled trial, 1312 patients were ran-      utilised. In addition, several of the trials included
domised to receive either selenium or placebo.         in this report aggressively treated patients with
                                          RESPIRATORY CANCERS                                          163

no evidence of nodal involvement or those with        trials. In the European trial, the median survival
early nodal involvement only, a group that by         time was 26 months for patients receiving pre-
today’s standards would not be subjected to post-     operative chemotherapy plus surgery, compared
operative radiation therapy. More recent studies      to 8 months for patients treated with surgery
looking at the role of PORT have concluded            alone.16 In the MD Anderson trial, the median
that PORT does not prolong survival, but does         survival of the 32 patients randomised to the
enhance local control. The most comprehensive         surgery-alone group was 11 months compared
randomised trial in this regard was performed         to 64 months in the 28 patients randomised to
by the Lung Cancer Study Group and it demon-          the combined-modality arm.17 Of note, how-
strated major improvement in intrathoracic dis-       ever, is the fact that updated results of the MD
ease control.13 For those patients receiving tho-     Anderson trial, while still statistically significant,
racic radiotherapy, the intrathoracic failure rate    showed a narrowing of the survival curves, with a
was only 3%, compared to 43% for patients not         median survival of 14 months and 21 months for
receiving post-operative radiotherapy, although       the surgery alone and combined modality arms,
no significant survival advantage was identified.       respectively.18
                                                         A larger trial has recently been reported.19
Adjuvant Chemotherapy: Given the propensity           Three hundred and fifty-five patients with stage I,
of these resected patients to relapse with distant    II or IIIA disease were randomised to three
disease, adjuvant post-operative chemotherapy         cycles of chemotherapy followed by surgery or
has been of significant interest. A meta-analysis      to surgery alone. Median survival (37 months
published in 1995 found a small improvement in        vs. 26 months) and 2-year survival (52% vs.
survival with post-operative adjuvant chemother-      59%) were not statistically different between
apy that borderlined on statistical significance       the two groups. However, a subset analysis in
(p = 0.08),14 leading some clinicians to conclude     which patients who died within 150 days of peri-
that adjuvant chemotherapy was of benefit. How-        operative problems were excluded revealed a
ever, a randomised intergroup study has been          0.77 reduction in risk which was statistically sig-
completed in which patients were randomised           nificant (p = 0.03). Other subset analysis looked
to receive either radiotherapy plus chemotherapy      at outcome by patient stage and found that
(cisplatin and etoposide for four cycles) or radio-   the patients with N0/N1 disease who received
therapy alone. The median and long-term survival      chemo/surgery had a hazard ratio of 0.68, com-
of the two arms was nearly identical.15 Once          pared to patients with N2 disease, where the haz-
again, the fact that the meta-analysis included       ard ratio was 1.04.
older studies, in which chemotherapy regimens,           Despite the results of the Depierre trial,
staging and other clinical characteristics were       many clinicians continue to use pre-operative
different, may account for this discrepancy.          chemotherapy for patients with stage IIIA dis-
Although the role of neoadjuvant chemotherapy         ease. An intergroup study evaluating chemo/RT
is under investigation, it cannot be routinely rec-   vs. chemo/RT surgery has recently been com-
ommended until the results of randomised clinical     pleted; these results are eagerly awaited.
trials confirm clinical benefit.
Pre-operative Chemotherapy plus Surgery:                          Locally Advanced ‘Bulky’
There have been two small randomised stud-                          Stage IIIA/IIIB Disease
ies involving surgery with or without pre-
operative chemotherapy which popularised this         The optimal treatment for bulky stage IIIA and
approach. Both involved 60 patients and both          stage IIIB disease is also controversial. Current
report response rates of 35–62% following induc-      investigational efforts are directed at identify-
tion chemotherapy. Both have also reported pro-       ing the optimal combined-modality approach,
longed survival, prompting early closure of both      involving treatments directed at local control
164                                   TEXTBOOK OF CLINICAL TRIALS

of the disease, i.e., surgery or radiotherapy,         combined with cisplatin, although there are clear
and micrometastatic disease, i.e., chemother-          differences in toxicity and cost.31,32
apy. Possibilities include radiotherapy only, pre-
operative chemotherapy, or chemotherapy plus                     Second-Line Chemotherapy
                                                       Docetaxel was recently approved for the second-
Chemotherapy plus Radiation Therapy: Chemo-
                                                       line treatment of NSCLC, based upon two
therapy plus radiotherapy is the treatment of
                                                       clinical trials. One trial compared two doses of
choice for patients with bulky or inopera-
                                                       docetaxel with best supportive care, and found an
ble stage III disease. Two randomised studies
                                                       improvement in median and long-term survival,
have demonstrated an improvement in median
                                                       despite a low response rate of 7%.33 The other
and long-term survival with chemotherapy fol-
                                                       trial compared docetaxel to either vinorelbine or
lowed by radiation therapy versus radiotherapy
                                                       ifosfamide (the treatment physician was allowed
alone.20,21 More recently, two randomised trials
                                                       to choose) and found an improvement in long-
have shown that concurrent chemoradiotherapy
                                                       term, although not median survival.34
results in prolonged survival, albeit at the expense
of enhanced toxicity, compared to sequential
treatment.22,23 Other active areas of investiga-                      ‘Targeted’ Therapy
tion include choice of chemotherapy, fractiona-
tion and treatment fields.                              Given the overall poor results with standard cyto-
   Recently, weekly, low-dose ‘sensitising’ che-       toxic therapies and the number of advances that
motherapy plus radiation therapy has become            have been made recently in our understanding
popular, primarily due to lower toxicities when        of the biology of cancer, a strong interest has
administered with radiotherapy than ‘standard’         emerged in targeting pathways unique to neo-
dose chemotherapy.24 However, this schedule has        plastic cells. One such example is the epidermal
never been looked at in a formal phase III setting,    growth factor receptor (EGFr), which has been
so its relative efficacy compared to standard dose      found to be expressed in the majority of patients
chemotherapy has not been rigorously assessed.         with lung cancer. Based upon two phase II tri-
                                                       als in previously treated NSCLC patients, in
                Stage IV Disease
                                                       which response rates of 10–20% were found,35,36
                                                       two phase III trials were initiated comparing
Several meta-analyses have demonstrated that           chemotherapy plus an EGFr inhibitor, ZD1839,
chemotherapy improves survival in patients with        with chemotherapy in untreated NSCLC. Some-
metastatic NSCLC (approximately 10% 1-year             what surprisingly, no benefit was observed in
survival untreated vs. 35–40% 1-year sur-              these trials.37,38 These unexpected findings have
vival with treatment),25,26 particularly if the        resulted in clinical researchers, statisticians and
chemotherapy is platin-based.14 In the past            the pharmaceutical industry re-aiming the princi-
10 years, numerous different cytotoxic drugs           ples of study design.
have become available for the treatment of
lung cancer patients. These include, among              TREATMENT: SMALL-CELL LUNG CANCER
others, vinorelbine, the taxanes (docetaxel and
paclitaxel), gemcitabine and the topoisomerase         Small-cell lung cancer differs from NSCLC in
I inhibitors (irinotecan and topotecan). Ran-          a number of important ways: (1) it has a more
domised studies have shown that these agents           rapid clinical course and natural history, with the
improve survival when combined with cisplatin,         rapid development of metastases, symptoms and
as compared to cisplatin alone,27,28 or the other      death; (2) it exhibits features of neuroendocrine
agent alone.29,30 However, there is probably lit-      differentiation in many patients which may
tle difference in outcome between agents when          be distinguishable histopathologically and is
                                        RESPIRATORY CANCERS                                        165

associated with paraneoplastic syndromes; and       phase II studies is only between 3% and 11%.
(3) unlike NSCLC, SCLC is exquisitely sensitive     Median survival is about 20 weeks.40 Results of a
to both chemotherapy and radiotherapy, although     randomised trial comparing topotecan with CAV
resistant disease often develops. Because of the    (cyclophosphamide, adriamycin and vincristine)
rapid development of distant disease and its        as second-line therapy revealed no difference in
extreme sensitivity to the cytotoxic effects of     response rates, duration of response, or survival
chemotherapy, this mode of therapy forms the        between the two groups.41
backbone of treatment for this disease.
                                                         Chemotherapy plus Chest Irradiation
               First-Line Therapy

A number of combination chemotherapeutic reg-       Numerous studies have been done with chemo-
imens are available for SCLC. With these            therapy and thoracic radiotherapy for patients
chemotherapy regimens, overall response rates of    with limited-stage SCLC. Conflicting results have
75–90% and complete response rates of 50%           been attributed to differences in chemother-
for localised disease can be anticipated. For       apy regimens and different schedules integrat-
extensive-stage disease, overall response rates     ing chemotherapy and thoracic radiation, con-
of about 75% with complete response rates of        current, sequential and ‘sandwich’ approaches.
25% are common. Despite these high response         Two recent meta-analyses concluded that thoracic
rates, however, the median survival time remains    radiation does result in a small but significant
about 14 months for limited-stage disease and       improvement in survival and major control of
7–9 months for extensive-stage disease. Less        the disease in the chest, although no conclusions
than 5% of extensive-stage patients have long-      could be made regarding the optimal sequencing
term survival of greater than 2 years.              of chemotherapy and thoracic radiation.25,42
   A phase III randomised trial has been reported
                                                    Fractionation of Radiotherapy: For limited-stage
in abstract form, in which patients with SCLC
                                                    SCLC, thoracic radiotherapy has been known
were randomised to the control arm of etoposide
                                                    to improve survival, but the best ways of inte-
and cisplatin, versus cisplatin and the topoiso-
                                                    grating chemotherapy and thoracic radiotherapy
merase I inhibitor, irinotecan.39 Median survival
                                                    are uncertain. In order to settle this question, a
and 1-year survival was 420 days and 60% in
                                                    phase III randomised clinical trial was conducted
the cisplatin/irinotecan arm and 300 days and
                                                    in which 417 patients with limited SCLC were
40% in the cisplatin/etoposide arm. If ongo-
ing phase III studies confirm these results, cis-    randomised to receive a total of 45 Gy of radio-
platin/irinotecan would become the first combi-      therapy, either twice-daily over a 3-week period or
nation of chemotherapy to improve survival over     once-daily over a 5-week period, concurrently with
cisplatin/etoposide in SCLC patients in decades.    four 21-day cycles of cisplatin plus etoposide.43
                                                    Twice-daily radiotherapy improved median sur-
                                                    vival as compared with once-daily radiotherapy
             Second-Line Therapy
                                                    (23 months vs. 19 months, p = 0.04). However,
No curative regimens for patients with recur-       grade 3 or 4 oesophagitis was significantly more
rent disease have been identified. Topotecan has     frequent with twice-daily than with once-daily
a 20–40% response rate in patients with ‘sen-       fractionation (32% vs. 16%, p < 0.001).
sitive’ SCLC, those patients who relapsed two
or more months after their first-line therapy,               Prophylactic Cranial Irradiation
with a median survival of 22–27 weeks. For
patients with ‘refractory’ disease which pro-       Numerous trials have demonstrated that prophy-
gressed through or within 3 months of comple-       lactic brain irradiation (PCI) does not enhance
tion of first-line therapy, the response rate in     survival, but does decrease the risk of brain
166                                  TEXTBOOK OF CLINICAL TRIALS

metastases without a decrease in mental func-         standard methods have been proposed.49,50 These
tion.44 However, a recent meta-analysis demon-        methods typically include initial dose-escalation
strated a small but statistically and clinically      in a single patient and a later switch-over to
significant improvement in survival with PCI.45        standard dose-escalation at the earliest indication
                                                      of dose-limiting toxicity, and may also include
                                                      intra-patient dose-escalation.50
          METHODOLOGIC ISSUES                            In order to address the failure of the standard
                                                      dose-escalation designs to provide an estimate
With the traditional cytoreductive and cytotoxic      of the probability of toxicity at the recom-
chemotherapy, both as single agents and in com-       mended dose level, several new approaches
bination, there are well-established and accepted     have been proposed, including the continual
designs for phases I, II and III clinical tri-        reassessment method.51 This method is primar-
als. In general these designs are based on the        ily based on Bayesian statistical modelling of the
paradigm that with the increased myelosuppres-        dose–toxicity relationship with a targeted toxicity
sion, tumour cells are more likely to be killed,      probability for the MTD. With radiotherapy con-
leading to shrinkage of tumours, and that there       cerned with late-onset toxicities as the primary
is a monotonically increasing dose–response and       endpoint, the standard dose-escalation design for
dose–toxicity relationship. It is also assumed that   phase I clinical trials is inadequate because of the
tumour shrinkage will eventually lead to clinical     long-term follow-up required for late-onset toxic-
benefit such as prolonged survival or improved         ities associated with radiotherapy. With late-onset
quality of life. In essence, tumour shrinkage has     toxicities, the continual reassessment method has
served as a surrogate for clinical benefit.            been extended by statistical models for the distri-
                                                      bution for time to toxicity and by pooling toxicity
                                                      information across patients receiving the same
                                                      dose level.52
In typical phase I clinical trials with acute dose-
                                                                 PHASE II CLINICAL TRIALS
limiting toxicities as the primary endpoint, a
standard dose-escalation scheme with a cohort         In phase II clinical trials with cytotoxic chemo-
of fixed number of patients treated at each dose       therapy, multi-stage designs with objective tumour
level is used to estimate the so-called maximum       response defined as shrinkage of tumour by more
tolerated dose (MTD) or safe dose46,47 to be          than 50% as the primary endpoint are widely
used in subsequent phase II studies. However,         used.53 – 55 These are essentially sequential designs
the choice of the initial dose and dose levels        in the sense that a decision to treat additional
have been rather ad hoc. Worse yet, the standard      patients for establishment of clinical efficacy is
dose-escalation design does not provide a well-       predicated by the observed clinical efficacy or
defined basis for estimation of the MTD and            safety with the patients from the previous stages.
is known to have several shortcomings such            This is primarily to avoid treating patients with
as slow dose escalation at the beginning and          seemingly ineffective therapy.
underestimation of the targeted dose-limiting            Typically these designs are based on tests
toxicity.48 Most critically, the standard design      of statistical hypotheses with specific minimally
does not provide an estimate of the probability       acceptable and maximally unacceptable tumour
of toxicity at the recommended dose level.            response rates associated with type I and II
Nevertheless this standard dose-escalation design     error probabilities. Given these design parame-
for phase I clinical trials has served a useful       ters available from historical data, there are many
function in this setting.                             candidate designs. In order to select a design,
   In order to avoid slow dose-escalation and         one may use either the minimax or the opti-
underestimation, a number of variations on the        mality criterion.56 Subject to type I and II error
                                           RESPIRATORY CANCERS                                           167

probabilities, the minimax designs minimised the        considered simultaneously in a parametric mix-
maximum sample size required, while the opti-           ture model.
mal designs minimised the expected sample size
under the null hypothesis that the true response
                                                                 SMALL-CELL LUNG CANCER
rate is less than or equal to the maximally
unacceptable response rate. Oftentimes they are
                                                        As was noted earlier, small-cell lung cancer is
very disparate, causing confusions to those not
                                                        known to be biologically distinct from other his-
so statistically sophisticated. A graphical search
                                                        tologic subtypes of lung cancer in both laboratory
method may be used to search for what appears
                                                        and clinical studies. It is the most chemosensitive
to be a compromise between the minimax and
                                                        type of lung cancer and as a consequence it poses
the optimal designs with more desirable practi-
                                                        some difficulties in development of investiga-
cal features such as having much smaller max-
                                                        tional cytotoxic drugs. For example, there is eth-
imum sample size than the optimal design and
                                                        ical concern for testing investigational cytotoxic
much smaller expected sample size than the min-
                                                        drugs in previously untreated small-cell lung can-
imax design.57
                                                        cer patients.
                                                           As a result of these observations, it has
          PHASE III CLINICAL TRIALS                     been suggested that different phase II designs
                                                        be used depending on whether patients had
Overall survival typically being the ultimate           been previously treated with cytotoxic drugs or
criterion for evaluation of the efficacy of cancer       have relapsed following treatment with cytotoxic
treatment in phase III clinical trials, a traditional   drugs.63 Also depending on whether patients are
randomised, controlled design with time to death        refractory to or have relapsed during previous
due to all causes as the primary endpoint has           treatment, different values for minimally accept-
become recognised as a golden standard for              able and maximally unacceptable response rates
establishment of standard therapies in cancer.          should be used in phase II clinical trials. Different
However, depending on the disease setting, other        considerations should be given to elderly patients
endpoints such as time to disease progression,          or patients with poor prognosis as well.
time to treatment failure, etc. may be appropriate
as a surrogate endpoint despite the problems
associated with the surrogate endpoint.58                 TARGETED THERAPY AND CYTOSTATIC
   It has been argued that the traditional way of                      DRUGS
moving to phase III trials based on the results
of phase II trials perhaps was the cause of fail-       Advances in molecular biology and cancer genet-
ure of many experimental therapies including the        ics coupled with biotechnology are bringing forth
recent failure of experimental therapies including      a number of new novel agents which appear
novel targeted therapies such as matrix metallo-        to target molecular pathways such as cancer
proteinase inhibitors and epidermal growth factor       initiation, angiogenesis, invasion or metastasis.
receptor inhibitors.59 One approach is to com-          Examples include antiangiogenesis agents, epi-
bine phase II and III trials into two-stage designs     dermal growth factor receptor inhibitors, pro-
involving selection and testing based on accept-        tein kinase inhibitors, matrix metalloproteinase
able primary endpoints or in combination with           inhibitors and other so-called molecular targeted
auxiliary endpoints for phase III trials.60,61 A        therapies. These new agents are not expected
sequential Bayesian phase II/III design has been        to shrink tumours. Instead they are expected to
proposed for a non-small-cell lung cancer involv-       inhibit tumour growth or prevent metastasis as
ing an adjuvant adenovirus for p53.62 In this           they have demonstrated in a number of animal
Bayesian design, local control of unresectable          models. With the emergence of these different
stage II or III NSCLC and overall survival are          classes of agents with entirely different mode of
168                                    TEXTBOOK OF CLINICAL TRIALS

action and expected therapeutic effects, the tradi-                          REFERENCES
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Textbook of Clinical Trials. Edited by D. Machin, S. Day and S. Green
 2004 John Wiley & Sons, Ltd ISBN: 0-471-98787-5
                      National Heart, Lung, and Blood Institute, Bethesda, MD 20892 2482, USA

                    INTRODUCTION                                        public benefits, particularly if the treatment is
                                                                        simple and inexpensive, such as aspirin. Again
Most of the principles in developing, managing                          because the condition is common, when there are
and analysing clinical trials in cardiovascular                         potential treatments that are simple to administer,
diseases are the same as for other conditions.                          trials may be conducted in communities outside
There are some special aspects, however, that we                        of academic health centres, with their special
will review here, and then provide examples for                         expertise and facilities.
in the subsequent sections.                                                Another important consideration is that athero-
   A major point that influences many of the clini-                      sclerotic and hypertensive cardiovascular dis-
cal trials is that in developed countries, and unfor-                   eases are chronic conditions, often taking decades
tunately more and more in developing nations,                           to develop and lasting many years after being
cardiovascular disease is common. Atherosclero-                         first diagnosed. Clinical trials, therefore, may be
sis and hypertension are the primary causes of                          initiated well before the development of risk fac-
cardiovascular disease in adults, although there                        tors (sometimes called primordial prevention),
are many contributing factors to these (often                           after the development of risk factors, but before
termed risk factors). Although clinical trials have                     the occurrence of organ damage (primary pre-
been conducted in other causes of cardiovas-                            vention), or after organ damage has occurred
cular disease, including congenital conditions,                         (secondary prevention). Some interventions are
there are far fewer trials in these areas. There-                       potentially useful in all three settings, but others,
fore, because in developed countries most heart                         particularly expensive or invasive approaches,
disease, stroke and peripheral vascular diseases                        may be best suited for secondary prevention.
are due to atherosclerosis and hypertension, and                        The relative importance of risk factors and clin-
because most of the cardiovascular disease clini-                       ical findings may also differ, affecting the likely
cal trials have been conducted in developed coun-                       impact of the interventions. After a heart attack,
tries, this chapter will emphasise those.                               for example, how well the surviving myocardium
   Because cardiovascular diseases are common,                          functions in pumping blood may be more impor-
small treatment benefits may yield important                             tant in determining longevity than cholesterol

Textbook of Clinical Trials. Edited by D. Machin, S. Day and S. Green
 2004 John Wiley & Sons, Ltd ISBN: 0-471-98787-5
176                                    TEXTBOOK OF CLINICAL TRIALS

level (though the latter has been clearly shown         the body, such as the kidneys or the legs (as
to affect recurrent infarctions and death). Often,      in intermittent claudication), may be affected.
treatments for atherosclerotic or hypertensive car-     Even within a single organ such as the heart,
diovascular diseases do not cure the underlying         the presentation of cardiovascular disease may
conditions. Rather, they may reduce the likeli-         take various forms, such as angina pectoris,
hood of having clinical sequelae or control the         myocardial infarction, cardiac arrhythmias of
serious consequences of disease.                        different sorts, heart failure and sudden death.
   As noted, the common causes of cardiovas-            The interventions studied in clinical trials may
cular diseases (atherosclerosis and hypertension)       be directed at any of those, though some
are multifactorial in origin. Atherosclerosis may       interventions, such as blood pressure lowering
be influenced by cholesterol level, blood pres-          drugs, may affect more than one outcome.
sure, cigarette smoking, obesity, physical activ-          One issue in designing and interpreting the
ity, inflammatory processes, diabetes, age and           results of cardiovascular disease trials is choice of
genetics, plus other factors. Hypertension may be       the outcome. As noted, interventions may affect
influenced by things such as diet (intake of salt        only one aspect of the disease. Therefore, inves-
and various nutrients), obesity, physical activ-        tigators would prefer to use as the outcome of
ity, stress or emotion, and genetics. With regard       interest only that most likely to be modified by
to genetic influences, it is not thought that the        the treatment. But for outcomes such as cause-
common cardiovascular diseases or their risk fac-       specific mortality, that is not easy. Even a rather
tors are influenced by single genes. Rather, there       broad outcome such as death due to cardiovascu-
are likely to be many genes that interact with          lar disease has limitations, because many deaths
environmental conditions to effect most common          are unwitnessed and autopsies much less common
cardiovascular diseases. Because of the multiple        than in the past. When finer splits are used, such
risk factors, clinical trial interventions that alter   as death due to arrhythmia or myocardial infarc-
individual factors might yield only modest reduc-       tion, the difficulties mount.2 Similar problems
tions in clinical outcomes such as myocardial           exist for non-fatal events, such as myocardial
infarction or death from cardiovascular causes.         infarction. In the Framingham Heart Study, more
Antihypertensive drugs, though, that lower blood        than 25% of myocardial infarctions were ‘silent’,
pressure regardless of the reason for the hyper-        that is, occurred without symptoms and were only
tension, have been shown to give impressive             recognised on electrocardiographic examination.3
reductions in stroke,1 much of which is due to          Extra efforts need to be made to identify these,
hypertension. On the other hand, treating hyper-        as they convey considerable risk of death, even
tension has led to only modest reductions in heart      though they are asymptomatic.
disease, probably because the other risk factors           Because many of the cardiovascular disease
for heart disease were unchanged. The multifac-         conditions are common, there is rarely a short-
torial nature of much cardiovascular disease has        age of people with the condition of interest
led some to design trials that have attempted to        for most clinical trials. Particularly with mul-
intervene on several factors simultaneously.            ticentre, in fact, multinational, trials, there are
   Whether as part of a clinical trial, or because      adequate numbers of potential participants so
of usual clinical care, many participants in car-       that studies using clinical outcomes are feasi-
diovascular disease clinical trials are on multi-       ble. It is usually not necessary to resort to trials
ple interventions. This can affect adherence to         with surrogate endpoints on account of partici-
study protocol and may lead to various drug             pant unavailability. However, when a trial seeks
interactions.                                           special subtypes of cardiovascular disease, sub-
   We typically think of cardiovascular disease as      ject availability becomes more of an issue. It is
affecting the heart, as in coronary heart disease,      still usually unnecessary to conduct trials with
or the brain, as in stroke, but other parts of          surrogate endpoints, but extra efforts do have
                                              CARDIOVASCULAR                                           177

to be made to identify and enroll the partic-              TRIALS OF PHARMACOLOGIC AGENTS
ipants. Connected with this, many physicians
sub-specialise in particular types of cardiovas-        Pharmaceutical agents are the most common
cular disease. Involving the kind of physician          interventions tested in clinical trials of cardio-
most likely to have knowledge of and access             vascular disease. Most trials of drugs are sim-
to the relevant patient population is therefore         ilar in structure and design to trials in any
essential.4                                             other field of medicine. A few points, how-
   The large size of many cardiovascular                ever, should be made. Because, as noted above,
clinical trials means that stratification to ensure      most cardiovascular disease takes decades to
balance among key baseline factors is usually           develop, there is a long period when people
unnecessary, with the notable exception of site,        have few if any symptoms. The likely exis-
in multicentre trials. Site is almost always a          tence of atherosclerosis, for example, is usu-
stratification variable. Beyond that, investigators      ally determined by the presence of risk factors,
should stratify on at most a very few variables.        such as hypertension, hyperlipidaemia or fam-
For example, for studies of heart failure, we           ily history, advanced age in people who have
often stratify by left ventricular ejection fraction;   the typical lifestyle of most Western countries,
for studies of arrhythmia, we might stratify by         and the use of sophisticated imaging methods.
type of arrhythmia and ejection fraction; for           Prevention of the sequelae of atherosclerosis is
primary prevention trials, we might stratify by         therefore quite feasible. Because participants in
age and sex; and for trials of blood pressure           trials of primary prevention are asymptomatic,
lowering, we would stratify by prior use of             several principles apply. First, serious or trou-
antihypertensive drugs.                                 blesome adverse events due to interventions in
   One feature of trials in cardiovascular dis-         people who are generally healthy are unaccept-
ease that always needs to be considered is the          able and not tolerated by the participants. There-
dramatic reduction in mortality from heart dis-         fore, only drugs that are well-characterised (and
ease and stroke over the past few decades in            are presumably safe and well-tolerated) are gen-
most developed countries.5 As a result of a             erally studied in prevention trials. Second, the
combination of improved prevention and much             rate of clinical events is likely to be low. Unless
better medical care, death rates in developed           the trials use surrogate outcomes, they need to
countries have decreased to a level that makes          be very large (thousands and sometimes tens of
mortality outcome studies less feasible. From a         thousands of participants) and long (often five
public health and a patient standpoint, this is         years or more). Third, people who are asymp-
certainly a happy state to be in, but it means          tomatic and consequently notice no obvious ben-
that clinical trials must be designed with the          efit from treatment may have trouble adhering to
expectation that the event rates may be consider-       the regimen, especially in a long trial. Therefore,
ably less than expected. The trials need either         a considerable ‘drop-out’ rate must be built into
to be much larger, or else the outcome needs            the sample estimate, increasing the size of the
to be a combination of death and other clini-           trial even more.
cal events.                                                Among the first large clinical trials in car-
   The remainder of this chapter will consider          diovascular disease were trials of lipid lower-
issues in specific trials. It is divided into trials     ing. The Coronary Drug Project, which began
of drugs or biologics, trials of devices and            in the 1960s, tested five interventions (clofibrate,
surgical procedures, and trials of lifestyle or         nicotinic acid, dextrothyroxine, and two doses of
other non-pharmacologic interventions. For fuller       equine estrogen) against a placebo in men with a
discussions of various cardiovascular disease           history of a myocardial infarction.7,8 These early
clinical trials, see the book, Clinical Trials in       efforts at lipid modification were only modestly
Cardiovascular Disease.6                                successful. The interventions had major adverse
178                                   TEXTBOOK OF CLINICAL TRIALS

events and three were stopped before the sched-        reductions in all-cause mortality and in coronary
uled end of the trial. In addition to the adverse      heart disease events.
events, the amount of lipid lowering was rela-            The 4S trial compared simvastatin against
tively small, in general, so the lack of improve-      placebo in 4444 participants with known coro-
ment in mortality, the primary outcome, was            nary heart disease and elevated serum cholesterol.
perhaps not surprising. Nicotinic acid was shown       The intervention lowered low-density lipoprotein
to reduce non-fatal reinfarction, however, and         cholesterol by 35% and mortality by 30%.11 The
post-trial follow-up disclosed a significant reduc-     CARE trial compared pravastatin against placebo
tion in mortality.9 A key finding in the Coronary       in 4159 post-myocardial infarction patients. The
Drug Project was that the mortality rate in the        baseline serum cholesterol level was somewhat
control group was only two-thirds of that pre-         lower in this trial than in the 4S trial. As in
dicted when the study was started. This proba-         4S, there was greater than a 30% reduction in
bly reflected selection of better risk participants,    low-density lipoprotein cholesterol and a 24%
but improved care may also have played a role.         relative benefit in the primary outcome of coro-
This phenomenon is one that many cardiovas-            nary heart disease death plus non-fatal myocar-
cular trials conducted since the Coronary Drug         dial infarction.12 The MRC/BHF Heart Protection
Project have had to take into account in the sam-      Study extended these finding to those who had
ple size estimates.                                    coronary heart disease or were otherwise at high
   The next large lipid-lowering trial was the         risk, regardless of the baseline cholesterol level.13
Lipid Research Clinics Coronary Primary Preven-           As a result of these and other trials of choles-
                                                       terol lowering and trials of blood pressure reduc-
tion Trial.10 This trial compared cholestryramine
                                                       tion, new evidence-based guidelines for treatment
resin versus placebo to see if there would be a dif-
                                                       of risk factors such as hyperlipidaemia and hyper-
ference in the primary outcome of coronary heart
                                                       tension have been developed and widely dissem-
disease death or non-fatal myocardial infarction
                                                       inated. Therefore, regardless of whether the trial
in 3806 men free of prior evidence of heart
                                                       is one of primary prevention or in people with
disease, but with hyperlipoproteinaemia. There
                                                       known end-organ damage, the control group must
were 155 events in the intervention group and          be adequately treated. This means that the event
187 in the placebo group (one-sided p < 0.05).         rate in the control group will be less than it has
This study was one of the first to show bene-           been in past years, making it even more difficult
fits from lipid lowering, even though some ques-        to detect benefit from a new intervention.
tioned the significance of the results, given the          An example of a recent trial designed to mimic
one-sided test.                                        clinical practice illustrates some of these issues.
   More definitive outcomes from cholesterol            The Antihypertensive and Lipid-Lowering Treat-
lowering had to wait for the development of            ment to Prevent Heart Attack Trial, or ALLHAT,
agents that were more effective in lowering            compared treatment, in a blinded fashion, begin-
lipids and, importantly, better tolerated. The clin-   ning with three different antihypertensive agents
ical trials of hydroxymethylglutaryl coenzyme A        against the control, which was thiazide diuretic
(HMG-CoA) reductase inhibitors (‘statins’) were        treatment, in more than 40 000 people aged 55
primarily conducted in the 1990s. Trials such          or over who had hypertension and at least one
as the Scandinavian Simvastatin Survival Study         other risk factor. Thus, the hypertension compo-
(4S),11 the Cholesterol and Recurrent Events           nent of ALLHAT used an ‘active control’ arm.
(CARE) trial12 and the MRC/BHF Heart Pro-              The primary outcome of this component was
tection Study13 have clearly demonstrated that         fatal coronary heart disease or non-fatal myocar-
cholesterol lowering in both people with known         dial infarction. ALLHAT also included a lipid-
heart disease and in those at high risk, but with-     lowering agent in over 10 000 of the enrolled
out evidence of heart disease, leads to impressive     participants in a factorial design. The primary
                                             CARDIOVASCULAR                                            179

outcome for the lipid component was all-cause             Rates of death in people who have had a
mortality; this part of ALLHAT was an open, or         myocardial infarction used to be quite high. Mod-
non-blinded study.14 – 16                              ern therapy has reduced those rates remarkably.
   One of the antihypertensive agents, an alpha-       Thus, trials using mortality alone as an end-
adrenergic blocker, was stopped early because          point may no longer be feasible even in sur-
although there was little difference in the primary    vivors of a heart attack, unless a very high
outcome, there was a significant increase in            risk group is studied. This has led to increased
heart failure in the alpha-adrenergic blocker arm,     use of combination endpoints, such as car-
compared with the diuretic arm. The other two          diovascular mortality plus non-fatal myocardial
antihypertensive treatments, a calcium channel         infarction. The Heart Outcomes Prevention Eval-
blocker and an angiotensin-converting enzyme           uation (HOPE) study compared the angiotensin-
inhibitor, continued to the scheduled end of the       converting enzyme inhibitor ramipril against
trial. There were no differences between either        placebo in 9297 people with either known vas-
of these arms and the active control thiazide          cular disease or diabetes plus another risk factor.
diuretic arm for the primary outcome. There were       The primary outcome was myocardial infarction,
some differences in secondary outcomes, with the       stroke or death from cardiovascular causes. Thus,
diuretic being superior to the other agents for        even though this was a high-risk sample, and
heart failure, for example. The blood pressure         the sample size was considerable, it was neces-
component of ALLHAT showed that in an active           sary to have a combination endpoint to achieve
control trial, a very large sample size needed to be   adequate power. There was a highly significant
used to achieve adequate power, even when the          and clinically impressive reduction in the primary
primary outcome was a combination of events.           outcome from ramipril.18
Also contributing to the need for a large sample          A similar study is the Prevention of Events
was the fact that about 30% of the participants        with Angiotensin-Converting Enzyme Inhibitor
who had a follow-up visit at five years had             Therapy, or PEACE.19 This trial is not yet
discontinued the study drug.                           completed, but it too compares an angiotensin-
   With respect to the lipid component, there          converting enzyme inhibitor (trandolapril) against
was no significant difference in total mortality,       standard therapy in over 8000 people with
despite the fact that many other studies have          documented coronary heart disease and a left
shown benefit from lipid-lowering treatments.17         ventricular ejection fraction of at least 40%.
One explanation may be that there was only             The reason for the ejection fraction criterion
a modest difference in low-density lipoprotein         is that angiotensin-converting enzyme inhibitors
cholesterol between the two groups. Almost 30%         have been shown to be beneficial in those
of the control group participants were receiving       with heart failure or low ejection fraction. This
non-study lipid-lowering therapy by the end            eligibility criterion, however, also means that
of the trial. The non-blinded design probably          the event rate is lower than if those with
helped foster that. The public campaigns aimed         impaired ejection fraction were included. So in
at getting people to reduce their cholesterol levels   order to have adequate power, even in this
undoubtedly played a role. Also, people who            relatively large study, a combination of events
were thought to require lipid-lowering therapy         is necessary as the primary outcome. Originally,
and those already on such therapy were not             the sample size was set at 14 000, and the
eligible to be enrolled. Because only those            primary outcome was cardiovascular death and
already entered in ALLHAT for the hypertension         non-fatal myocardial infarction. Early in the trial,
component were candidates for the lipid-lowering       primarily for feasibility reasons, the sample size
component, the originally expected number of           was reduced to 8100 and the primary outcome
about 20 000 enrollees turned out to be 10 355,        expanded to include the need for coronary
further limiting the study power.                      revascularisation procedures. Procedures such as
180                                    TEXTBOOK OF CLINICAL TRIALS

need for revascularisation are often included as        use of second, third and even fourth choice
part of the endpoint. This can be appropriate, but      drugs is built into the protocol. For example,
is subject to considerable bias if the trial is not     in the Systolic Hypertension in the Elderly
blinded, which PEACE is.                                program,20 a multicentre, randomised, double-
   Antihypertensive agents and lipid-lowering           blind, placebo-controlled, community-based trial,
drugs have generally been approved by drug              4736 participants with isolated systolic hyperten-
regulatory agencies on the basis of their effects       sion were randomised to receive either chlorthali-
on blood pressure and cholesterol, rather than on       done, 12.5 mg daily, or matching placebo. The
their effects on clinical outcomes. The clinical        goal systolic blood pressure differed for each
outcomes, however, are so important that many           participant depending upon initial systolic blood
trials have successfully tested their effects on        pressure. If the blood pressure remained above
death, myocardial infarction and stroke.11 – 16,18,20   the goal at two consecutive monthly visits, the
   Cardiac ventricular arrhythmias are known to         dose was increased to 25 mg of chlorthalidone
correlate with total and sudden death. Therefore,       or matching placebo daily. If the participants
for years, it was thought that drugs that reduced       were still above the goal at two consecutive vis-
cardiac arrhythmias should be approved on               its, 25 mg of atenolol daily or matching placebo
the basis of their antiarrhythmic effect, on            was added. In participants who still did not
the assumption that they would be clinically            reach the goal systolic blood pressure, the dose
beneficial. However, when the trials were done           was increased to 50 mg of atenolol or matching
that looked at clinical outcomes, it was seen that      placebo. If atenolol was contraindicated, 0.05 to
arrhythmia suppression was not a good surrogate         0.1 mg of reserpine or matching placebo daily
for mortality.                                          was substituted. Blood pressure above a pri-
   The Cardiac Arrhythmia Suppression Trial             ori established escape levels, despite maximal
(CAST) tested whether suppression of ventric-           stepped-care therapy or corresponding placebo,
ular arrhythmias by any of three antiarrhythmic         was an indication for prescribing open-label
drugs would reduce the incidence of sudden car-         active drug therapy.20
diac death. In the first part of this trial, over           Some trials of pharmaceutical agents compare
1700 patients whose ventricular arrhythmias were        strategies, rather than drugs. Recently, the Atrial
suppressed by encainide, flecainide or moricizine        Fibrillation Follow-up Investigation of Rhythm
were randomly assigned to the drug that was             Management (AFFIRM) evaluated which of two
most effective in suppressing the arrhythmia or         approaches for treating patients with atrial fib-
matching placebo. However, two of the drugs,            rillation was better.23,24 Participants had to have
encainide and flecainide, were soon seen to sig-         atrial fibrillation, be over age 65 (or under 65 and
nificantly increase both sudden death and all-           at high risk for stroke) and the enrolling physi-
cause mortality and they were discontinued early        cian had to deem it appropriate to treat patients
in the study.21 The study was continued with            as part of the assigned strategy for up to five
moricizine as the only antiarrhythmic drug. This        years. AFFIRM included 4060 people, enrolled at
too was stopped ahead of schedule because of            over 200 sites in Canada and the United States,
adverse trends in mortality.22 As a result of           who were randomised to either rhythm or rate
CAST, the use of surrogate outcomes in many             control strategies for managing their atrial fib-
clinical trials has been seriously questioned.          rillation. Investigators could select from various
   Another feature of many drug trials in car-          options on an approved menu of pharmacologic
diovascular disease is that a ‘stepped care’            and non-pharmacologic therapies. Cardioversion
approach is used. This is common in trials              and antiarrhythmic drugs were used to maintain
of blood pressure lowering. Because a sin-              sinus rhythm (called ‘rhythm control’). Agents
gle drug is often either insufficiently effec-           such as digitalis, calcium channel blockers and
tive or not well tolerated by the participant,          β-blockers, or ablation of the atrioventricular
                                              CARDIOVASCULAR                                                 181

junction and pacemaker implantation, were used          experience in implanting a device, an interven-
to control the ventricular response rate from the       tion might be claimed to be not beneficial, or
atrial fibrillation (called ‘rate control’). The trial   even harmful, when in the hands of a more skilled
showed that there was no significant difference in       operator it would be beneficial. This was seen in
the primary outcome (all-cause mortality), though       the Department of Veterans Affairs trial compar-
there was a trend favouring the rate control group,     ing surgical and medical management of angina
and there were fewer adverse effects in the rate        pectoris.25 Thirteen hospitals participated in this
control group.                                          trial. Three of the hospitals had surgical mortality
                                                        considerably greater than the other 10. The results
                                                        comparing surgery against medical care were
    TRIALS OF DEVICES AND SURGICAL                      favourable for surgery among patients at high risk
              PROCEDURES                                of death from their disease, even when all 13 hos-
                                                        pitals were included in the analysis. However, for
Devices and surgical procedures are commonly            lower risk patients, only the comparison involv-
used in patients with heart disease. Examples of        ing the 10 hospitals with better surgical results
devices are replacements for heart valves, stents       showed benefit from surgery. These data may
that help keep coronary vessels that have been          reflect normal variation, but they raise the issue
opened patent, cardiac pacemakers and cardiac           of requiring a certain level of experience from
defibrillators. Examples of surgical procedures          the surgeons before they participate in a trial.
are corrections of congenital abnormalities, coro-         The issue of skill of the operators who insert a
nary artery bypass grafts (CABG) and aneurysm           device also needs to be emphasised. Most recent
resection. Trials of various surgical procedures        clinical trials of device implantation require that
are usually surgery versus medical treatment or         the operators have experience with a certain min-
surgery versus device implantation. Examples            imum number of devices before being allowed
are coronary artery bypass graft procedures in          to participate in the trial. This does not guar-
patients with ischaemia that are compared against       antee that only highly skilled operators will be
use of thrombolytic agents or against implanta-         involved, but it means that the trial is a better
tion of coronary artery stents, or coronary bypass      test of how the device will perform in close to
graft procedures in patients with stable angina         optimal circumstances. An example is the expe-
pectoris that have been compared against best           rience required of investigators and the establish-
medical therapy. Less often, there are trials com-      ment of minimum standards for the device and
paring one surgical procedure against another.          lead systems used in the Antiarrhythmics Versus
Devices may be compared against surgery, as             Implantable Defibrillators (AVID) trial.26
noted, or against medical care, or sometimes,              A second, related issue is how broadly the
against another device.                                 study results can be generalised if only the
   Obviously, as with all clinical trials, the ques-    most experienced surgeons participate in the
tions in these kinds of trials need to be important     trial. After a drug study shows benefit from
and the answer relevant, the study needs to be          a new pharmaceutical agent, presumably most
appropriately designed and carried out, and the         practitioners are able to administer the drug in
data must be properly analysed. In addition, there      a safe, effective manner. Transferring surgical
are certain features of such studies that need to       technique and skill from investigators in the trial to
be considered. First, there is an unavoidable inte-     others is less straightforward. Similarly, if a device
gration of the intervention being employed and          is shown to be beneficial, and then used more
the technique with which it is done. The skill          widely by less well-trained operators, the results
of the investigator is far more important than          will not be as positive as in the clinical trial setting.
in, for example, drug trials. Unless the inves-            Trials of both devices and surgical procedures
tigator has considerable surgical competence or         affect the way in which the primary trial outcome
182                                    TEXTBOOK OF CLINICAL TRIALS

is assessed. Because of the invasive nature of             Changes in surgical technique or modifications
the intervention, it is likely, indeed expected, that   in devices while the study is being conducted
there will be an early adverse experience associ-       can cause difficulties in interpreting the results of
ated with the procedure. The trauma involved; the       clinical trials. If, partway through a study, there is
consequences of anaesthesia, particularly if gen-       an important change in the intervention, depend-
eral anaesthesia is used; and the risks of infection    ing on the outcome, it may be hard to reach a
will almost inevitably lead to morbidity and per-       clear conclusion about the possible benefits of
haps mortality early after the intervention. There-     the intervention. In the past, implantable car-
fore, the study needs to be designed such that          dioverter defibrillators required a thoracotomy.
it lasts long enough for any hoped-for benefit           This carried considerable risk that needed to
to overcome the early unfavourable experience.          be considered when inserting the device. Leads
Sometimes, the expected benefit does not appear          that could be inserted transvenously were sub-
for quite some time. Not only the investigators,        sequently developed, reducing the early com-
but institutional ethics committees and prospec-        plication rate. The AVID trial and the Cana-
tive study participants need to understand this         dian Implantable Defibrillator Study (CIDS) trial,
implication.                                            both of which compared implantable cardioverter
   An example is the Program on the Surgical            defibrillators against medical therapy in peo-
Control of Hyperlipidemia.27,28 This trial com-         ple resuscitated from cardiac arrest, were in the
pared partial ileal bypass surgery against medical      process of enrolling patients when the switch
therapy in patients with a prior myocardial infarc-     in practice from primarily using thoracotomy-
                                                        based defibrillators to transvenous defibrillators
tion. The goal was to decrease the absorption of
                                                        occurred.26,29 Because both types of defibrilla-
lipids, thereby reducing serum cholesterol. For
                                                        tor performed similarly, there was no problem in
the first two years of the trial, there was lit-
                                                        combining the results. This was particularly the
tle difference in the primary outcome, all-cause
                                                        case because it was shown significantly in AVID
mortality, with the surgical group doing slightly
                                                        and with a strong trend in CIDS that the defib-
worse than the control group. The curves crossed
                                                        rillator was more effective in reducing mortality
after about three years, and at the scheduled end       than antiarrhythmic drug therapy. If there were
of the trial, there was a non-significant trend in       no difference, or if drug therapy turned out to be
favour of surgery. The study investigators fol-         superior overall, questions about the validity of
lowed the participants after the formal end of the      the trial might have been raised, given the mid-
trial. The trend in favour of surgery continued and     study switches in device use.
five years after the end, the mortality difference          Trials of cardiovascular devices involve sev-
was statistically significant.28                         eral other issues that are not common to other
   This study shows that data monitoring com-           kinds of trials. One is the decision during study
mittees need to consider how long to wait to            design as to the primary question. The device is
see if the benefit appears and counterbalances the       developed to meet certain specifications. These
known risks. Even though the primary outcome            include minimising the possibility of rejection by
was not sufficiently adverse early in the trial to       the patient, reducing the likelihood of develop-
justify stopping, other factors combined with lack      ment of thrombi and emboli, physical character-
of benefit might have influenced a monitoring             istics such as size and weight, and, importantly,
committee to do so. For example, in POSCH,              does it do what it is designed to do. Does a
there were side effects such as diarrhoea and,          defibrillator detect and convert life-threatening
more seriously, a higher rate of kidney stones          rhythm disturbances? Does a pacemaker detect
and gallstones.27 The slight early adverse trend in     and correct severe bradycardia? Can a stent be
mortality plus the increased morbidity could have       easily employed and will it retain its structural
led to a decision to stop the study prematurely.        integrity? These are engineering questions that
                                             CARDIOVASCULAR                                           183

should be addressed and satisfactorily answered        in 196 patients with heart failure, a prior myocar-
before a clinical trial is conducted. The clinical     dial infarction, left ventricular ejection fraction
trial should be designed to answer the questions       less than or equal to 35%, a documented episode
posed by the clinician. Will the device reduce         of asymptomatic unsustained ventricular tachy-
mortality and/or morbidity, what is the resteno-       cardia, and inducible, non-suppressible ventricu-
sis/occlusion rate, and what are the risks and side    lar tachyarrhythmia on electrophysiologic testing.
effects? The answers to these questions incor-         In this very high-risk group of patients, the defib-
porate the structural and functional aspects of        rillator led to highly significant reductions in
the device, the skill of the person inserting the      all-cause and cardiac mortality.34 A subsequent
device, and the often unknown biologic interac-        study by the same group of investigators (MADIT
tion between patients and the device.                  II) assessed whether the implantable defibrilla-
   The fact that only devices designed and             tor would reduce mortality in patients with a
fully expected to be mechanically functional           prior myocardial infarction and left ventricular
are used raises a serious ethical issue. If the        ejection fraction less than or equal to 30%. Elec-
device defibrillates, for example, how can it           trophysiologic testing was not used to identify
be withheld from someone with known life-              high-risk patients. Because the risk of mortality
threatening cardiac arrhythmias? This was faced        was lower in this study than in the prior study,
in the AVID trial.30,31 The rationale for the          742 patients were randomised to receive either
trial was that the balance between expected            the implantable defibrillator or conventional med-
reduction in death due to arrhythmias versus           ical therapy. Here too, there was a significant
death from other causes, plus adverse events such      reduction in mortality in the defibrillator group.35
as infection, and the possible seriously impaired         One trial of a device that raised considerable
quality of life, was uncertain.                        questions about ethics was the Randomised Eval-
   A key issue is the risk level of the patients       uation of Mechanical Assistance for the Treat-
being enrolled. If the patients are at truly very      ment of Congestive Heart Failure (REMATCH),
high risk of arrhythmic death, even though             which was conducted from 1997 to 2001. This
optimal medical therapy is being used, then it         trial compared use of a left ventricular assist
might be inappropriate to randomise them to            device versus medical therapy in 129 patients
medical therapy if a possibly useful device or         with end-stage heart failure who were not can-
surgical procedure exists. The defibrillator trials     didates for cardiac transplantation. The one-year
that were done showed that in moderately high-         survival was 52% in the group receiving the left
risk patients, the use of the defibrillator saved       ventricular assist device and 25% in the medical
lives with an acceptable number of adverse             therapy group, a highly significant difference. At
events. If the risk level is less, however, as might   two years, the rates of survival were 23% and 8%.
be the case in patients with better left ventricular   There were over twice as many serious adverse
ejection fraction, the balance between benefit          events (infection, bleeding, device malfunction)
and potential harm might remain unknown, and           in the device group as in the medical arm.36,37
the use of a defibrillator might not be justified,          Because the expected survival rate in these
absent clear demonstration of benefit in a clinical     patients was so low, there were many questions
trial.32,33                                            about the ethics of randomisation. It was known
   Trials have looked at various ways of identi-       that the device was mechanically sound, and
fying patients at sufficiently high risk to see if      worked in the short-term as a bridge to trans-
defibrillators are beneficial, but not at so high        plantation. The justification for the trial was that
risk that it would be unethical to randomise. The      long-term benefit, either for survival or quality
Multicentre Automatic Defibrillator Implantation        of life, was unknown. For a more extensive dis-
Trial (MADIT) compared use of an implanted             cussion of the design issues and ethics of this
defibrillator versus conventional medical therapy       kind of trial, using REMATCH as an example,
184                                   TEXTBOOK OF CLINICAL TRIALS

see the report of a conference on mechanical car-      To the extent that the devices in the ‘strategy-
diac support.38                                        approach’ trial are similarly effective, the results
   It is uncommon (and often impractical) for          can be more broadly generalised to a class of
trials of devices or surgical procedures to be         devices. There is a risk, however, that devices
blinded. Occasionally, however, this can be            made by one manufacturer will be better than
done. One such trial was Mode Selection Trial          others, blurring the outcome of the trial.
in Sinus Node Dysfunction (MOST).39 Dual-                 Another feature of device and surgical trials
chamber (atrioventricular) pacing was compared         is that unlike most drugs (vaccines being an
with single-chamber (ventricular) pacing in 2010       exception) that need to be administered regularly,
patients with clinically important bradycardia.        devices are implanted and expected to work
The primary outcome was death or non-fatal             for a long time, and surgery, unless reversed,
stroke. All patients received a dual-chamber           can be life-long. Batteries and other components
device, but in those randomised to single-             may need to be replaced, but unless there are
chamber pacing, only one lead was activated,           problems, they last for years. This is generally a
therefore mode of pacing was randomised rather         strength of such trials. There is less problem with
                                                       compliance to protocol and long-term follow-
than type of device. Physician investigators and
                                                       up is not only feasible, but desirable. The
patients were blinded regarding whether the
                                                       several coronary artery bypass graft surgery trials
patient was in the dual- or single-chamber arm;
                                                       assessed outcome 10, and in some cases more
cross-over at the last follow-up was 31.4% for
                                                       than 20 years after the initial procedure.41
those assigned to ventricular pacing, almost half
                                                          If a drug trial turns out not to show benefit
of these due to pacemaker syndrome. This was in        from the drug, simply stopping administration
contrast to another study that inserted only single-   is usually sufficient. But what if the device or
chamber devices in those randomised to that            surgery trial turns out not to show benefit? What
group and dual-chamber devices only in those           is the obligation of the investigator, especially if
randomised to the dual-chamber group. Here the         the device or procedure is shown by the trial to
cross-over rate was 2.7%.40 This latter trial was      be harmful? The Coronary Artery Bypass Graft
not blinded, but cross-over from single- to dual-      (CABG) Patch trial42 compared transthoracic
chamber pacing would have required another             implantation of cardioverter defibrillators against
procedure, accounting for the low cross-over rate.     control in patients undergoing CABG surgery.
   As with many drug trials, trials of devices         At the end of an average 32 months follow-
can look at either single devices (or upgrades         up, there was no significant mortality difference
of these devices as they become available) or          between the groups. All patients were given the
classes of devices. The AVID26 trial compared          results of the trial and subsequent therapy was
the use of advanced-generation units with tiered       individualised. All patients were urged to have
therapy capable of antitachycardia pacing, car-        electrophysiologic testing to see if they were at
dioversion and defibrillation, as well as brady-        high risk of serious arrhythmia, and thus possibly
cardia pacing, made by more than one company,          in need of the defibrillator in the future. About
against any of several drugs (though primarily         40% of the patients in the intervention group
amiodarone), thus testing whether the strategy of      elected to have the device turned off or removed
using implantable defibrillators was preferable to      [J.T. Bigger, personal communication].
a strategy of pharmacologic approach. This kind
of trial is more likely to be done by public organ-
isations, such as the National Institutes of Health,         TRIALS OF BEHAVIOUR CHANGE
than by industry. Industry-supported trials, such
as the previously discussed MADIT,34 almost            Trials of behaviour change are fairly common
always compare a single manufacturer’s device.         in heart disease. They include trials aimed at
                                            CARDIOVASCULAR                                             185

smoking prevention or cessation; diet change          and pressure can affect the trials in major ways.
for weight loss, blood pressure reduction or          If there are changes in restaurant or workplace
cholesterol reduction; and exercise for risk factor   smoking regulations during the time of a trial
reduction and better outcomes in people with a        looking at ways to get people to stop smoking,
heart attack or heart failure.                        the likely trends in the control group as a result of
   These sorts of trials have several aspects that    the new regulations will make detection of benefit
make them different from most other trials. First,    from the intervention more difficult.
there is considerable cross-over or recidivism by        Examples of successful trials of diet inter-
the study participants. The interventions are ones    vention are the Dietary Approaches to Stop
that many can either implement on their own           Hypertension (DASH) trial43 and a subsequent
or stop because they are difficult to maintain.        trial of the DASH diet with different lev-
Second, partly as a consequence of the first, the      els of sodium intake.44 The first DASH study
trials are quite resource intensive on the part of    enrolled 459 adults with systolic blood pressure
the interventionists. Implantation of devices or      under 160 mm Hg and diastolic pressure 80 to
surgical procedures require major efforts by the      95 mm Hg. Participants were randomly allocated
investigator or surgeon, but usually only on a one-   to one of three groups: a diet rich in fruits and
time basis. Trials of behaviour change require        vegetables; a diet rich in fruits and vegetables
considerable effort on a continuing basis to help     plus low-fat dairy products and reduced satu-
participants stay with a change from what may         rated fat (‘combination’ diet); or a control diet
have been a life-long habit of smoking, eating        with fruit, vegetable and fat content similar to
poorly or sedentary lifestyle. Third, again as a      that commonly eaten in the United States. At the
consequence of the first two factors, the study        end of eight weeks, both of the intervention diets
duration is often much shorter than with other        reduced blood pressure, with a greater reduction
types of trials. Getting people to adhere to an       from the diet containing low-fat dairy products.
exercise programme for months, let alone years,       The second DASH study enrolled 412 partici-
is extraordinarily difficult. And of course volun-     pants in a factorial design trial. Participants were
teers willing to be randomised to exercise or no      assigned to either the DASH combination diet
exercise will have more of an interest in exercise    or the control diet and to any of three levels of
than the general public. Therefore, those allo-       sodium intake. The moderate and low sodium
cated to the no-exercise programme group will         intake diets reduced blood pressure in both the
have more of a tendency to cross-over. Fourth,        DASH diet and control diet groups. The DASH
because of the generally shorter duration of the      diet led to lower blood pressure than the control
trials, surrogate outcomes are more often used        diet at each sodium level.
than in other trials in heart disease. Rather than       In the DASH studies, the food was spe-
assessing clinical outcomes such as heart dis-        cially prepared and provided to the partici-
ease or stroke, the behaviour trials will often use   pants. Whether or not the DASH-type diet can
weight change, biochemical measures, or attitude      be maintained, over time, in people obtain-
or knowledge assessed by questionnaires or inter-     ing their food in the usual way, was stud-
views. Fifth, standardisation of the intervention     ied in PREMIER, a trial of 810 participants
and measurement of the degree of compliance are       whose blood pressure is greater than opti-
more complicated. Unless highly controlled feed-      mal or who have mild hypertension.45 Partic-
ing studies are performed, we have only modestly      ipants were randomised to one of three arms:
good ways of assessing overall food and nutri-        advice only; comprehensive lifestyle interven-
ent intake. This is particularly so if maintenance    tion using behavioural approaches; and a com-
of caloric intake is one of the objectives of the     bined comprehensive lifestyle intervention plus
trial, as weight would not be able to serve as a      the DASH diet. The behavioural approaches
marker of change in diet. Sixth, societal changes     consisted of 18 counselling sessions. Unlike
186                                  TEXTBOOK OF CLINICAL TRIALS

DASH, the participants were not provided spe-         enough magnitude to alter mortality. This is what
cially prepared foods. The primary outcome was        happened in some of the early trials of cholesterol
systolic blood pressure six months after randomi-     lowering that failed to show improvement in
sation. At six months, the systolic blood pressure    mortality. The early lipid-lowering drugs were
had decreased by 11.1 mm Hg in the combined           not as effective as the current ones in reducing
group, 10.5 mm Hg in the behavioural interven-        cholesterol. Third, the measures of depression
tion group, and 6.6 mm Hg in the advice only          and social support, particularly when obtained
group. The largest reductions in diastolic blood      shortly after a major event such as a heart attack,
pressure and in the percentage of people with         might not reflect true ‘baseline’. Fourth, however,
hypertension were also seen in the combined           even though mortality and recurrent infarction
group, with the behavioural intervention group a      were unchanged, the apparent improvements in
close second. Thus, a combination of behavioural      depression and social support are not trivial
approaches and dietary changes can result in          findings. Unlike surrogate outcome variables that
meaningful blood pressure reduction. Even so,         have little clinical meaning, these outcomes are
the DASH diet, unlike in the previous feed-           clinically important in their own right.
ing studies,43,44 did not contribute significantly        Often, it is more appropriate to conduct
beyond the comprehensive lifestyle intervention       behaviour change trials in community settings,
alone. The adoption of the diet in PREMIER            with one group of communities compared against
was not as intensive as in the feeding studies.       another. The changes, in order to be effective,
Whether the changes observed in PREMIER per-          need to be community-wide. An example of
sist at 18 months is being assessed.45                efforts to improve response time to symptoms of
   A different kind of behavioural intervention       a heart attack was the Rapid Early Action for
trial was the Enhancing Recovery in Coronary          Coronary Treatment (REACT) trial. This study
Heart Disease (ENRICHD)46 study. This trial           involved 10 matched pairs of cities. One group
enrolled 2481 patients at 73 hospitals who had        of cities received intervention through the media,
had a myocardial infarction within the previous       community organisations, and professional and
28 days. In addition, all participants had depres-    patient education in an effort to improve the
sion, low social support, or both. Because depres-    response time in the event of symptoms of an
sion and poor social support are associated with      acute myocardial infarction. The other group of
increased mortality after a heart attack, it was      cities served as the control. The primary outcome
thought that intervening on those factors might       was time from symptom onset to arrival in the
lead to improved survival. Those randomised           hospital emergency department. REACT showed
to intervention received counselling; the control     increased use of the emergency medical system,
group received usual medical care. Both groups        but no difference between the groups in time to
received information on heart disease risk factors.   arrival at the hospital.48
Although the intervention decreased depression           There have been several trials aimed at chang-
and improved social support, there was no dif-        ing multiple risk factors for heart disease in com-
ference at three years in the primary outcome of      munity settings.49 – 51 These trials showed small
death or recurrent myocardial infarction (24.1%       differences between the intervention communities
vs. 24.2%).47                                         and the control communities in selected variables.
   The ENRICHD study raises several issues.           In general, however, they were not particularly
First, despite the association between depression     successful in achieving large differences despite
and heart disease, treatment of depression may        intensive education efforts. The reasons are prob-
not lead to change in mortality from heart disease.   ably multiple. Among them are that the interven-
That is, depression may not be a causative factor.    tions were not delivered in sufficiently persua-
Second, the observed improvement in depression        sive manners and that the control communities
and social support may not have been of great         showed changes because of national attention to
                                               CARDIOVASCULAR                                                 187

the need to stop smoking, improve diet and get                 Woosley RL, Singh SN, eds, Arrhythmia Treat-
better preventive medical attention.                           ment and Therapy. New York: Marcel Dekker
   The less than outstanding results from these                (2000) 323–42.
                                                          5.   National Institutes of Health and National Heart,
community-wide efforts at behaviour change                     Lung and Blood Institute. Morbidity & Mortality:
illustrate both the difficulties in achieving behav-            2002 Chart Book on Cardiovascular, Lung, and
iour change and the problems in community, as                  Blood Diseases. U.S. Department of Health and
opposed to individual, interventions.                          Human Services, Public Health Service, National
                                                               Institutes of Health (2002).
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