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xii
duciary duty, the duty to protect the public from harm, privacy, consent,
scientic integrity, and conicts of interest.
The last third of the book moves to safe prescribing and practice, opening
with the errors associated with the medication use process in Chap. 15. The
various types of medication errors, methods of detection, factors that contribute to error, and strategies for risk mitigation are discussed—including educational interventions, error reporting systems, and the role of medication safety
ofcers. Chapter 16 outlines the various study designs of Post-Authorisation
Safety Studies (PASS) used to identify ADRs, and the various challenges in
diagnosing and managing ADRs. This chapter also summarises various strategies to predict and thereby prevent ADRs such as pharmacogenetics, use of
omics, and in silico approaches including articial intelligence.
To facilitate the decision-making process in drug safety and subsequent
communication of drug safety issues to patients and their families, identifying and utilising appropriate health and medicines information sources is
critical. Chapter 17 discusses various information sources for drug safety and
communicating risks in practice. Chapter 18 describes and distinguishes
appropriate and inappropriate polypharmacy, and outlines the tools to identify inappropriate prescribing, and the approaches to involving patients in
discussions about their medicines. The concept of deprescribing, and the purpose and process involved is discussed in this chapter. The complexities of
special patient groups are covered in Chaps. 19 to 22, including the paediatric
population (Chap. 19), older people (Chap. 20), pregnancy and breast feeding
(Chap. 21), and renal and hepatic diseases (Chap. 22). These chapters outline
the main factors that increase the risk of medication safety incidents in these
special patient populations. Key safety considerations for prescribing medications in these populations are discussed. The benets of pharmacogenomics have been forecast for many years, with a tipping point into wider utility
occurring in recent years. Chapter 23 covers the key developments in the
application of pharmacogenetics in improving drug safety and the exciting
possibilities to reduce the harm of medicines they promise.
As with any human task, our achievements may not meet our original
vision, but we hope that we have covered most of the key aspects of pharmacovigilance and drug safety. However, we are aware that some areas covered
as elements of a chapter might be thought to deserve a chapter in their own
right by some readers. The eld of industry and regulatory pharmacovigilance is very wide, as are the issues in clinical practice, and we welcome
feedback on the content of the book. Although we took utmost care in avoiding errors through a two-tier review; editors and expert reviewers, any suggestions, feedback, errors noticed, and ideas for additional elements would be
welcomed.
We hope you enjoy the book and nd it useful.
Preface
Nizwa, Oman JimmyJose
Birmingham, UK AnthonyR.Cox
London, UK VibhuPaudyal
Acknowledgements
We are immensely grateful for the contributions made by all authors involved
from across the globe who gave their valuable time to complete this book.
The authors represent a wealth of expertise and interest in pharmacovigilance
in the pharmaceutical industry, healthcare practice, drug safety research,
health economics, policy, and patient and public involvement, and we are
humbled by their dedication to this project. Additionally, these independent
experts and researchers selessly invested time as peer reviewers during the
production of this book, providing thorough and constructive insights. We
would particularly like to thank Brian Edwards, Olav Spigset, and Francisco
J. de Abajo for their outsized contributions.
In addition to the chapter authors who performed this role, we would like
to thank Andrew McLachlan, Ann Daly, Christine Erikstrup Hallgreen, Deb
Pasko, Derek Stewart, Gianluca Triro, James Stevenson, Kavitha Saravu,
Kumi Om, Marleen van Gelder, Patrick Edwards, Pramod Kumar, Saval
Khanal, Shusen Sun, and Tanja Fens for their time and efforts in reviewing
the manuscripts.
We are thankful to our parent institutions for the support provided in our
endeavours. We are also indebted to the support offered by Springer staff,
especially Susanne Dathe, the project editor, and the production editors.
Susanne supported us relentlessly from the initial proposal during the pandemic to completion, and her sincere regular follow-ups and responses to
queries were a welcome boost during difcult times.
Vibhu and Anthony would also like to personally thank Jimmy for his
leadership as lead editor throughout this process.
xiii
Contents
Part I Principles and Practice of Pharmacovigilance
and Drug Safety
1 Introduction to Drug Safety and Pharmacovigilance . . . . . . . . . 3
Jimmy Jose, Anthony R. Cox, and Andrew Bate
2 An Overview of Immunological Reactions to Drugs . . . . . . . . . . 31
Sowmya Nagarajan, Bernard Yu-Hor Thong,
Rashmeet Bhogal, and Mamidipudi Thirumala Krishna
3 Predisposing Factors for Adverse Drug Reactions. . . . . . . . . . . . 45
Jimmy Jose and Francisco J. de Abajo
4 Drug Interactions and Their Management . . . . . . . . . . . . . . . . . . 77
Suzanne McCarthy and Aoife Fleming
5 Economics of Medication Safety, with a Focus on
Preventable Harm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
Rachel A. Elliott
6 Principles of Pharmacovigilance and Drug Regulation . . . . . . . 135
Lourens T. Bloem, Menno E. van der Elst,
and Olaf H. Klungel
7 Clinical Trials Safety Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
Pipasha Biswas, Nilima Justice, and Himal Biswas
8 Causality Assessment in Pharmacovigilance . . . . . . . . . . . . . . . . 191
Madhan Ramesh and Anand Harugeri
9 Pharmacoepidemiologic Studies . . . . . . . . . . . . . . . . . . . . . . . . . . 209
Deborah Layton
10 Spontaneous Reporting Systems . . . . . . . . . . . . . . . . . . . . . . . . . . 231
Jan Petracek and Marcela Fialova
11 Communicating Drug Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251
Marco Tuccori, Irma Convertino, Sara Ferraro,
Marco Bonaso, Giulia Valdiserra, and Emiliano Cappello
xv
xvi
12 Patient and Public Involvement in Pharmacovigilance . . . . . . . . 273
Florence van Hunsel, Manal M. Younus,
and Anthony R. Cox
13 Collaborative Approaches to Establishing and
Implementing Pharmacovigilance Systems . . . . . . . . . . . . . . . . . 295
Brian Edwards and Angela Caro-Rojas
14 Ethics in Pharmacovigilance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319
Alison Thompson and Ana Komparic
Part II Safer Prescribing and Drug use in Practice
15 Medication Errors in Healthcare . . . . . . . . . . . . . . . . . . . . . . . . . . 341
Myungsun Ro, Daniel Degnan, and John Hertig
16 Methods to Detect, Predict, and Prevent Adverse Drug
Reactions in Pharmacovigilance and Clinical Practice . . . . . . . . 369
Jeffrey Pradeep Raj, Nithya J. Gogtay,
and Suparna Chatterjee
17 Information Sources for Drug Safety and
Communicating Risks in Practice . . . . . . . . . . . . . . . . . . . . . . . . . 387
Vivien Tong, Mathias Møllebæk, and Parisa Aslani
Contents
18 Polypharmacy and Deprescribing . . . . . . . . . . . . . . . . . . . . . . . . . 405
Alpana Rajesh Mair, Margaret Jordan, and Judy Mullan
19 Safe Prescribing and Monitoring in Pediatrics . . . . . . . . . . . . . . 437
Jeremy S. Stultz and Milap C. Nahata
20 Safe Prescribing and Monitoring in the Older Person . . . . . . . . 459
Alpana Rajesh Mair, Amil Rajesh Mair, Sarah N. Hilmer,
and Lisa Kouladjian O’Donnell
21 Safe Prescribing and Drug Use in Pregnancy
and Breastfeeding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 483
Hedvig Nordeng, Eva Jirsová, and Olav Spigset
22 Safe Prescribing in Patients with Kidney and Hepatic
Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 511
Wubshet Tesfaye, Ronald L. Castelino, Monica Zolezzi,
and Fatima Small
23 Clinical Applications of Pharmacogenetics in Improving
Drug Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 539
Katja S. Just and Julia C. Stingl
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 551
Part I
Principles and Practice of
Pharmacovigilance and Drug Safety
Introduction toDrug Safety
andPharmacovigilance
JimmyJose, AnthonyR.Cox, andAndrewBate
1
Abstract
This chapter will introduce the main terms and
concepts related to drug safety. This includes
denitions, epidemiology, diagnosis, and classication of adverse drug reactions (ADRs) as
well as the shift to a more holistic view of drug
safety in relation to medication errors, issues
in clinical practice, and regulatory approaches.
The development of modern pharmacovigilance and drug safety practices can be attributed to a series of drug safety events that took
place throughout the twentieth century. Even
with high-quality randomized controlled trials, the safety of new medicines is not guaranteed due to limitations of the clinical trials,
such as trial size, exclusion of subjects at risk
of developing ADRs, short trial durations, and
J. Jose (*)
Pharmacy Practice, School of Pharmacy, College of
Health Sciences, University of Nizwa,
Nizwa, Oman
e-mail: jimmy.jose@unizwa.edu.om
A. R. Cox
Clinical Pharmacy and Drug Safety School of
Pharmacy, College of Medical and Dental Sciences
University of Birmingham, Birmingham, UK
A. Bate
GSK, Brentford, UK
London School of Hygiene and Tropical Medicine,
London, UK
the nature of potential ADRs. Clinical trials
are unlikely to detect infrequent ADRs or
those that are delayed. Once marketed, large
numbers of individuals can be exposed to the
drug and detection of new ADRs is possible.
Spontaneous reporting of ADRs by healthcare professionals and patients is one of the
primary methods of detecting new safety signals, and post-marketing observational studies
using real-world data are used to investigate
potential signals. For methodological reasons,
several terms related to ADRs, as well as dictionaries of ADRs, have been developed,
which are essential for the quantitative examination of drug safety issues. Pharmacovigilance
is a collaborative venture including healthcare professionals, patients, regulators, and
pharmaceutical companies to ensure that the
chances of nding new safety issues are
maximized.
Even following successful detection of an
ADR, the complex communication and ethical
issues present challenges. In clinical practice,
the burden of harms generally comes from the
most frequently used drugs, and good patient
management is enhanced by understanding of
the principles and methods in pharmacovigilance and the safe use of medicines. At the
local level, managing polypharmacy in an
aging population will become increasingly
challenging. The future of pharmacovigilance
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024
J. Jose et al. (eds.), Principles and Practice of Pharmacovigilance and Drug Safety,
https://doi.org/10.1007/978-3-031-51089-2_1
3
4
J. Jose et al.
will see major developments in pharmacoinformatics, articial intelligence, and pharmacogenomics. Continued educational efforts at
both the undergraduate and postgraduate levels are required to enhance the effective practice of drug safety and pharmacovigilance.
Keywords
Adverse drug reactions · Adverse events ·
Pharmacovigilance · Drug safety · Patient
safety
Learning Objectives
After reading this chapter, the reader should be
able to:
• Understand the origins of drug safety and
pharmacovigilance.
• Understand the importance of drug safety at
population and individual patient levels.
• Describe the various denitions of the key
terms in drug safety and pharmacovigilance.
• Understand the basic principles that govern
the practice of drug safety.
• Describe the key aspects of pharmacovigilance systems and regulation.
Key Points
• Pharmacovigilance is an evolving sci-
ence consisting of multiple methodologies, with complex communication
issues with health- care professionals,
patients, and broader society.
• Understanding the key terminology is
useful for applying pharmacovigilance
in clinical practice.
• Among other skills, quantitative and
clinical skills are important for pharmacovigilance science, which underscores
the importance of multidisciplinary
pharmacovigilance teams.
• Pharmacovigilance has the safety of
individual patients and the assessment
of the harm of medicines at the population level as its central tenets.
1 Introduction
Drug safety and pharmacovigilance encompass a
wide eld of knowledge, from individual risk
factors and management of adverse effects in
patients to population-level science to detect the
novel risks of medicines. This includes complex
and evolving methodologies as well as difcult
communication issues regarding the risks. This
opening chapter puts the knowledge in context,
provides a brief overview of the eld, and outlines the key concepts and denitions that are
needed to negotiate the remaining chapters in this
book.
The science of optimizing the safety of medicines is called pharmacovigilance, which comes
from the Greek word pharmakon (medicinal substance) and the Latin word vigilia (to keep
watch). A relatively new science, it has largely
developed since the middle of the twentieth century. Pharmacovigilance has been dened by
Rawlins as ‘the process of identifying, and then
responding to, safety issues about marketed
drugs’ [1] and by Mann and Andrews as ‘the
study of the safety of marketed drugs under the
practical conditions of clinical use in large communities’ [2]. These denitions help capture the
core element of pharmacovigilance, which is
focused on detecting the harms of a medicine following its marketing among the general population. However, as noted by Rawlins,
pharmacovigilance is more than the detection of
safety issues. Knowledge of a problem is nothing
without an effective process of choosing the right
action to take once it is found and being able to
communicate that action well. The concise denition of pharmacovigilance by the World Health
Organization (WHO) captures these elements:
‘Pharmacovigilance is the science and activities
relating to the detection, assessment, understanding and prevention of adverse effects or any other
medicine/vaccine related problem’ [3].
Considering the activities specically related to
vaccines, the Council for International
Organizations of Medical Sciences (CIOMS)/
WHO Working group on vaccine pharmacovigilance dened vaccine pharmacovigilance ‘as the
science and activities relating to the detection,
1 Introduction toDrug Safety andPharmacovigilance
5
assessment, understanding and communication
of adverse events following immunization and
other vaccine- or immunization-related issues,
and to the prevention of untoward effects of the
vaccine or immunization’ [4].
Being able to detect a signal of potential harm
is the rst step, but, without further case assessments and signal testing with pharmacoepidemiological methodologies, only a limited
understanding can be obtained. Understanding
the potential mechanisms of an adverse drug
reaction (ADR) may provide a clue to the risk
factors or mechanisms to prevent such harm. For
the purpose of simplicity and following the usual
method of representation, the term‘drug’used in
the remainder of this chapter and the entire book
also encompasses the term ‘vaccines’, unless
otherwise specied. While harm can be prevented by the withdrawal of a drug from the market, its restricted use, or labelling changes
facilitating its safer use, much of pharmacovigilance deals with the communication of the complex balances between benets and harms to
professionals and the public. Even so, a drug’s
withdrawal requires a well-justied and clear
communication plan to avoid raising disproportionate public concern. Pharmacovigilance is
therefore an activity that surrounds the entire life
of a medicine and is related to all aspects of a
drug’s continued safety.
2 History
Medicines are intended to exert a benecial pharmacological effect on patients. Sometimes such
effects work as intended, whereas, at other times,
unintended harmful effects may occur. At both
the population and individual levels, a mix of
both benets and harms will coexist, with complex decisions and personal preferences inuencing drug therapy. The complexity of modern
medicine, an aging world population, and the
increase in polypharmacy all mean that the challenges in pharmacovigilance are increasing,
despite the improvements in the eld over the
past century.
The history of harmful effects of medicines
has been punctuated with tragedies, some of
which may have been preventable with knowledge at that time. It is beyond the scope of this
chapter to comprehensively review the history of
pharmacovigilance, which is covered in several
other texts [5–8], but a brief overview of some
historical cases can help understand the context
of modern pharmacovigilance—which has often
proceeded in a paroxysmal manner following
tragic events. Further details can be found in
Chap.6.
Although the adverse effects of medicines
have been noted since ancient times, one of the
rst systematic attempts to do so was made in
the nineteenth century following several deaths
related to early general anesthetic use. A collaborative commission was set up by The
Lancet and The British Medical Journal to
examine the safety of chloroform. Published in
1893, it is notable that this commission set up
a reporting system for physicians to report
anesthesia-related deaths [6]. In 1937, an early
antibiotic, sulfanilamide, was reformulated
into a liquid preparation by the Massengill
Company, leading to the deaths of 107 people,
most of whom were children. Diethylene glycol had been used in the formulation, with the
company scientists being unaware of its already
known toxicity. This led to an amendment of
the United States 1906 Food and Drug
Administration Act in 1938 to avoid such incidences in the future [9]. Tragically, outbreaks
of diethylene glycol contamination of medicines have still been leading to poisoning and
deaths periodically ever since, with more than
300 deathsoccurring in 2022, mostly of children under 5 years of age, in Uzbekistan,
Ghana, and The Gambia [10].
The development of modern pharmacovigilance as an international collaborative science
arose because of the thalidomide tragedy in the
1960s. Thalidomide was rst marketed in 1957
and had been declared suitable for use in pregnancy and nursing mothers by the company
Chemie Grünenthal without supporting evidence
of safety [11]. In 1961, an Australian doctor,
6
J. Jose et al.
William McBride, who had prescribed the drug
to several female patients, drew attention to a
potential causal link to deformities in the babies
of the women he had treated [12]. Despite
increasing concerns, the company continued to
market the drug as safe, until eventual withdrawal. At this point, thousands of babies had
been born with congenital malformations
because of maternal exposure to thalidomide,
with no awareness that a teratogenic effect
existed [13].
A widespread effect had been missed, with
no central overview of the incidence of the congenital defects. This direct articulation of the
need to effectively compare experiences of suspected adverse effects of medicines was the
spur that led to the widespread setting up of
organized national surveillance systems in the
early 1960s as well as the WHO Program to
collect such data internationally in 1968 [14].
Major advances in monitoring capability, or
legislative responsibilities regarding pharmacovigilance, have arisen because of further drug
or vaccine safety events. Examples include the
late detection of sclerosing peritonitis caused
by practolol in 1975 [15], the withdrawal of
benoxaprofen in 1982 following reports of hepatotoxicity and deaths [16], and the withdrawal
of the cyclooxygenase (COX)-2- selective nonsteroidal anti-inammatory drug (NSAID)
rofecoxib in 2004 following the nding of a
signicantly increased risk of cardiovascular
events in clinical trials [17]. In the latter case,
as one example, this led to the Food and Drug
Administration (FDA) Amendments Act of
2007, which, in turn, led to the creation of the
FDA Sentinel Initiative, a national resource for
monitoring safety across more than 100 million
patient lives with data captured during routine
care delivery [18].
3 The Importance
ofPharmacovigilance
The modern drug development process has the
ability to expediently test and identify safety issues
in the developmental stages of a drug, even before
it is used in human trials. Safety has an increased
focus in the clinical development life cycle, and
data regarding safety issues not only form part of
the safety assessment of new drugs entering the
market but also inform pharmacovigilance plans
to monitor the product once it is released to the
wider population. However, the inherent weakness
of premarketing studies, such as the highly selective patient group, therelatively small size of clinical trials compared to real-world exposure to new
drugs, and the limited duration of therapy and follow-up, make continued post-marketing surveillance essential. In addition, routine health care is
unavoidably signicantly different to controlled
trials. It is therefore essential to continue to monitor for emerging safety issues, or for new information on known safety issues, once medicinal
products are used as part of routine real-world
health-care delivery—where practice often differs
from clinical trials.
Pharmacovigilance is critically important
not only for individual patients but also at the
public health level, both in identifying new
issues and in managing known safety issues. In
addition to individual patient suffering, the
impact and scale of drug safety failure on a
population can be high. This varies by setting
and the nature of exposure and outcome, and
there is a wide variation in estimates, but one
such analysis conducted across multiple US
hospital databases estimated that adverse drug
events occurred in 2.1% of all inpatient stays
and were present on admission in 5.1% of
stays, with the management of such adverse
drug events estimated to cost US $28 billion
annually [19]. More details on the economic
burden of drug safety can be found in Chap.5.
In the case of new medicines, the importance
of the rapid detection of safety signals is highlighted by the fact that nearly 20 million people were exposed to 5 drugs in the US market
that were later withdrawn for safety issues
[20]. Although media reporting may xate on
the failures of drug regulation, modern pharmacovigilance science, which started during
the latter part of the twentieth century, has
undoubtedly saved lives and averted widespread misery.
1 Introduction toDrug Safety andPharmacovigilance
7
4 The Principles
ofPharmacovigilance
andDrug Regulation
Pharmacovigilance is essential to ensure safety
whenever people take medicines, whether the
medicine is under development or as part of routine health care. Thus, pharmacovigilance should
be in place across all clinical trial phases and for
post-marketing usage. Its objective is to ultimately identify and understand safety issues as
precisely and promptly as possible so that the
benet–harm of marketed medicines is favourable in a specic dened population, the risk is
communicated, and, when there is differential
risk across individuals, it is managed appropriately to minimize it. Usage is monitored for as
long as medicines are marketed, and, if, for
example, in subpopulations the benet–harm is
unfavourable, then this will be identied and
steps taken to mitigate it, such as by the inclusion
of new contraindications. Medicines regulation
around the world denes how this is done and
ensures that the pharmaceutical industry complies with the regulation all with the ultimate goal
of ensuring patient safety and trust in the system.
Accordingly, pharmacovigilance legalization
covers all phases of the evaluation and usage of
medicines. For more details on how medicines
regulation is coordinated, please refer to Chap. 6.
Additionally, please refer to the following articles as examples: Santoro et al. [21] and Park
[22]. Although there is much international variability, there are efforts to harmonize approaches
through international organizations like the
International Council for Harmonisation of
Technical Requirements for Pharmaceuticals for
Human Use (ICH), which is particularly valuable
to international organizations and companies that
market medicines across different geographies
[23].
5 Terminology
Consistent drug safety terminology, with clear
and unambiguous denitions is critical to enable
prescribers, patients,manufacturers, and regula-
tors to understand each other. The confusion that
exists due to different terms and denitions used
in the eld of drug safety by researchers, practitioners, and regulatory agencies is a concern [24].
This can inuence various activities related to
drug safety such as in routine clinical practice,
safety reporting, and communications. A complete description of all the terms used in pharmacovigilance in the pharmaceutical industry and
the regulatory eld can be obtained from the specialist chapters in this book, but the fundamental
terms frequently used in clinical practice are discussed below.
Two commonly used terms in drug safety,
namely ‘adverse drug reactions (adverse reactions)’ and ‘adverse drug effects (adverse
effects),’ refer to the same phenomenon, though
they are different in perspective. While an adverse
effect is seen from the point of view of the drug,
an adverse reaction is seen from the point of view
of the patient [24]. Drug X caused an ‘adverse
effect’ in patient Y, whereas patient Y developed
an ‘adverse reaction’from drug X.Terms that are
commonly used to denote all the harmful effects
of drugs in the general sense are ‘toxic
effect’and‘side effect’.Technically, an‘adverse
reaction’ or an ‘adverse effect’ seems to be a better term to use than the above two [24]. It is worth
noting that a side effect can be benecial and is
often used as a lay term for an ADR and that a
toxic effect is not common atnormal doses.
The WHO’s denition of an ADR is ‘a
response to a drug that is noxious and unintended
and occurs at doses normally used in man for the
prophylaxis, diagnosis or therapy of disease, or
for modication of physiological function’ [25].
Although this denition, which was rst published in 1972, is still widely used, it has certain
drawbacks. Adverse effects can occur at doses
other than those that are used in the way that the
denition describes, for example, after a test
dose. All adverse effects need not be noxious or
harmful as the denition indicates and can
include those effects that are inconvenient and
not harmful per se [24]. Although there are many
other denitions available in the literature, as
additional information, few other denitions for
ADRs are included in Table 1.1. The common
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