Table Of ContentRosier ffirs.tex V3 - 06/20/2014 10:48 A.M. Page i
Global New Drug Development
Rosier ffirs.tex V3 - 06/20/2014 10:48 A.M. Page iii
Global New Drug
Development
An Introduction
Jan A. Rosier
University College Dublin, Ireland
Mark A. Martens
Consultant in Pre-clinical Development and Toxicology, Belgium
Josse R. Thomas
University of Leuven, Belgium
http://www.u-l-l-a.org/
Rosier ffirs.tex V3 - 06/20/2014 10:48 A.M. Page iv
This edition frst published 2014 © 2014 by John Wiley & Sons, Ltd
Registered offce: John Wiley & Sons, Ltd, The Atrium, Southern Gate, Chichester, West Sussex,
PO19 8SQ, UK
Editorial offces: 9600 Garsington Road, Oxford, OX4 2DQ, UK
The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK
111 River Street, Hoboken, NJ 07030-5774, USA
For details of our global editorial offces, for customer services and for information about how to
apply for permission to reuse the copyright material in this book please see our website at
www.wiley.com/wiley-blackwell.
The right of the author to be identifed as the author of this work has been asserted in accordance
with the UK Copyright, Designs and Patents Act 1988.
All rights reserved. No part of this publication may be reproduced, stored in a retrieval system,
or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or
otherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the
prior permission of the publisher.
Designations used by companies to distinguish their products are often claimed as trademarks. All
brand names and product names used in this book are trade names, service marks, trademarks or
registered trademarks of their respective owners. The publisher is not associated with any product or
vendor mentioned in this book.
Limit of Liability/Disclaimer of Warranty: While the publisher and author(s) have used their best
efforts in preparing this book, they make no representations or warranties with respect to the
accuracy or completeness of the contents of this book and specifcally disclaim any implied
warranties of merchantability or ftness for a particular purpose. It is sold on the understanding that
the publisher is not engaged in rendering professional services and neither the publisher nor the
author shall be liable for damages arising herefrom. If professional advice or other expert assistance
is required, the services of a competent professional should be sought.
Library of Congress Cataloging-in-Publication Data
Rosier, Jan A., author.
Global new drug development : an introduction / Jan A. Rosier, Mark A. Martens,
and Josse R. Thomas.
p. ; cm.
Includes bibliographical references and index.
ISBN 978-1-118-41488-0 (cloth)
I. Martens, Mark A., author. II. Thomas, Josse R., author. III. Title.
[DNLM: 1. Drug Discovery. 2. Drug Industry–organization & administration. QV 745]
RS420
′
615.1 9–dc23
2014013906
A catalogue record for this book is available from the British Library.
Wiley also publishes its books in a variety of electronic formats. Some content that appears in print
may not be available in electronic books.
Set in 10.5/13pt TimesTenRoman by Laserwords Private Limited, Chennai, India
1 2014
Rosier ftoc.tex V3 - 05/28/2014 11:34 A.M. Page v
Contents
Series Foreword ix
Preface xi
Acknowledgements xiii
Abbreviations xv
Introduction xxi
1 Drug Life Cycle 1
1.1 Introduction 1
1.2 Drivers of the search for a new drug 2
1.2.1 Strategic criteria 3
1.2.2 Scientific and technical criteria 3
1.2.3 Operational criteria 4
1.3 Structure of a drug life cycle 5
1.4 Costs and risks of drug research and development 6
1.4.1 Cost drivers 6
1.4.2 Estimates of drug development costs 7
1.5 Risks of drug R&D 7
1.5.1 Failure and success rates in drug development 7
1.5.2 Net present value 8
1.6 Value for patient and society 9
1.7 The end of a drug’s life 9
1.8 Management 10
References 10
2 Drug Discovery and Design 13
2.1 Introduction 13
2.2 Approaches in drug discovery 14
2.2.1 Phenotypic based 14
2.2.2 Target based 14
2.2.3 Molecular drug design 15
Rosier ftoc.tex V3 - 05/28/2014 11:34 A.M. Page vi
vi CONTENTS
2.3 The drug discovery process 16
2.3.1 Exploratory phase 17
2.3.2 Assay development 17
2.3.3 Screening 18
2.3.4 Hit-to-lead 18
2.3.5 Lead optimisation 19
References 21
3 Drug Development: General Aspects 23
3.1 Introduction 23
3.2 The objective of drug development 23
3.3 Drug development organisations and teams 24
3.4 Drug development streams 27
3.4.1 Chemical and pharmaceutical development 27
3.4.2 Nonclinical development 31
3.4.3 Clinical development 33
3.4.4 Interaction between the development streams 35
3.5 Phases in drug development 36
3.5.1 Early development 36
3.5.2 Late development 38
3.5.3 Milestones in drug development 38
3.6 Regulatory environment 44
3.6.1 Legislation and guidelines 44
3.6.2 Regulatory authorities and organisations 45
3.6.3 Regulatory processes and documents 48
3.7 Quality management 58
3.7.1 General principles 58
3.7.2 Good Practices 59
3.7.3 Standard Operating Procedures (SOP) 69
3.7.4 Quality control 70
3.7.5 Audits and inspections 71
3.7.6 Quality risk management 73
3.8 Project risk management 75
3.8.1 Nature of risk 75
3.8.2 Types of risk 76
3.8.3 Analysis of risk and ‘show stoppers’ 77
3.9 Ethical considerations 78
3.9.1 General aspects 79
3.9.2 Use of experimental animals 80
3.9.3 Experiments involving human subjects 82
3.10 The global nature of drug development 87
References 89
4 Methods and Techniques Used in Drug Development 91
4.1 Introduction 91
4.2 Chemical and pharmaceutical development 91
4.2.1 Physicochemical characterisation of the active ingredient 92
4.2.2 Formulation of the active ingredient 94
4.2.3 Determination of the quality of the active ingredient and the drug
product 99
4.3 Nonclinical development 106
4.3.1 Pharmacokinetics 107
4.3.2 Safety pharmacology 119
4.3.3 Toxicology 125
Rosier ftoc.tex V3 - 05/28/2014 11:34 A.M. Page vii
CONTENTS vii
4.4 Clinical development 139
4.4.1 Pharmacometrics 139
4.4.2 Biomarkers 140
4.4.3 Imaging techniques 142
4.4.4 Human electrocardiography 146
4.4.5 Clinical trial methodology 147
4.4.6 Organisational challenges in clinical drug trials 163
References 166
5 The Early Development of a New Drug 169
5.1 Introduction 169
5.2 Pre-clinical phase 170
5.2.1 Chemical and pharmaceutical development 170
5.2.2 Nonclinical development 180
5.2.3 Clinical development 190
5.2.4 Integration and decision making 196
5.3 Clinical phase 200
5.3.1 Chemical and pharmaceutical development 201
5.3.2 Nonclinical development 215
5.3.3 Clinical development 226
5.3.4 Integration and decision making 250
References 251
6 The Late Development of a New Drug 253
6.1 Introduction 253
6.2 Pre-approval development 254
6.2.1 Chemical and pharmaceutical development 254
6.2.2 Nonclinical development 282
6.2.3 Clinical development 297
6.2.4 Integration and decision making 311
6.3 Marketing authorisation 316
6.3.1 Marketing authorisation procedures 316
6.3.2 Granting of marketing authorisation 325
6.3.3 Compassionate use and medical need programmes 326
6.3.4 Market access 327
6.4 Post-approval development 328
6.4.1 Chemical and pharmaceutical development 328
6.4.2 Nonclinical development 329
6.4.3 Clinical development 333
6.4.4 Integration and decision making 345
References 347
7 Special Drug Developments 351
7.1 Introduction 351
7.2 Development of orphan drugs 351
7.3 Paediatric drug development 354
7.3.1 PK-based dose selection 355
7.3.2 Clinical trial-based dose selection 356
7.4 Geriatric drug development 356
7.5 Development of fixed-dose drug combinations 358
7.6 Other special drug developments 360
References 360
Rosier ftoc.tex V3 - 05/28/2014 11:34 A.M. Page viii
viii CONTENTS
8 Drug Commercialisation 361
8.1 Introduction 361
8.2 Market access 363
8.2.1 Drug pricing 363
8.2.2 Drug reimbursement 364
8.2.3 Additional hurdles 369
8.3 Pharmaceutical marketing 370
8.3.1 The pharmaceutical market 370
8.3.2 General marketing principles 372
8.3.3 Pharmaceutical marketing activities 374
8.3.4 Drug promotion regulation 381
8.4 Independent drug information 382
8.5 Rational use of medicines 383
References 384
Epilogue 387
Index 391
Rosier fbetw.tex V3 - 05/28/2014 9:42 A.M. Page ix
Series Foreword
ULLA postgraduate Pharmacy Series
TheULLA Pharmacy Series is an innovative series of introductory text books
for postgraduate students and researchers in the pharmaceutical sciences.
This series is produced by the ULLA Consortium (European University
Consortium for Pharmaceutical Sciences). TheConsortium is aEuropean aca-
demic collaboration in research and teaching of the pharmaceutical sciences
that is constantly growing and expanding. The Consortium was founded in
1992 and consists of pharmacy departments from leading universities through-
out Europe including:
• Faculty of Pharmacy, Uppsala University, Sweden
• School of Pharmacy, University College London, UK
• Leiden/Amsterdam Center for Drug Research, University of Leiden and
Vrije Universiteit Amsterdam, The Netherlands
• Drug Research Academy, Faculty of Health and Medical Sciences,
University of Copenhagen, Denmark
• Faculty of Pharmacy, Paris-Sud University, France
• Department of Pharmacy, University of Parma, Italy
• Faculty of Pharmaceutical Sciences, University of Leuven (KU Leuven),
Belgium
• Faculty of Pharmacy, University of Helsinki, Finland
The editorial board for the ULLA series consists of several academics from
these European Institutions who are all experts in their individual feld of
pharmaceutical science.
Previous titles include:
Pharmaceutical Toxicology
Paediatric Drug Handling
Molecular Biopharmaceutics
Rosier fbetw.tex V3 - 05/28/2014 9:42 A.M. Page x
x SERIES FOREWORD
International Research in Healthcare
Facilitating Learning in Healthcare
Biomedical and Pharmaceutical Polymers
Inhalation Drug Delivery
The titles in this ground breaking series are primarily aimed at PhD students
and will also have global appeal to postgraduate students undertaking mas-
ters or diploma courses, undergraduates for specifc courses, and practising
pharmaceutical scientists.
Further information can be found at www.ullapharmsci.org.
Rosier f04.tex V1 - 05/28/2014 9:40 A.M. Page xi
Preface
This book is written for students in pharmacy, veterinary and humanmedicine,
chemistry and life sciences who have chosen to study drug development, and
for any reader who would like to gain a better insight into drug develop-
ment. The complete life cycle of a new drug is described in this book, with an
emphasis on drug development. It should be regarded as an introduction and
is intended to help students and interested readers on their way to exploration
and self-tuition.
The objective of this book is neither to serve as a comprehensive textbook
that describes detailed drug development methods and processes nor to
offer comparative overviews of regulatory guidelines. Other books have
been published that address specifc aspects of drug development and discuss
legislation and guidelines issued by national and international authorities in
greater detail. For example, in vitro and in vivo laboratory techniques that
are used during the discovery and development of new drugs are described
in great detail in a number of textbooks, but their integration, relevance
and interdependency into the larger context of drug development is lacking.
It is the intention of this book to fll the gap between detailed descriptions
of isolated drug development processes, techniques and approaches and
general overviews of pharmaceutical R&D that provide no insight into
the interactions between all the activities that constitute a full new drug
development process.
On reading this book the reader will have gained a better understanding of
the multidisciplinary character of drug development, the interaction between
the different scientifc disciplines involved and the terms and concepts used.
He/she will have gained more confdence in accessing relevant internet
websites and databases for specifc guidance offered by regulatory agencies
and drug development organisations. If the interested reader wants to delve
deeper into specifc aspects of drug development, references are given to
specialised books, publications of the peer-reviewed literature and regulatory
guidelines.
