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Herausgeber: John Wiley & Sons
Kategorie: Wissenschaft und neue Technologien
Serie: Postgraduate Pharmacy Series
Sprache: Englisch

Beschreibung

The development of new drugs is very complex, costly and risky. Its success is highly dependent on an intense collaboration and interaction between many departments within the drug development organization, external investigators and service providers, in constant dialogue with regulatory authorities, payers, academic experts, clinicians and patient organizations. Within the different phases of the drug life cycle, drug development is by far the most crucial part for the initial and continued success of a drug on the market.

This book offers an introduction to the field of drug development with a clear overview of the different processes that lead to a successful new medicine and of the regulatory pathways that are used to launch a new drug that are both safe and efficacious.

"This is the most comprehensive and detailed book on drug development I have ever read and I feel that it is likely to become a staple of drug development courses, such as those taught at Masters Level in my own University.... I think in the light of increasing integration of company and academic approaches to drug development both sides can read this book... (and, therefore)... this book could not be more timely."
—Professor Mike Coleman, University of Aston, UK ( from his review of the final manuscript)

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Leseprobe

Cover

Title Page

Series Foreword

ULLA postgraduate Pharmacy Series

Preface

Acknowledgements

Abbreviations

Introduction

Chapter 1: Drug Life Cycle

1.1 Introduction

1.2 Drivers of the search for a new drug

1.3 Structure of a drug life cycle

1.4 Costs and risks of drug research and development

1.5 Risks of drug R&D

1.6 Value for patient and society

1.7 The end of a drug's life

1.8 Management

References

Chapter 2: Drug Discovery and Design

2.1 Introduction

2.2 Approaches in drug discovery

2.3 The drug discovery process

References

Chapter 3: Drug Development: General Aspects

3.1 Introduction

3.2 The objective of drug development

3.3 Drug development organisations and teams

3.4 Drug development streams

3.5 Phases in drug development

3.6 Regulatory environment

3.7 Quality management

3.8 Project risk management

3.9 Ethical considerations

3.10 The global nature of drug development

References

Chapter 4: Methods and Techniques Used in Drug Development

4.1 Introduction

4.2 Chemical and pharmaceutical development

4.3 Nonclinical development

4.4 Clinical development

References

Chapter 5: The Early Development of a New Drug

5.1 Introduction

5.2 Pre-clinical phase

5.3 Clinical phase

References

Chapter 6: The Late Development of a New Drug

6.1 Introduction

6.2 Pre-approval development

6.3 Marketing authorisation

6.4 Post-approval development

References

Chapter 7: Special Drug Developments

7.1 Introduction

7.2 Development of orphan drugs

7.3 Paediatric drug development

7.4 Geriatric drug development

7.5 Development of fixed-dose drug combinations

7.6 Other special drug developments

References

Chapter 8: Drug Commercialisation

8.1 Introduction

8.2 Market access

8.3 Pharmaceutical marketing

8.4 Independent drug information

8.5 Rational use of medicines

References

Epilogue

Index

End User License Agreement

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Guide

Cover

Table of Contents

Preface

Introduction

Begin Reading

List of Illustrations

Figure 1.1

Figure 2.1

Figure 2.2

Figure 3.1

Figure 3.2

Figure 3.3

Figure 3.4

Figure 3.5

Figure 3.6

Figure 4.1

Figure 4.2

Figure 4.3

Figure 4.4

Figure 4.5

Figure 4.6

Figure 4.7

Figure 4.8

Figure 4.9

Figure 4.10

Figure 4.11

Figure 4.12

Figure 4.13

Figure 4.14

Figure 4.15

Figure 4.16

Figure 4.17

Figure 4.18

Figure 4.19

Figure 4.20

Figure 4.21

Figure 5.1

Figure 5.2

Figure 5.3

Figure 5.4

Figure 5.5

Figure 5.6

Figure 5.7

Figure 5.8

Figure 5.9

Figure 5.10

Figure 6.1

Figure 6.2

Figure 6.3

Figure 6.4

Figure 6.5

Figure 6.6

Figure 6.7

Figure 6.8

Figure 6.9

Figure 6.10

Figure 6.11

Figure 6.12

Figure 6.13

Figure 6.14

Figure 6.15

Figure 6.16

Figure 6.17

Figure 6.18

Figure 6.19

Figure 6.20

Figure 6.21

Figure 6.22

Figure 6.23

Figure 8.1

Figure 8.2

Figure 8.3

List of Tables

Table 3.1

Table 3.2

Table 3.3

Table 3.4

Table 3.5

Table 3.6

Table 3.7

Table 3.8

Table 3.9

Table 3.10

Table 3.11

Table 4.1

Table 4.2

Table 4.3

Table 4.4

Table 4.5

Table 4.6

Table 4.7

Table 4.8

Table 4.9

Table 4.10

Table 4.11

Table 5.1

Table 5.2

Table 5.3

Table 5.4

Table 5.5

Table 5.6

Table 5.7

Table 5.8

Table 5.9

Table 5.10

Table 6.1

Table 6.2

Table 6.3

Table 6.4

Table 6.5

Table 6.6

Table 6.7

Table 6.8

Table 7.1

Table 7.2

Table 8.1

Table 8.2

Table 8.3

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

Registered office: John Wiley & Sons, Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK

Editorial offices: 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 offices, 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 identified 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 specifically disclaim any implied warranties of merchantability or fitness 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

Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books.

1 2014

Series Foreword

ULLA postgraduate Pharmacy Series

The ULLA 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). The Consortium is a European academic 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 throughout 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 field of pharmaceutical science.

Previous titles include:

Pharmaceutical Toxicology

Paediatric Drug Handling

Molecular Biopharmaceutics

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 masters or diploma courses, undergraduates for specific courses, and practising pharmaceutical scientists.

Further information can be found at www.ullapharmsci.org.

Preface

This book is written for students in pharmacy, veterinary and human medicine, 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 development. 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 specific 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 fill 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 scientific disciplines involved and the terms and concepts used. He/she will have gained more confidence in accessing relevant internet websites and databases for specific guidance offered by regulatory agencies and drug development organisations. If the interested reader wants to delve deeper into specific aspects of drug development, references are given to specialised books, publications of the peer-reviewed literature and regulatory guidelines.

Although drug development is a structured process, it allows for the adaptation of the several steps to be taken due to the specific needs of the therapeutic area, the nature of the drug and its route of administration. Since the concept of the book is an introduction to drug development we chose to limit the scope to the development of small molecules with a preference for the oral route of administration. The development of large molecule drugs (e.g. monoclonal antibodies, oligonucleotides) and vaccines—also referred to as biologic(al)s or biopharmaceuticals—are not discussed because the strategies followed in their development are different from those applied in the ‘traditional’ approach of small molecules. The development of biologicals requires a separate book.

An introduction to drug development necessarily includes an introduction to the legislation and regulatory guidelines that govern these processes. However, it is not the ambition of this book to offer a detailed description of all relevant guidelines nor does it quote texts from these guidelines. It has been written from the viewpoint of a drug development team and the individuals who are involved in and committed to the development of a drug and takes the reader through the consecutive steps, while referring to relevant guidelines when needed. For practical reasons preference is given to guidelines issued by the International Conference on Harmonisation (ICH), the European Medicines Agency (EMA) and the US Food and Drug Administration (US FDA).

Regulatory authorities from around the world use different terms to describe processes and phases in drug development. For example, the European Union (EU) guidelines refer to a ‘pre-authorisation phase’ to discuss the processes that take place before the drug is granted a marketing authorisation. The US FDA uses the term ‘pre-approval phase’ to denote the same stage of development. In this book preference is given to the terminology used by the regulatory authorities of the region in the world where the regulatory process applies. For example, the term IND (Investigational New Drug) Application is used for a clinical trial authorisation in the USA, whereas the term Clinical Trial Application (CTA) is used for the same process in the EU. When processes are discussed that are applicable to both regions in the world preference is given to the terminology generally used by drug development teams. In very specific cases, the differences in terminology are clearly explained to avoid confusion.

Jan A. RosierMark A. MartensJosse R. Thomas

Acknowledgements

We would like to thank Arthur Van Aerschot, professor in medicinal chemistry and head of the Department of Pharmaceutical and Pharmacological Sciences at the University of Leuven (KU Leuven) who invited us to write a book on drug development as part of the ULLA series of textbooks in pharmaceutical sciences.

We are also indebted to the experts in drug research and development, regulatory sciences and pharmaceutical business who were so kind as to review parts of the book that belong to their field of expertise and offered their comments:

Bart De Spiegeleer, expert in drug quality and registration, professor at the Faculty of Pharmaceutical Sciences of Ghent University (UGent); Luc Janssens, senior director worldwide CMC regulatory affairs at Janssen R&D, Belgium; Kenny Simmen, vice-president infectious diseases discovery at Janssen R&D, Belgium; Gerben Van ′t Klooster, vice-president drug development at Galapagos, Belgium; Araz Raoof, vice-president and global functional head discovery sciences at Janssen R&D, Belgium; Jan De Hoon, clinical pharmacologist, professor at the Faculty of Medicine of the University of Leuven (KU Leuven) and head of the Center for Clinical Pharmacology of the university hospitals of Leuven (UZ Leuven), Belgium; Katelijne De Nys, radiation oncologist, professor at the Faculty of Medicine of the University of Leuven (KU Leuven), head of the Clinical Trial Center of the university hospitals of Leuven (UZ Leuven) and president of the committee for reimbursement of drugs (CTG-CRM) at the National Institute for Insurance of Disease and Invalidity (RIZIV-INAMI), Belgium; Lieven Annemans, health economist, professor at the Faculty of Medicine and Health Sciences of Ghent University (UGent) and at the Faculty of Pharmacy of the Vrije Universiteit Brussel (VUB), Belgium; and Marijke Van Zieleghem, group product manager, marketing department, Servier Benelux, Belgium.

We are grateful to the reviewers who were appointed by Wiley as experts in the field of drug development for the help they provided to us in the early phases of the writing of this book: Michael Coleman, professor of toxicology at Aston University, Birmingham, UK and Louis Lazo Radulovic, adjunct professor of toxicology at the University of Michigan, USA.

We would also like to thank the students in pharmaceutical sciences of the University of Leuven (KU Leuven) who read certain parts of the book and provided feedback on the content and the clarity of the texts: Sophie Bogaert, Anne Calsius, Christel Claes, Barbara Mertens, Chloé Scheldeman and Eveline Wijckmans.

The authors wish to thank the staff of Wiley Publishers, particularly Fiona Seymour, senior project editor, who steered us through this project with great patience.

The understanding and support of our families, sometimes taken for granted, was key to the successful completion of this book. Therefore we would like to dedicate this book to our spouses, children and grandchildren.

Jan A. RosierMark A. MartensJosse R. Thomas

Abbreviations

ACE

Angiotensin-Converting Enzyme

ADME

Absorption, Distribution, Metabolism and Excretion

ADR

Adverse Drug Reaction

Adverse Event

Assessment factor

AIDS

Acquired Immuno-Deficiency Syndrome

ALARP

As Low As Reasonably Practicable

AMS

Accelerator Mass Spectrometry

APD

Action Potential Duration

API

Active Pharmaceutical Ingredient

ARR/RD

Absolute Risk Reduction or Risk Difference

ASMF

Active Substance Master File

AUC

Area Under the Curve (plasma concentration versus time curve of a drug)

BCOP

Bovine Corneal Opacity and Permeation (assay)

BCS

Biopharmaceutics Classification System

BIA

Budget Impact Analysis

CABG

Coronary Artery Bypass Graft (surgery)

CAM

ChorioAllantoic Membrane

CAPA

Corrective And Preventive Actions

CBA

Cost-Benefit Analysis

CDER

Center for Drug Evaluation and Research (FDA)

CEA

Cost-Effectiveness Analysis

CEP

Certificate of the European Pharmacopoeia

CER

Comparative Efficacy/Effectiveness Research

CHMP

Committee for Medicinal Products for Human use (EMA)

Confidence Interval

tot

Total Body Clearance

CMA

Cost-Minimization Analysis

max

Maximum Plasma Concentration

CMC

Chemistry, Manufacturing, and Controls

CNS

Central Nervous System

CoG

Cost of Goods

CRA/CSM

Clinical Research Associate or Clinical Study Monitor

CRF

Case Report Form

CRO

Contract Research Organisation

CRP

C-Reactive Protein

(X-ray) Computed Tomography

CTA

Clinical Trial Application or Clinical Trial Authorisation or Clinical Trial Agreement

CTD

Common Technical Document

CUA

Cost-Utility Analysis

Cardiovascular

DMC/DSMB

Data Monitoring Committee or Data and Safety Monitoring Board

DMF

Drug Master File

Environmental Assessment (USA)

EAD

Early After Depolarisation

EBM

Evidence-Based Medicine

European Commission

Concentration at which an Effect is observed in 50% of the tested population

ECG

Electrocardiogram

EEA

European Economic Area (European Union plus Norway, Iceland and Liechtenstein), sometimes described as the ‘European Community’ or ‘Europe’ or the ‘European region’

EMA

European Medicines Agency

EoPh2

End of Phase 2

Endpoint

EPAR

European Public Assessment Report

ERA

Environmental Risk Assessment (EU)

ETT

Exercise Tolerance Test

European Union, currently 28 Member States