Table Of ContentA GUIDE TO CLINICAL DRUG RESEARCH
A GUIDE TO CLINICAL DRUG RESEARCH
edited by
ADAM COHEN
Professor of Clinical Pharmacology,
University of Leiden,
Leiden, The Netherlands
and
Director of the Centre for Human Drug Research,
Leiden University Hospital,
Leiden, The Netherlands
and
JOHN POSNER
Clinical Pharmacologist
Glaxo WeUcome PLC
Beckenham, Kent, UK
Springer-Science+Business Media, B.V.
Library of Congress Cataloging-in-Publication Data
A guide to clinical drug research I edited by Adam Cohen and John
Posner
p. cm.
Includes index.
1. Drugs--Research. I. Cohen, Adam. II. Posner, John.
IDNLM: 1. Clinical Trials--methods. 2. Research Design. aV771
G946 19951
RM301.27.G85 1995
615' . 19--dc20
DNLM/DLC
for Library of Congress 95-8825
ISBN 978-94-015-8465-4 ISBN 978-94-015-8463-0 (eBook)
DOI 10.1007/978-94-015-8463-0
Printed on acid-free paper
All Rights Reserved
© 1995 Springer Science+Business Media Dordrecht
Originally published by K1uwer Academic Publishers in 1995.
Softcover reprint ofthe hardcover 1st edition 1995
No part of the material protected by this copyright notice may be reproduced or utilized in any
form or by any means, electronic or mechanical, including photocopying, recording or by any information
storage and retrieval system, without written permission from the copyright owner.
Contents
Foreword by Prof. Dr. D.D. Breimer Vll
List of contributors
IX
1. Clinical research: From idea to publication
2. Facilities and equipment 11
3. What does the investigator need to know about the drug? 17
4. The first administration of a new active substance to humans 39
5. Planning and coordinating the study 57
6. The study protocol 65
7. Study design 75
8. Data management and statistical analysis 85
9. Ethical considerations 99
10. Aspects of study conduct III
11. Good clinical practice 127
12. Communicating clinical research 139
13. Clinical research in a developing country 157
14. Computers in clinical research 171
Index 199
v
Foreword
Clinical drug research forms the experimental basis for efficacy and safety assessment of
new therapeutic agents in man. In other words, it allows us to obtain relevant
information on how to effectively and safely use a drug in an individual patient. Clinical
research is a of key importance for developing and validating new concepts in clinical
pharmacology and therapeutics, using already existing and new biologically active
agents. Increasingly, it is also conducted to compare different treatment regimens in
order to reveal that one is superior to another.
In recent years clinical drug research has advanced strongly with the availability of
new pharmacokinetic, pharmacodynamic and clinical methods and sophisticated ethical
and quality assurance standards, automated and on line data management. This has
made such research much more efficient and informative. The quality of the information
to be obtained depends on a clear definition of the question to be answered or hypothesis
to be tested, a scientifically sound concept has to be translated into an appropriate study
design, protocol and data evaluation. Dissemination of the information obtained using
the appropriate channels should also be considered an important objective of any study.
This book is a 'Guide to Clinical Drug Research' in the literal sense of the word. It
provides the reader with relevant information about every aspect of drug research in
man, from the initial research idea to the ultimate publication and with every step in
between. Never before has such a comprehensive text with such attention to practical
detail been put together. The Editors, who started their career working together at the
clinical pharmacology department of the Well come Research Laboratories in
Beckenham, are very experienced in clinical drug research and very knowledgeable
about what is needed to perform such research to up-to-date ethical scientific and
technical standards. They have managed to successfully involve a number of colleagues
working in clinical pharmacology or other departments in the pharmaceutical
industry. In addition, experts from other fields have written about important topics.
This book is not only of great importance for scientists and other persons engaged
in clinical drug research. Much of the principles and technical aspects discussed are
relevant for any type of clinical research. The use of this knowledge in any clinical
research project will undoubtedly lead to improved quality and relevance.
Douwe D.Breimer, Ph.D.
Professor of Pharmacology,
Director of Research of the
Leidenl Amsterdam Center for Drug
Research, Leiden University
VII
List of contributors
Nigel S. Baber, MB, BSc, FRCP, FFPM Jos Hennen, MSc
Clinical Pharmacologist Project Leader Clinical Data
Glaxo Wellcome PLC Management Systems
Greenford Road CHDR Leiden
Greenford, Middlesex UB6 ORE, UK Zernikedreef 10
Chapter 3 2333 CL Leiden, The Netherlands
Chapter 14
Peter van Brummelen, MD, PhD
Director of Clinical Pharmacology William P. Howlett, DTM&H, FRCP (I),
F. Hoffmann-la Roche Ltd. PhD
Grenzacherstrasse 124 Consultant Physician
CH-4002 Basel, Switzerland Kilimanjaro Christian Medical Centre
Chapter 12 Moshi, Tanzania
Chapter 13
Douglas E. Busch, PhD
Busch International Dossiers and Les Huson, PhD
Strategies Medical Statistician
95 River Road Glaxo Wellcome PLC
Topsfield, MA 01983, USA Wellcome Research Laboratories
Chapter 12 Langley Court
Beckenham, Kent BR3 3BS, UK
Adam F. Cohen, MD, PhD Chapter 7
Professor of Clinical Pharmacology
CHDR Leiden Gregor B. E. Jemec, MD
Zernikedreef 10 Assistant Professor of Dermatology
2333 CL Leiden, The Netherlands Bispeberg Hospital
Editor University of Copenhagen
DK-2400 Copenhagen, Denmark
Chapter 9
IX
LIST OF CONTRIBUTORS
Alfred H.J. van Meurs Patricia Sohl, MD
Consultant Paediatrician Nyhavn 45-IFAL
Kilimanjaro Christian Medical Centre DK-I051 Kopenhagen, Denmark
Moshi, Tanzania Chapter 9
current address:
Juliana Children's Hospital Jean Soul-Lawton
Dr van Welylaan 2 Clinical Research Scientist
2566 ER The Hague, The Netherlands Glaxo Wellcome PLC
Chapter 13 Wellcome Research Laboratories
Langley Court
Fiona Peachy, PhD Beckenham, Kent BR3 3BS, UK
International Project Manager Chapter 11
Glaxo Wellcome PLC
Wellcome Research Laboratories Steve Warrington, MA, MD, FRCP,
Langley Court FFPM
Beckenham, Kent BR3 3BS, UK Medical Director
Chapter 8 Hammersmith Medicines Research Ltd.,
Ward E2
John Posner, BSc, PhD, FRCP, FFPM Central Middlesex Hospital
Clinical Pharmacologist Acton Lane
Glaxo Wellcome PLC London NWlO, UK
Wellcome Research Laboratories Chapter 10
Langley Court
Beckenham, Kent BR3 3BS, UK
Editor
x
Clinical research: From idea to publication
This book is about the practical aspects of performing clinical Introduction
drug research starting from the conception of an idea through
to publication of a completed piece of research in a peer
reviewed scientific journal. In the last two or three decades it
has become progressively more difficult to perform good clinical
research. There are a number of reasons for this:
The volume of scientific literature published is now so vast
that it is easy to miss important pieces of research which
might impact on the project of interest to you.
As the cost of health care rises, concern about the cost-effect
iveness of therapeutic agents and strategies has increased. It
is no longer good enough to demonstrate that a new medi
cation is relatively safe and effective; rather it is necessary to
provide evidence that it is superior to another treatment or
even that there is an advantage over not treating the patient
at all.
Concerns about protection of subjects in clinical trials and
fears of scientific fraud have led to a situation in which the
development and licensing of new medicines has become
highly regulated. Good Clinical Practice (GCP) and Good
Laboratory Practice (GLP) have certainly contributed to the
quality of medical research but place an enormous burden on
the clinical researcher both in terms of resources and sheer
complexity. Great care must be taken to ensure that all the
activities necessary to perform successful clinical research do
not compromise patient care. There are times when ethical
issues may arise in reconciling these two.
The first medicines were given for diseases in which the patho
physiology was fairly well understood and for which the
indicators of therapeutic efficacy were clear. Thus, in 1948 a
trial of streptomycin for the treatment of tuberculosis (generally
considered to be the first controlled clinical trial) only required
109 patients to achieve its objectives. Nowadays, many in-
1 / CLINICAL RESEARCH: FROM IDEA TO PUBLICATION
fections can be cured by drugs or prevented with vaccines,
hypertension, thyroid disorders and even epilepsy can usually be
controlled quite well. The endpoints are now much more dif
ficult to achieve such as the reduction of secondary myocardial
infarction or mortality by long term intervention with a part
icular treatment strategy. The current therapeutic challenges are
diseases like cancer, rheumatoid arthritis, Alzheimer's dementia,
septic shock and multiple sclerosis. The pathophysiology of
these conditions is often poorly understood and complex
therapeutic strategies are often required. The scale of work
involved in determining the efficacy of these strategies is much
greater. The ISIS IV study, which investigated three different
drugs alone and in combination for the treatment of myocardial
infarction required almost 60,000 patients! The complexity of
these studies demands a multidisciplinary approach. This has
changed the clinical scientist from somebody who could work
almost single-handed to a manager of a large group of people
and considerable financial resources.
Anyone wanting to start a new research project is obviously
best advised to do this in an established environment with
experience in all operational aspects of performing clinical drug
research. However this is not always possible and individual
researchers are faced with the unenviable task of discovering for
themselves, expending a great deal of effort on reinventing the
wheel. Just as a travel guide allows you to visit a town more
effectively than by rediscovering all important sites by yourself,
this guide should ensure a more rapid entry into the field of
clinical research. The emphasis will be on drug research but the
principles and most of the detail should be applicable to all
types of clinical research.
The generation It is not difficult to have good ideas for clinical research. Whilst
of ideas still students or during the course of carrying out their clinical
duties most doctors are curious about why they do what they do
to patients or why a particular disease behaves as it does.
Likewise, scientists working in a medical field will be inquisitive
by nature and training. This curiosity, the wanting to know
'how' or 'why' is the basis of all ideas for research.
Limiting and When you have an idea, write it down as soon as possible. Some
focussing ideas people have fleeting ideas at unpredictable moments, while
driving home from work or in the middle of the night. It pays to
write them down in a rough format so that they won't be
2
