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- Herausgeber: John Wiley & Sons
- Kategorie: Fachliteratur
- Sprache: Englisch
Pharmacovigilance is the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problems. This introductory guide is designed to aid the rapid understanding of the key principles of pharmacovigilance. Packed full of examples illustrating drug safety issues it not only covers the processes involved, but the regulatory aspects and ethical and societal considerations of pharmacovigilance. Covering the basics step-by-step, this book is perfect for beginners and is essential reading for those new to drug safety departments and pharmaceutical medicine students. The second edition is thoroughly revised and updated throughout and includes a new chapter on clinical aspects of pharmacovigilance.
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Seitenzahl: 268
Veröffentlichungsjahr: 2017
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Table of Contents
Cover
Title Page
About the authors
Foreword
Preface to the Second Edition
Preface to the First Edition
Acknowledgements
List of Abbreviations
1 What is Pharmacovigilance and How Has it Developed?
Origins and Definition of Pharmacovigilance
Scope and Purposes of Pharmacovigilance
Development of Pharmacovigilance
Development of Pharmacoepidemiology
Oral Contraceptives and ‘Pill Scares’
Hormone Replacement Therapy (Menopausal Hormone Therapy)
Selective Serotonin Re‐uptake Inhibitors
COX‐2 Inhibitors
Glitazones
Pandemrix
Conclusions
2 Basic Concepts
Adverse Drug Reactions
The Concept of Safety
Causation – Was the Drug Responsible?
Conclusions
3 Types and Sources of Data
Pre‐clinical Studies
Human Volunteer Studies (Phase I)
Clinical Trials (Phase II and III Studies)
Post‐marketing Surveillance (Phase IV Studies)
Spontaneous ADR Reporting Systems
Pharmacoepidemiological Studies
Prescription‐Event Monitoring
Registries
Systematic Reviews and Meta‐analysis
Conclusions
4 The Process of Pharmacovigilance
Overview – A Risk Management Process
Signal Detection
Evaluation and Investigation
Taking Action
Communication
Measuring the Effectiveness of the Risk Minimisation Process
Crisis Management
Conclusions
5 Regulatory Aspects of Pharmacovigilance
Legislation and Guidelines
Key Elements of European Legislation
Guidelines
Regulatory Pharmacovigilance Systems
Obligations of Pharmaceutical Companies
Company Pharmacovigilance Systems
ADR Reporting
Periodic Safety Update Reporting
Post‐authorisation Safety Studies
Risk Management Planning
Conclusions
6 International Collaboration
International Regulatory Collaboration
World Health Organization
Council for International Organizations of Medical Sciences
International Council on Harmonisation
International Scientific Collaboration
International Professional Societies
Conclusions
7 Clinical Aspects of Adverse Drug Reactions
Clinical Burden of ADRs
Important ADRs and Minimising Risk
Common Clinical Scenarios
Important Patient Populations
Improving Patient Safety in Clinical Practice
Conclusions
8 Ethical and Societal Considerations
Stakeholders and Their Perspectives
Ethical Principles
Informed Consent
Privacy and Confidentiality
Ethical Issues for the Pharmaceutical Industry
Ethical Safeguards in Relation to Safety
Transparency
Conflicts of Interest
Conclusions
9 Future Directions
Current Limitations
Meeting the Challenges
Education
Public Health and Policy
Conclusions
10 Learning More About Pharmacovigilance
Books
Journals
The Internet
Courses
International Societies
Final Conclusions
Glossary
Index
End User License Agreement
List of Tables
Chapter 02
Table 2.1 Summary of dose‐relatedness, time course and susceptibility (DoTS) categories.
Table 2.2 Comparison between the number of extra cases produced by differing relative risks according to the level of baseline risk.
Chapter 03
Table 3.1 Example of risk data from a cohort study design.
Table 3.2 Example of risk data from a case–control study design.
Chapter 04
Table 4.1 Example of proportional reporting ratio (PRR) calculation: rifabutin and uveitis.
Table 4.2 Descriptors originally proposed by a Council for International Organizations of Medical Sciences (CIOMS) working group.
Table 4.3 Potential for actions to improve safety related to sections of the Summary of Product Characteristics (SPC).
Table 4.4 Key requirements for a successful drug safety communication (ABOUT).
Table 4.5 Basic model for a drug safety communication.
Chapter 05
Table 5.1 Good pharmacovigilance practice (GVP) Modules.
Table 5.2 Structure of the Periodic Safety Update Report (PSUR).
Table 5.3 Structure of an EU risk management plan.
List of Illustrations
Chapter 01
Figure 1.1 Child affected by thalidomide‐induced phocomelia.
Chapter 02
Figure 2.1 The triangular relationship between a confounder, an exposure and an outcome. By influencing both the probability of being exposed and the probability of the outcome occurring, a confounder distorts the relationship of interest (i.e. between the exposure and outcome).
Chapter 04
Figure 4.1 Plot of proportional reporting ratio (PRR) vs. chi‐squared (from UK spontaneous ADR reporting data); the number of reports is used as the symbol.
Figure 4.2 Plot of PRR over time for captopril and cough (from UK spontaneous ADR reporting data); the number of reports is used as the symbol.
Chapter 05
Figure 5.1 Drug exposure versus time, demonstrating the usual situation that, while quite large numbers of patients are exposed in pre‐marketing trials for a few months, very few have been observed for more than 2 years.
Chapter 07
Figure 7.1 Photograph of patient with toxic epidermal necrolysis (TEN).
Chapter 09
Figure 9.1 Model for excellence in pharmacovigilance.
Guide
Cover
Table of Contents
Begin Reading
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An Introduction to Pharmacovigilance
Second Edition
Patrick Waller
Formerly Honorary Professor,London School of Hygiene and Tropical Medicine,London, United Kingdom
Mira Harrison‐Woolrych
Honorary Research Associate Professor,Dunedin School of Medicine, University of Otago,New Zealand; Senior Medical Assessor, Vigilance and RiskManagement, Medicines and Healthcare products RegulatoryAgency (MHRA), London, United Kingdom and Secretary Generalof the International Society of Pharmacovigilance (ISoP)
This edition first published 2017. © 2017 John Wiley & Sons LtdFirst edition published 2010 by John Wiley & Sons Ltd
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The contents of this work are intended to further general scientific research, understanding, and discussion only and are not intended and should not be relied upon as recommending or promoting a specific method, diagnosis, or treatment by physicians for any particular patient. The publisher and the author make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of fitness for a particular purpose. In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of medicines, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each medicine, equipment, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. Readers should consult with a specialist where appropriate. The fact that an organization or Website is referred to in this work as a citation and/or a potential source of further information does not mean that the author or the publisher endorses the information the organization or Website may provide or recommendations it may make. Further, readers should be aware that Internet Websites listed in this work may have changed or disappeared between when this work was written and when it is read. No warranty may be created or extended by any promotional statements for this work. Neither the publisher nor the author shall be liable for any damages arising herefrom.
Library of Congress Cataloging‐in‐Publication Data
Names: Waller, Patrick, 1957 January 30– author. | Harrison‐Woolrych, Mira, author.Title: An introduction to pharmacovigilance / Patrick Waller, Mira Harrison‐Woolrych.Description: 2nd edition. | Chichester, West Sussex, UK ; Hoboken, NJ : John Wiley & Sons Inc., [2017] | Includes bibliographical references and index.Identifiers: LCCN 2016059298| ISBN 9781119289746 (pbk.) | ISBN 9781119289753 (Adobe PDF) | ISBN 9781119289784 (epub)Subjects: | MESH: Pharmacovigilance | Drug Monitoring–methods | Drug‐Related Side Effects and Adverse Reactions | Pharmaceutical Preparations–standardsClassification: LCC RM302.5 | NLM QV 771 | DDC 615/.7042–dc23 LC record available at https://lccn.loc.gov/2016059298
A catalogue record for this book is available from the British Library.
Cover Design: WileyCover Credit: © Jorg Greuel/Gettyimages
The book is dedicated to the memory of the late Dr Susan M. Wood, an inspirational person who worked tirelessly in the field of pharmacovigilance for 10 years before her premature death in 1998.
About the authors
Patrick Waller was an Honorary Professor at the London School of Hygiene and Tropical Medicine 2011–2016 and Chair of the Independent Scientific Advisory Committee (ISAC) for Medicines and Healthcare products Regulatory Agency (MHRA) database research 2012–2016. He graduated in medicine in Sheffield, and then trained in clinical pharmacology and public health. Subsequently he worked at the Drug Safety Research Unit in Southampton and the Medicines Control Agency in London. He was Chairman of the EU Pharmacovigilance Working Party 1998–2000 and an independent consultant in pharmacovigilance and pharmacoepidemiology 2002–2011.
Mira Harrison‐Woolrych is an Honorary Research Associate Professor at the Dunedin School of Medicine, University of Otago. With a background in clinical obstetrics and gynaecology, she has over 20 years’ experience in pharmacovigilance in both the UK and New Zealand. She is currently Secretary General of the International Society of Pharmacovigilance (ISoP). As a Senior Medical Assessor at the UK MHRA, Mira specialises in women’s medicines and in 2015 edited the textbook Medicines for Women. Between 2003 and 2013, she was the Director of the NZ Intensive Medicines Monitoring Programme (IMMP) and has an extensive list of pharmacoepidemiology research publications. She has also served on several national and international pharmacovigilance committees.
Foreword
No effective medicine is without risk, and full understanding of a medicine’s safety profile is only achieved after wide clinical use. The advent of new therapies which hold the promise of transforming disease outlook means that patients and healthcare professionals are unwilling to wait to access them. It also means that the uncertainties around the balance of benefits and risks at the time of first availability of a new medicine may be greater than ever.
With every therapeutic advance, the boundaries between categories of healthcare products – medicines, advanced therapies, diagnostic agents – become ever more blurred and the practice of medicine more personalised to the individual patient. The continuing need for the study of medicines safety in wider populations could perhaps be called into question.
In fact, the study of drug safety in clinical use has moved to centre stage in public health, precisely because of the recognition that although by and large adverse effects are rare, it is only by undertaking systematic large‐scale surveillance that we can detect serious problems early and take prompt action to minimise harms – as it were, to ‘fix it while you fly’.
Pharmaceuticals are used internationally and the need for effective drug safety monitoring is recognised worldwide. A signal of a safety issue associated with a new medicine introduced in a public health programme in a resource‐limited setting is just as relevant to a patient who may receive the same medicine in a high‐tech healthcare environment. The political landscape may shift, but pharmacovigilance knows no borders.
The detection and evaluation of adverse effects associated with medicines involves specialists from a range of scientific disciplines who are attracted by the challenges of adding new knowledge that supports safe use of medicines. But pharmacovigilance can only be effective if it is relevant to the daily lives and embedded in the professional practice of all those who use medicines – the prescriber, the patient and their carer. There is clear evidence that reports from patients provide invaluable information on the impact of an adverse effect on life and work, and are of an equivalent level of seriousness to those from healthcare professionals.
This all adds up to the value of a broad appreciation and an up‐to‐date understanding of the principles and practice of pharmacovigilance. This new edition of a clear and succinct yet comprehensive guide to the field provides exactly the right introduction for those new to the challenges and the excitement of pharmacovigilance. It conveys the importance to public health protection of an effective safety net to pick up new information, and the need for well‐planned strategies to generate new evidence as an enabler of innovation.
Everyone who uses a medicine has a part to play in helping to fill the knowledge gaps on safety in as near to real‐time as possible. While pharmacovigilance has now moved on to more robust forms of evidence than reliance on individual case reports of adverse effects, the alert prescriber or patient who observes a possible link between a medicine they are using and an adverse effect is still the cornerstone of pharmacovigilance. The appreciation that each one of us has a role in drug safety means that this updated book is not only a welcome but an essential guide.
Dr June Raine CBEDirector of Vigilance and Risk Management of MedicinesMedicines and Healthcare Products Regulatory Agency, London, UK and Chair of the EU Pharmacovigilance Risk Assessment Committee
Preface to the Second Edition
The general aim of this book – to provide a brief and broad introduction for newcomers to the field which can be read through in a few hours – has not changed since publication of the first edition in early 2010. In this second edition, we have updated every chapter to reflect pharmacovigilance practice in mid‐2016 and have also broadened its international scope. Pharmacovigilance today is a global activity and our aim is to provide a short introduction relevant to readers worldwide. In response to feedback received on the first edition, we have added a new chapter on clinical aspects of pharmacovigilance (Chapter 7), which we hope will help readers without a medical background understand the importance of drug safety in ‘real life’. For reference, we have added a list of all the abbreviations used in the book and we have also considerably expanded the glossary.
All scientific books are at risk of rapidly becoming out of date. When this one was first published, major changes in the landscape of regulatory pharmacovigilance were already in progress, particularly in the European Union (EU). During the intervening years, these changes have come into force and bedded down (see Chapter 5). In June 2016, the UK electorate voted to leave the EU and the full implications of ‘Brexit’ are not yet clear. However, the need for international collaboration in pharmacovigilance will not diminish and we expect that the worldwide networks discussed in Chapter 6 will be more important than ever before.
We hope that the new edition of this book will prove useful to those entering this interesting and important field. Life may have moved on, but the challenges involved in monitoring the safety of medicines – and taking effective action to protect patients from harm – remain as great as ever.
Patrick Waller, UKMira Harrison‐Woolrych, New ZealandSeptember 2016
Preface to the First Edition
Everyone knows that safety is important but, apart from a few people whose job it is to oversee safety, this is probably something that most people have at the back of their minds for most of the time. There are likely to be two reasons for this – first, safety is about something adverse not happening (and we tend to be more concerned about things which are happening) and, secondly, it seems to be human nature to think that ‘it will not happen to me’, perhaps as a mechanism for coping with potential threat of something devastating.
The past decade has seen a marked rise in the numbers of people working in the field of clinical drug safety or pharmacovigilance, mostly in the pharmaceutical industry. The trend seems likely to continue, hopefully reflecting a greater focus on the safety of medicines. This book is specifically targeted at newcomers to the field who, of necessity, are often narrowly focused, and it aims to provide them with a brief and broad introduction to the field. My purpose here is to aid rapid understanding of the environment and key principles of pharmacovigilance at the industry–regulatory interface.
My background is in regulation and my experience is of the UK and EU systems and I readily acknowledge these inherent biases in my narrative. This book probably will not help the newcomers with detailed day‐to‐day aspects of their job but I hope it will enable them to see where they fit into a bigger picture. I have assumed that readers will at least have a science degree but not necessarily much specific knowledge about drugs.
The new entrant needs to know how we got where we are today. The most important historical drug safety issues have shaped the development of pharmacovigilance and I have therefore used these as a starting point. I hope that the book will also help the newcomers to appreciate that they are now working in an interesting and important field that is likely to develop much in the near future.
I have deliberately not included any reference citations within the text since, initially, I hope the reader will want to read on rather than go elsewhere. Ample references can be found in the larger texts on to which the reader should next move. In the last chapter, I have selectively cited some important sources that might usefully be consulted for further reading. A glossary defining key terms is provided at the end for reference.
Patrick Waller
Acknowledgements
We are most grateful to Ian Boyd and Nourieh Hoveyda who provided valuable comments on the whole redrafted manuscript for this edition. We are also grateful to the following people for review of specific chapters and useful suggestions: Priya Bahri, Keith Beard, Stephen Evans, Valerie Joynson, Marie Lindquist, Julie Williams and Jonathan Woolrych. We would also like to thank the Medicines and Healthcare products Regulatory Agency for providing data from the Yellow Card scheme.
List of Abbreviations
ACE
angiotensin converting enzyme
ADR
adverse drug reaction
AE
adverse event
ATC
Anatomical Therapeutic Chemical (classification system)
CIOMS
Council for International Organizations of Medical Sciences
COX
cyclo‐oxygenase
CSM
Committee on Safety of Medicines
CTD
Common Technical Document
CYP450
cytochrome P450
DIA
Drug Information Association
DoTS
dose‐relatedness, time course and susceptibility
DSRU
Drug Safety Research Unit
DSUR
Development Safety Update Report
EBGM
empirical Bayes geometric mean
ECG
electrocardiogram
EMA
European Medicines Agency
ENCePP
European Network of Centres for Pharmacoepidemiology and Pharmacovigilance
ESoP
European Society of Pharmacovigilance (now ISoP)
ESTRI
Electronic Standards for the Transfer of Regulatory Information
EU2P
European Programme in Pharmacovigilance and Pharmacoepidemiology
FDA
Food and Drug Administration
2G
second generation (oral contraceptive)
3G
third generation (oral contraceptive)
GP
general practitioner
GVP
good pharmacovigilance practice
HRT
hormone replacement therapy
IBD
international birth date
IC
information component
ICH
International Council (formerly Conference) on Harmonisation of Technical Requirements for Pharmaceuticals for Human Use
ICMRA
International Coalition of Medicines Regulatory Authorities
IMMP
Intensive Medicines Monitoring Programme
ISoP
International Society of Pharmacovigilance
ISPE
International Society for Pharmacoepidemiology
MA
marketing authorisation
MedDRA
Medical Dictionary for Regulatory Activities
MGPS
Multi‐Item Gamma Poisson Shrinker
MHRA
Medicines and Healthcare products Regulatory Agency
MHT
menopausal hormone therapy
MMR
measles, mumps and rubella (vaccine)
NOAC
novel oral anticoagulant
NSAID
non‐steroidal anti‐inflammatory drug
OC
oral contraceptive
OTC
over‐the‐counter (medicine)
PASS
post‐authorisation safety study
PBRER
Periodic Benefit–Risk Evaluation Report
PEM
prescription‐event monitoring
PIDM
Programme for International Drug Monitoring
PIL
Patient Information Leaflet
PPAR
peroxisome proliferator‐activated receptor
PRAC
Pharmacovigilance Risk Assessment Committee
PRR
proportional reporting ratio
PSUR
Periodic Safety Update Report
QPPV
qualified person for pharmacovigilance
RMP
risk management plan
ROR
reporting odds ratio
SAMM
Safety Assessment of Marketed Medicines
SIG
special interest group
SJS
Stevens–Johnson syndrome
SPC (or SmPC)
Summary of Product Characteristics
SSRI
selective serotonin re‐uptake inhibitor
SUSAR
serious and unexpected suspected adverse reaction
TEN
toxic epidermal necrolysis
TGA
Therapeutic Goods Administration
UMC
Uppsala Monitoring Centre
UNESCO
United Nations Educational, Scientific and Cultural Organization
VTE
venous thromboembolism
WHO
World Health Organization
WHO‐ART
World Health Organization Adverse Reaction Terminology
WHO‐PIDM
World Health Organization Programme for International Drug Monitoring
WMA
World Medical Association
1What is Pharmacovigilance and How Has it Developed?
Origins and Definition of Pharmacovigilance
In the beginning, there was thalidomide. The history of drug safety goes back further but, for practical purposes, the story of modern pharmacovigilance begins there.
In the late 1950s there was little, if any, regulation of medicines outside the USA (where thalidomide was not allowed on to the market), and their testing and development was almost entirely in the hands of pharmaceutical companies. In the case of thalidomide, unjustified claims of safety in pregnancy were made, and its use as a sedative and treatment for nausea and vomiting was targeted at pregnant women. The drug turned out to be a teratogen, producing a variety of birth defects but particularly limb defects known as phocomelia (Figure 1.1). Worldwide, about 10 000 babies were affected, particularly in Germany where the drug was first marketed. As phocomelia was otherwise a very rare congenital abnormality, a major increase in its incidence did not go unnoticed in Germany, but the cause was initially thought to be environmental. In 1961, a series of just three cases of congenital anomalies associated with thalidomide use in Australia was reported in The Lancet, the problem was finally recognised and the drug withdrawn from sale.
Figure 1.1 Child affected by thalidomide‐induced phocomelia.
At the beginning of the 1960s, publication of possible adverse effects of drugs in the medical literature was effectively the only mechanism for drawing attention to them. Thalidomide produced a non‐lethal but visible and shocking adverse effect, leading people to ask why so many damaged babies had been born before anything had been done? This question is central to subsequent developments. It is unlikely that we will ever be able to predict and prevent all the harms that may be caused by medicines, but limiting the damage to much smaller numbers is now achievable. Today we would expect to be able to identify an association between drug and outcome analogous to thalidomide and phocomelia after the occurrence of less than 10 cases, so at least three orders of magnitude more effectively than six decades ago.
The overriding lesson learnt from thalidomide was that we cannot just wait until a drug safety problem hits us. The thalidomide tragedy of the 1960s led directly to the initial development of the systems we have in place today, although it is only since the early 1990s that the term pharmacovigilance has become widely accepted.
Pharmacovigilance is defined by the World Health Organization as ‘The science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug‐related problems.’ There are other definitions but this very broad one seems to be the most appropriate because there is a clear implication that the process is one of risk management. This is a concept that is applicable to many aspects of modern life but, surprisingly, its explicit use in relation to pharmaceuticals is a fairly recent development.
Thalidomide is not merely of historical interest, as in recent years it has made a comeback on to the market in some countries but with very narrow indications and extensive safeguards. The reasons for this exemplify the point about risk management, as the risk of fetal malformation can be successfully managed by avoidance of the drug during pregnancy. It also demonstrates another concept that is central to the practice of pharmacovigilance – the balance of benefit and risk. Thalidomide has benefits in some diseases that are otherwise difficult to treat (e.g. refractory multiple myeloma) and these appear to outweigh the risk of fetal malformation if there is an effective pregnancy prevention scheme in place. A further point that thalidomide illustrates well – and which is relevant to many other drug safety issues – is that not everyone is at the same risk of a particular adverse effect. In this case, a substantial part of the population (including men and also women who are not of childbearing capacity) are not at risk of phocomelia.
Main Lessons Learned from Thalidomide
The thalidomide tragedy taught us many lessons:
The need for adequate testing of medicines prior to marketing.
The need for government regulation of medicines.
The need for reporting systems to
identify
the adverse effects of medicines.
The potential safety implications of unproven marketing claims.
Most medicines cross the placenta and this results in fetal exposure.
Avoidance of unnecessary use of medicines in pregnancy.
That some risks can be successfully minimised.
The ramifications of the thalidomide tragedy were manyfold, but the key lesson for the development of pharmacovigilance was that active systems for detecting hazards are needed. Within a few years this had been taken forward with the introduction of voluntary (or ‘spontaneous’) schemes for reporting of suspected adverse drug reactions (ADRs). These have stood the test of time as an alerting mechanism or early warning system, and are covered in more detail in Chapter 3.
Scope and Purposes of Pharmacovigilance
In the past, the process of pharmacovigilance has often been considered to start when a drug is first authorised for use in ordinary practice. Nowadays, it is more commonly considered to include all safety‐related activity beyond the point at which humans are first exposed to a new medicinal product.
The ultimate purpose of pharmacovigilance is to minimise, in practice, the potential for harm that is associated with all active medicines. Although data about all types of ADRs are collected, a key focus is on identifying and preventing those that are defined to be serious. This is generally defined as an ADR that meets at least one of the following criteria:
Fatal
Life‐threatening
Causes or prolongs hospitalisation
Results in long‐term disability
All congenital anomalies.
The definition of serious also allows the application of medical judgement, such that a reaction can be considered serious even if there is not clear evidence that one of the above criteria is met. Non‐serious reactions are important to individual patients and health professionals involved in their treatment, but they can usually be managed clinically and impact less on the balance of benefit and risk for individual products and on public health in general.
Thus, pharmacovigilance can be seen as a public health function in which reductions in the occurrence of serious harms are achievable through measures that promote the safest possible use of medicinal products and/or provide specific safeguards against known hazards. Pregnancy prevention in users of thalidomide is an example of such a safeguard; monitoring white blood cell counts to detect agranulocytosis (absent white blood cells) in users of the antipsychotic drug clozapine is another (see Chapter 7).
In order to minimise harms, there is first a need to identify and assess the impact of unexpected potential hazards. For most medicines, serious ADRs are rare, otherwise their detection would result in the drug not reaching (or being withdrawn from) the market. For products that do reach the market, serious hazards are seldom identified during pre‐marketing clinical trials because sample sizes are invariably too small to detect them. In addition, the prevailing conditions of clinical trials – selected patients, short durations of treatment, close monitoring and specialist supervision – usually mean that the frequency of ADRs will be underestimated relative to what will really occur in ordinary practice.
During pre‐marketing clinical development and research on new medicines, the aims of pharmacovigilance are rather different from the broad public health functions described here. In volunteer studies and clinical trials, there is a need to protect individuals exposed to experimental products (from which they may derive no benefit) from potential harm. There is also a need to gather information on risks (including the frequencies at which they happen) in order to make a provisional assessment of safety and to plan for post‐marketing safety development (see Risk Management Planning in Chapter 5).
Development of Pharmacovigilance
We next consider some of the most important examples of drug safety issues and discuss how they have affected the development of pharmacovigilance practice from the 1960s to the present day.
Practolol
In the early 1970s another drug safety disaster occurred; this was the oculo‐mucocutaneous syndrome, a multi‐system disorder, caused by practolol (Eraldin), a cardioselective beta‐blocker used to treat angina and hypertension. As in the case of thalidomide, several thousand individuals were permanently damaged before the association was recognised. The fundamental problem in this instance was a failure of timely identification, as despite having an early warning system in place, the system was dependent on doctors suspecting an association between drug and disease. Probably because of the unusual nature of the syndrome – dry eyes, skin rash and bowel obstruction – and a long latency period (averaging almost 2 years in respect of the onset of the most serious bowel manifestations), relevant cases were not reported until the association was identified in the medical literature. Around 3000 cases were then retrospectively reported to the UK Yellow Card spontaneous ADR reporting scheme (see Chapter 3), an example of the potential effect of publicity on ADR reporting. Interestingly, subsequent attempts to develop an animal model of practolol toxicity failed, indicating that the problem could not have been predicted from pre‐clinical studies.
Main Lessons Learned from Practolol
Some adverse effects are not predictable from pre‐clinical studies.
Spontaneous reporting schemes are not always effective at identifying new ADRs.
