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Table 1.1 Denitions (commonly used) for adverse drug reactions in the literature
Denition References
An ADRa is dened as 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.
An ADR is ‘a response to a medicinal product which is noxious and unintended. Response
in this context means that a causal relationship between a medicinal product and an
adverse event is at least a reasonable possibility. Adverse reactions may arise from use of
the product within or outside the terms of the marketing authorisation or from occupational
exposure. Conditions of use outside the marketing authorisation include off-label use,
overdose, misuse, abuse and medication errors.’ This denition is adopted from Denition
EU Guideline on good pharmacovigilance practices (GVP)—Annex-I—Denitions (8
January 2014) (Rev 2). https://www.ema.europa.eu/en/documents/scientic- guideline/
guideline- good- pharmacovigilance- practices- annex- i- denitions- rev- 2- superseded_en.pdf
As described in the ICHc Topic E 2 A Clinical Safety Data Management: Denitions and
Standards for Expedited Reporting: ‘in the pre-approval clinical experience with a new
medicinal product or its new usages, particularly as the therapeutic dose(s) may not be
established: all noxious and unintended responses to a medicinal product related to any
dose should be considered adverse drug reactions’.
An ADR is dened as ‘a response to a medicinal product which is noxious and
unintended’ (Article 1 of Directive 2001/83/EC).
‘For purposes of prescription drug labeling, an adverse reaction is an undesirable effect,
reasonably associated with use of a drug, that may occur as part of the pharmacological
action of the drug or may be unpredictable in its occurrence. This denition does not
include all adverse events observed during use of a drug, only those adverse events for
which there is some basis to believe there is a causal relationship between the drug and
the occurrence of the adverse event.’
According to Food and Drug Regulations of Canada, an ADR is ‘a noxious and
unintended response to a drug which occurs at doses normally used or tested for the
diagnosis, treatment or prevention of a disease or the modication of an organic
function.’
The American Society of Health-System Pharmacists denes a signicant ADR as ‘any
unexpected, unintended, undesired, or excessive response to a drug that requires
discontinuing the drug (therapeutic or diagnostic), requires changing the drug therapy,
requires modifying the dose (except for minor dosage adjustments), necessitates
admission to a hospital, prolongs stay in a health care facility, necessitates supportive
treatment, signicantly complicates diagnosis, negatively affects prognosis, or results in
temporary or permanent harm, disability, or death.’
An ADR is an ‘An appreciably harmful or unpleasant reaction, resulting from an
intervention related to the use of a medicinal product; adverse effects usually predict
hazard from future administration and warrant prevention, or specic treatment, or
alteration of the dosage regimen, or withdrawal of the product.’
a
ADR adverse drug reaction
b
CIOMS Council for International Organizations of Medical Sciences
c
ICH International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use
World Health
Organization [25]
Council for International
Organizations of Medical
Sciencesb [26]
ICH [27]
European Medicine
Agency [28]
US Food and Drug
Administration [29]
Health Canada— Canada
Vigilance Program [30]
American Society of
Health-System
Pharmacists [31]
Aronson and Ferner [24]
J. Jose et al.
theme in all denitions is that the reaction is
undesired and unintended [32].
The use of the term‘at doses normally used in
man’in the WHO denition tries to differentiate
an ADR from‘toxicity’, which is a harmful effect
that occurs due to overexposure either due to
acute (acute drug toxicity) or chronic (chronic
drug toxicity) use. Drug toxicity is always considered to be dose-related, whereas the manifestations of drug toxicity may be related to
therapeutic effects or otherwise. Liver toxicity
because of acute exposure to higher doses of
paracetamol (paracetamol overdose) could be
considered as acute drug toxicity, which is
unrelated to the therapeutic effect of the drug. On
the other hand, excessive bleeding caused by
acute exposure to higher doses of warfarin (warfarin overdose) could also be considered as acute
toxicity but is related to the therapeutic effect of
the drug.
1 Introduction toDrug Safety andPharmacovigilance
9
Even though the terms ‘side effect’ and ‘ADR’
are used interchangeably, they are distinct by
nature. By the denition of the WHO, a side
effect is ‘any unintended effect of a pharmaceutical product occurring at doses normally used in
man, which is related to the pharmacological
properties of the drug’. The essential elements of
this denition are the pharmacological nature of
the effect, that the phenomenon is unintended,
and that it is in its normal dose [24, 33]. The term
mainly aims to indicate those unintended effects
of the drug that may occur side by side with its
main therapeutic effect and may include its benecial or harmful effects. In practice, it refers
more commonly to the harmful effects caused by
the drug. To elucidate the concept of the benecial part of the term ‘side effect’, let us consider
the anticholinergic effect of a tricyclic antidepressant (TCA). Since the anticholinergic effect
with a TCA is not associated with the main therapeutic effect (antidepressant effect), it could be
considered as a side effect. This side effect may
be troublesome for some individuals, whereas it
may be benecial for some others. A depressed
patient with irritable bowel syndrome may incidentally benet from the anticholinergic side
effect of a TCA when it is administered to the
patient as an antidepressant. The term ‘side
effect’ is more of a layman’s term to indicate the
negative effects of drugs and, ideally, should be
avoided professionally to avoid ambiguity and
risk of misclassication [34, 35]. The
term‘adverse effect’encompasses all unwanted
effects; it makes no assumptions about the mechanism, evokes no ambiguity, and avoids the risk
of misclassication [24].
A term commonly used in the eld of drug
safety and used interchangeably with an ADR is
‘adverse event’. An adverse event (AE) or an
adverse experience in drug safety is dened by
the WHO as ‘any untoward medical occurrence
that may present during treatment with a medicine, but which does not necessarily have a causal
relationship with this treatment’. To label an
untoward medical event as AE, there need not be
suspicion of a causal relationship. The basic point
is the coincidence of the time of the event with
the use of the drug [36]. The CIOMS has presented the denition with a slight modication to
include the events observed during clinical trials:
‘any untoward medical occurrence in a patient or
clinical trial subject administered a medicinal
product and which does not necessarily have a
causal relationship with this treatment’ [26]. For
vaccines, a specic term of art is often used:
adverse event following immunization (AEFI).
An AEFI is dened as ‘any untoward medical
occurrence following immunization, which does
not necessarily have a causal relationship with
the vaccine’. This AE may be any unfavourable
or unintended sign, an abnormal laboratory nding, a symptom, or a disease [37].
Looking at the difference between an ADR and
an AE, an ADR is an adverse outcome that can be
attributed, with some degree of probability, to the
use of the drug. An AE can be any unfavourable or
unintended sign, a symptom, or a disease temporally associated with the use of a medicinal product, whether or not considered related to the
medicinal product [35]. The term ‘AE’ can be
used when a causal link between the drug and the
untoward medical occurrence has not been
proven, whereas suspicion of a causal relationship
between the drug and the AE is essential to use the
term ‘ADR’ [33]. In effect, all ADRs are AEs, but
not all AEs are ADRs. The use of this term is particularly important in clinical trials in which not
all events are necessarily drug-induced [24]. It is
important to document all the events occurring in
the clinical trial subjects, as data regarding the
possible adverse effects of the investigational
drug are not much known during the clinical trial.
After identifying any possible relationship of the
AEs with the drug, the ADRs of the investigational drug could be better identied and documented at the time of marketing.
A few of the other commonly used terms and
denitions in drug safety are presented in
Table 1.2, and they will be appropriately discussed in the respective sections of this book.
It is important to differentiate between the
terms ‘serious’ and ‘severe’ adverse reaction and
use them appropriately. The ‘seriousness’ of an
ADR is a measure of the extent to which the reaction developed can or does cause harm. On the
other hand, the ‘severity’ of an ADR is a measure
of the extent to which the adverse effect develops
in an individual. For example, nitrates may cause
10
J. Jose et al.
severe headache in a patient, which may not be
serious, whereas drug-induced ventricular tachycardia of any severity is serious [24]. The
approach is somewhat different when severity is
Table 1.2 Denitions of a few other commonly used
terms in drug safety
Term Denition
Unexpected
adverse
reaction
Signal ‘A reported information on a possible
Serious
adverse event
(experience) or
reaction
‘An adverse reaction, the nature or
severity of which is not consistent
with domestic labelling or market
authorisation, or expected from
characteristics of the drug’ [36]
causal relationship between an
adverse event and a drug, the
relationship being unknown or
incompletely documented
previously’ [36]
‘Any untoward medical occurrence
that at any dose:results in death; is
life-threatening; requires inpatient
hospitalization or prolongation of
hospitalization; results in persistent
or signicant disability/incapacity;
is a congenital anomaly/birth
defect’ [26]
assessed using standard scales, and the same is
discussed in Chap. 16.
Medication errors may be a cause of AEs, but it
is not always so. Consequently, the term ‘medication error’ cannot be used interchangeably with
ADRs or AEs. The National Coordinating Council
for Medication Error Reporting and Prevention
denes it as ‘A medication error is any preventable
event that may cause or lead to inappropriate medication use or patient harm while the medication is in
the control of the health care professional, patient,
or consumer. Such events may be related to professional practice, health care products, procedures,
and systems, including prescribing, order communication, product labelling, packaging and nomenclature, compounding, dispensing, distribution,
administration, education, monitoring, and use’
[38]. The approach is somewhat different when
severity is assessed using standard scales and the
same is discussed in Chap. 16. Since medication
errors are preventable, AEs or ADRs caused by
medication errors are preventable as well. The relationship between medication errors, AEs, and ADRs
is depicted in Fig. 1.1. In everyday drug use, the
Medication Errors
(Preventable)
Adverse Events
Adverse Drug Reactions
Fig. 1.1 Relationship between medication errors, adverse events, and adverse drug reactions
1 Introduction toDrug Safety andPharmacovigilance
11
focus should always be on avoiding these preventable ADRs. Further details on medication errors,
including their types and severity, are provided in
Chap.15.
6 Classication ofAdverse
Drug Reactions
The classication of ADRs is essential to the
practice of pharmacovigilance and its clinical
understanding. Classication can help reveal the
mechanism behind the ADR and inform practical
considerations to prevent and manage the same. It
is useful for educational and practical purposes
for those working in regulatory and clinical settings [33]. It is also important in regulatory and
health-care settings where ADRs are evaluated.
Multiple methods of classifying ADRs have been
developed over the years. The most commonlyused is the Rawlins and Thompson’s classication of ADRs [39].
6.1 Rawlins andThompson’s
Classication ofAdverse Drug
Reactions
Rawlins and Thompson suggested that adverse
reactions and interactions can usually be logically, and clinically, divided into those that form
part of a drug’s normal pharmacological actions
(type A: augmented) and those that represent a
novel response (type B: bizarre) [39]. The major
differences between these two types of ADRs are
summarized in Table1.3.
6.1.1 Type AReactions
Type A reactions are the results of quantitatively
abnormal, pharmacological effects of drugs. They
are the most common type of ADRs, responsible
for 80% of the reactions [33]. Type A reactions can
be due to the primary (or intended) pharmacological property of a compound, such as hypotension
with antihypertensive agents and hypoglycemia
with antidiabetic agents. Other than the primary
pharmacological effects, type A reactions could be
due to the drug’s secondary pharmacological
Table 1.3 The major differences between type A and
type B reactions [33, 39, 40]
Features Type A Type B
Pharmacologically
predictable
Dose-dependent Yes No
Incidence Common Uncommon
Morbidity High Low
Mortality Low High
Preventability More likely by
Management Dose adjustment
Yes No
Less likely
appropriate drug
and dose
selection
Usually
might be
sufcient usually
or withhold
temporarily
require
complete
withdrawal of
drug.
Avoid use in
future
effects. An example is the anticholinergic effects
of tricyclic antidepressants and many antipsychotics causing tachycardia, constipation, dryness of
the mouth, and blurring of vision [33].
Type A reactions are usually considered to be predictable, dose-dependent, common, are rarely lifethreatening, and occur in individuals lying at the top
of dose–response curves for pharmacological effects.
Three potential causes for this type of response
include pharmaceutical, pharmacokinetic, and pharmacodynamic. Pharmaceutical factors such as differences in pharmaceutical formulation can give rise to
substantial alterations in the quantity of the drug that
is ‘available’ to reach its site of action. Individual differences in the pharmacokinetic variables of absorption, distribution, and elimination result in differences
in drug concentrations at the site of action.
Pharmacodynamic factors are due to the altered target organ sensitivity, which results in differing individual susceptibilities to drugs [39].
6.1.2 Type B Reactions
Type B reactions are bizarre, qualitatively
abnormal effects, which are seemingly unrelated to a drug’s desired pharmacological
effect. Examples include the severe skin reactions to some antiseizure drugs or antibiotics
or hepatoxicity associated with statins [39].
They are infrequent, are usually unknown
12
J. Jose et al.
before the drug is marketed, and are rst identied after use in the wider population [33].
Different mechanisms may play a role in the
development of type B reactions. By-products
of chemical synthesis can be involved, for
instance, aspirin anhydride, a contaminant
found in the commercial samples of aspirin, or
in vitro degradation products, such as those
arising from tetracyclines, may give rise to
toxic effects, which cannot be explained by the
pharmacological properties of the drugs. The
components of a pharmaceutical product such
as additives, excipients, colorizers, and binders
may themselves cause toxicity, or may react
with the drug, thus resulting in toxic derivatives leading to type B reactions. Development
of unusual, or novel, drug metabolites in the
body can also lead to these bizarre reactions.
Genetic factors resulting in altered target organ
responses can explain some type B reactions.
Examples are development of hemolysis with
oxidant drugs in patients with red cell glucose6-phosphate dehydrogenase deciency or certain hemoglobinopathies and the precipitation
of acute porphyria with enzyme-inducing
agents. Many of the type B reactions have an
immunological basis [39]. The immunological
basis of ADRs is discussed in detail in Chap.2.
6.1.3 Clinical Implications
In clinical practice, the focus of health-care
professionals should be on preventing and
reducing the occurrence of both type A and
type B ADRs. Reductions in type A reactions
can be achieved by ensuring appropriate drug
and dose selection for individual patients based
on their unique characteristics and disease
details, including comorbid conditions.
Ensuring patient compliance and appropriate
monitoring of therapeutic and toxic parameters
in the patient can contribute toward reducing
these predictable and dose- dependent effects.
On the other hand, obtaining an appropriate
medication history, use of ADR- alert mechanisms, close monitoring of predisposing factors before and during medication use, using
pharmacogenomic screening wherever appli-
cable, and patient education may be benecial
in reducing type B reactions.
6.1.4 Extended Classication
A number of ADRs vary from type A and type B
reactions, and the classication system of
Rawlins and Thompson’s underwent expansion
to accommodate those reactions which do not
appropriately t into this basic classication. The
classes, as per the expanded version of the basic
classication, are listed in Table1.4.
6.2 DoTS (Dose Relatedness,
Timing, andPatient
Susceptibility) Classication
Several criticisms of the Rawlins and Thompson’s
classication have been made over the years, especially as it has expanded in complexity. For example, the concept that some ADRs are not dose-related
Table 1.4 Extended classication of Rawlins and
Thompson’s classication [33, 40]
Classes Features Examples
Type C
(chronic):
dose- and
time-related
Type D
(delayed):
time-related
Type E
(exit):
withdrawal
Type F
(failure):
unexpected
failure of
therapy
Uncommon
Related to
cumulative
dose
Uncommon
Usually
dose-related
Occurs or
becomes
apparent
sometime
after use of
the drug
Uncommon
Occurs soon
after
withdrawal of
the drug
Common
Dose-related
Often caused
by drug
interactions
Hypothalamus–
pituitary–adrenal axis
suppression by
corticosteroids
Retinal toxicity with
hydroxychloroquine
Carcinogenesis
Opiate withdrawal
syndrome
Benzodiazepine
withdrawal syndrome
Beta-blocker rebound
effects after abrupt
discontinuation
Inadequate dose/level of
contraceptives in the
presence of enzyme
inducersresulting in
contraceptive failure
1 Introduction toDrug Safety andPharmacovigilance
13
has been criticized [41]. A new three-dimensional
classication system for ADRs based on dose relatedness, timing, and patient susceptibility (DoTS)
was proposed by Aronson & Ferner [42] and can
theoretically classify any ADR without further
expansions, and thus removes the concept of a nondose-related ADR.This comprehensive classication includes properties of both the reaction (the
time course of its appearance and its severity) and
the individual (the genetic, pathological, and other
biological differences that confer susceptibility). An
advantage of the DoTS system is its ability to focus
on examining the key risk factors and nature of the
ADR, which can inform future prevention and management of the ADR.
6.2.1 Dose Relatedness
According to this classication, all adverse effects
by drugs, including type B reactions, have a relation with the dose. ADRs can be classied as toxic,
collateral, or hypersusceptible. Toxic reactions are
those that occur at supratherapeutic doses; collateral reactions are those that occur at standard therapeutic doses; and hypersusceptible reactions are
those that occur at subtherapeutic doses in susceptible patients. Collateral reactions can include
those that occur due to a different pharmacological
effect from the therapeutic action and also those
that occur through the therapeutic pharmacological effect but at another site of action.
6.2.2 Time Relatedness
Many pharmacological effects depend on the
time course of its appearance. The time course of
ADRs is considered to be either time-dependent
or time-independent. Time-independent reactions may occur at any time during treatment,
independent of the duration of the course, either
when the concentration of the drug at the site of
action changes (for example, digoxin toxicity in
patients with renal dysfunction) or when the
pharmacological response is altered without a
change in concentration (for example, digoxin
toxicity in patients with hypokalemia).
On the other hand, time-dependent reactions
arise in relation to the duration of treatment. Six
subtypes of time-dependent reactions are
described—rapid, rst-dose, early, intermediate,
late, and delayed. Rapid reactions occur only
when a drug is administered too rapidly as in the
case of development of red man syndrome after
rapid administration of vancomycin. First-dose
reactions occur after the rst dose of a course of
treatment and not necessarily thereafter. An
example of this is the development of hypotension after the rst dose of an angiotensinconverting enzyme inhibitor. Early reactions
occur early in treatment and then subside with
continuing treatment. Examples include the early
symptoms of gastrointestinal adverse effects with
orlistat or the headache following the rst use of
nitrates [43]. Intermediate reactions occur after
some delay, but if the reaction has not occurred
after a certain time, then it is unlikely to develop
at a later stage. Examples are hypersensitivity
reactions of type II (thrombocytopenia due to
quinine). In late reactions, the risk of developing
the reaction at the beginning of treatment is rare
or nil, but the risk increases with continued or
repeated use; examples include many of the
adverse effects of corticosteroids and the ophthalmic adverse effects of hydroxychloroquine.
Delayed reactions are observed sometime after
exposure and can occur even after the drug is
withdrawn; examples include carcinogenesis
(such as the vaginal adenocarcinoma in female
children whose mothers used diethylstilbesterol
during pregnancy) and teratogenesis.
6.2.3 Susceptibility
The risk of an ADR differs among members of an
exposed population depending on the presence of
a single or multiple factors such as genetic variation, age, sex, physiological variation, exogenous
factors, and disease.
Table 1.5 presents examples of different ADRs
of the same drug enalapril classied under the
DoTS system.
One potential limitation of the DoTS classication system is that it may not be always easy to
t an individual ADR into a specic type based
on dose, time relatedness, and susceptibility. In
regular clinical practice, the application of the
DoTS system may enable practitioners to have a
better understanding of the pattern and contributing factors to a particular ADR, focusing the
mind of the prescribers on prevention and monitoring of adverse effects. An increased under-
14
as either
Table 1.5 Examples of DoTS classication applied to differing adverse effects of enalapril
Dry cough with enalapril
Do—collateral effect; T—intermediatea;
S—sex (female)
a
At times dry cough develops with the rst dose or could develop extremely late as well
b
Angioedema may develop later during treatment as well. Furthermore, it does not go away with continuing treatment
Angioedema with enalapril
Do—hypersusceptible; T—bearly;
S—race (Black patients)
Hypotension after the rst dose of
enalapril
Do—collateral; T—rst dose;
S—volume- depleted individuals,
patients additionally on diuretics
J. Jose et al.
standing of the susceptibility factors helps in
safer prescribing considering the patient and
drug-specic factors, such as the need for dose
reductions in renal failure.
6.3 Classication ofAdverse Eects
Induced by Biological Agents
ADRs induced by biological agents are often
target-related and linked to the biological outcomes of their action [44]. Based on the peculiar
features of biological agents, a new classication
of the adverse effects of biological agents has
been proposed [45].
This classication system differentiates adverse
effects into ve distinct types, namely, clinical
reactions because of high cytokine levels (type α),
hypersensitivity because of an immune reaction
against the biological agent (type β), immune or
cytokine imbalance syndromes (type γ), symptoms because of cross-reactivity (type δ), and
symptoms not directly affecting the immune system (type ε). This unique classication could help
better deal with the clinical features of side effects
with this specic class of drugs, to identify possible individual and general risk factors.
6.4 Classication Based on
Predictability, Frequency of
Occurrence, andPreventability
(1) toxicity from medication, (2) unavoidable
side effects, (3) pharmacological actions, and
(4) drug–drug interactions. Unpredictable
adverse reactions include (1) intolerance, in
which the patient experiences expected reactions at much lower doses or blood concentrations than usual; (2) idiosyncratic reactions,
which are often attributable to genetic or pharmacokinetic responses that cause reactions not
occurring in other subjects; and (3) allergic
(immunoglobulin [IgE- mediated]) or pseudoallergic (non-IgE-mediated) reactions [46, 47].
Knowledge of the predictability of individual
ADRs is of benet in clinical practice to prevent, identify, manage, and communicate information about ADRs.
Based on the frequency of occurrence of
ADRs, they are often classied as very common
(≥1/10), common (≥1/100 to <1/10), uncommon
(≥1/1000 to <1/100), rare (≥1/10,000 to
<1/1000), and very rare <1/10,000). This categorization is especially important for prescribing
decisions, reporting and managing ADRs, patient
communication, and regulatory actions. This
classication is benecial for categorizing ADRs
predictable or unpredictable and is further
discussed in Chap. 16 [48].
ADRs could be classied as preventable and
nonpreventable reactions based on assessment of
preventability of reactions based on specic
scales, as discussed in Chap. 16.
ADRs can also be categorized as either predictable or unpredictable. Predictable ADRs include
1 Introduction toDrug Safety andPharmacovigilance
15
7 Taxonomies
The adverse effects themselves require specic
denitions for uniform use in various situations
such as collating ADR reports to enable the
quantitative evaluation of drug safety signals.
Various dictionaries have been developed [24].
The Medical Dictionary for Regulatory Activities
(MedDRA) Terminology is the international medical terminology developed under the auspices of
the ICH. It was developed in the 1990s with version 1 adopted by the ICH in 1994 with the latest
edition being version 26, March 2023 [49].
Another classication system is the WHO
Adverse Reaction Terminology (WHO-ART),
which was developed and maintained by the
Uppsala Monitoring Centre (UMC) to serve as a
terminology for coding adverse reaction terms,
covering most medical terms needed in adverse
reaction reporting. Although its use has been
replaced by MedDRA, any user who requires it
for a specic purposecan contact the UMC [50].
Similar coding systems exist in other data collection systems. One example is the International
Classication of Diseases (ICD) now in its 11th
edition (ICD-11). Published by the WHO, it
serves a broad range of uses globally. For example, the clinical terms coded with the ICD are the
main basis for health recording and statistics on
diseases in primary, secondary, and tertiary care
as well as on cause of death certicates [51].
Although not specically created for the purpose
of ADR reporting, data coded by the ICD can be
used for specic and general purposes in postauthorization safety studies for identication,
reporting, and data analysis. The Systemized
Nomenclature of Medicine—Clinical Terminology (SNOMED-CT) is another similar standardized, international, multilingual core set of
clinical health-care terminologies that can be
used in electronic health records [52].
A series of international working groups was
convened by the CIOMS, in which representatives of regulatory bodies and pharmaceutical
companies, together with clinical experts and
staff members of the WHO and CIOMS, agreed
on standard denitions of selected terms for
ADRs and on the minimum requirements for the
use of the terms in international reporting, in the
framework of post-marketing surveillance [53].
The resulting publication Denitions and Basic
Requirements for the Use of Terms for Reporting
Adverse Drug Reactions aims to facilitate ef-
cient communication between people of diverse
cultural and linguistic backgrounds, and from
different medical care and education systems. It
was primarily designed to meet the needs of drug
regulatory authorities and drug safety departments of pharmaceutical companies as well as
for medical or other reporters of ADRs, to help
them document their case reports and communicate them to regulatory authorities or drug
manufacturers.
WHODrug Global is the international reference for medicinal product information and is
maintained by the UMC.The dictionary is used
to identify drug names and evaluate medicinal
product information, including active ingredients
and products’ anatomical and therapeutic classications, from nearly 150 countries. It consists of
medications with individual trade names linked
to the active ingredients, pharmaceutical form,
strength, marketing authorization holder, and
country of sales as well as a classication according to the WHO Anatomical Therapeutic
Chemical (ATC) classication [54]. WHODrug
Global’s standardized data help identify drugrelated problems in clinical trials and pharmacovigilance [55]. The eXtended EudraVigilance
Medicinal Product Dictionary (XEVMPD) is a
database designed to support the collection,
reporting, coding, and evaluation of medicinal
product data in a standardized and structured way
[56]. The main objective of the XEVMPD is to
assist the pharmacovigilance activities in the
European Economic Area (EEA).
8 Predisposing Factors
As noted earlier, the risk of an adverse reaction
differs among different members of an exposed
population [24]. Many factors can predispose
individuals to an ADR, including polyphar-
16
J. Jose et al.
macy, age (the elderly and children are more
prone), genetic variation (porphyria, CYP isoenzyme polymorphisms), sex (with females
being more susceptible in general and some
sex-specic ADRs in both sexes), physiological
variation (for example, pregnancy can inuence
the development of specic ADRs), exogenous
factors (drug–drug or drug–food interactions),
disease (renal and hepatic insufciency), and
variations in drug formulations [42, 57]. It is
important as far as possible to identify and have
an appropriate understanding of the predisposing factors for specic ADRs with specic
drugs.
Although basic information on the predisposing factors may be available at the time of marketing of the drug, much of this is obtained after
the drug is in general use. This highlights the
importance of spontaneous reporting, postmarketing studies, and timely evaluation of postmarketing safety data. Appropriate knowledge of
health-care professionals on predisposing factors
is essential for safe prescribing, dispensing, and
monitoring of medications. Patient education is
equally important based on the predisposing factors present for individual drugs. A further indepth discussion of these issues can be found in
Chap. 3.
Genetics plays a major role in interindividual
variability in the response to drug therapy in
terms of both efcacy and safety. The pathogenesis of an ADR could be inuenced by genomics,
and the identication of subpopulations with
altered sensitivity to medicines due to genomic
factors could provide important information that
could be used to mitigate the risk of ADRs [58].
Personalized medicine aims to provide individualized treatment and to predict the clinical outcome of different treatments in diverse patients
[59]. Pharmacogenetics, the study of genetic
causes of individual variations in drug response,
is one of the core elements of personalized medicine [59, 60]. Translational medicine, which is an
interdisciplinary science that links laboratory
research to clinical research, has been instrumental in bringing about drug safety-related applications of pharmacogenetics in clinical practice
[60]. The inuence of pharmacogenetics on drug
safety is further discussed in Chap. 23.
9 An Overview
ofPharmacovigilance
Systems
As already noted, the drug safety information
collected during the premarketing phase of drug
development is incomplete and post-marketing
surveillance after a drug launch is crucial. Much
of the world now has an established pharmacovigilance system, with the WHO Program for
International Drug Monitoring having more than
170 members and associates who cover 99% of
the world’s population. These pharmacovigilance
systems depend on spontaneous reporting of suspected ADRs by health-care professionals and
patients [36].
The primary AE reporting system in the
United States is MedWatch, the FDA Safety
Information and Adverse Event Reporting Program where health-care professionals and consumers voluntarily report ADRs, AEs, and
medication errors for entry into the FDA
Adverse Event Reporting System (FAERS)
database, with vaccine reports in a separate system called the Vaccine Adverse Event Reporting
System (VAERS). Other examples of established pharmacovigilance systems include The
Canada Vigilance Program and the Yellow Card
Scheme operated by the Medicines, and Healthcare Products Regulatory Agency (MHRA) and
the Commission on Human Medicines in the
United Kingdom (UK). National regulators and
the industry in Europe contribute to EudraVigilance, a system for managing and analysing
information on suspected adverse reactions to
medicines, which have been authorized or are
under study in clinical trials in the EEA. Such
pooling of spontaneous ADR reports, both
nationally and internationally, can expedite
ADR identication. The WHO, using the UMC
in Sweden, aims to assist in global ADR signal
detection through a database called VigiBase.
Individual countries throughout the world sub-
1 Introduction toDrug Safety andPharmacovigilance
17
mit ADR reports to VigiBase, and the trends are
tracked to identify signals [32]. There are deeper
discussions on pharmacovigilance systems
throughout this book, mainly in Chaps. 6, 7, 9,
and 13.
10 Methods
inPharmacovigilance
Although early clinical studies, toxicology
reports, and clinical trials may provide evidence
for some of the frequent adverse effects expected
from the pharmacology of a drug (the known
knowns) and potentially future possible ADRs
(the known unknowns), pharmacovigilance
must often deal with the unexpected ADRs that
cannot be predicted (the unknown unknowns).
As already noted, although randomized controlled trials (RCTs) are considered the gold
standard for discovering efcacy and are high in
some hierarchies of evidence, evidence for
harms comes from a more varied evidence base.
The idea of a reliable hierarchy of evidence
that ts any clinical topic has been described as
illusory by Rawlins [61], and there are various
arguments against the rigid use of categorical
hierarchies [62–64]. It has been argued that a
‘network of evidence’ may be a better term [65],
and there are instances in which forms of evidence considered lower in the usual hierarchical
structures of medicine are more important. Harms
is one of these areas.
As discussed previously, RCTs are poor at
identifying all relevant harms since they were primarily designed to detect efcacy in a single outcome. Although randomization is important for
studying efcacy, it can also be benecial for
identifying or studying safety issues, e.g.
APPROVe (Adenomatous Polyp Prevention on
Vioxx) Trial for rofecoxib [66]. Randomization
helps look for an imbalance in the rate of recording of outcomes across exposed and nonexposed
events, which can be indicative of safety issues.
However, many clinical trials fail to report ADRs
adequately when published. An examination of
clinical trials in six major medical journals found
that descriptions of AEs were missing in 18% of
the reports. A presentation of the severity of the
AEs was missing in 27.1% of studies, and reporting of withdrawals from the trial because of AEs
was absent in 47.4% of the studies [67]. Even
when AEs are adequately reported, RCTs cannot
detect relatively rare but important harms of
treatments, which can be varied and multiple.
Harms found during the post-marketing phase of
a medicine most commonly arise from spontaneous case reports and can be hypothesisgenerating. The next common source is
observational studies. In a review of 462 medications withdrawn from the market between 1953
and 2013, 72% were withdrawn based on ‘anecdotal reports’, i.e. spontaneous reports alone
[68]. Some anecdotes may provide strong certainty of a drug cause. Aronson and Hauben
described four types of spontaneously reported
ADRs to which a high level of condence of causality could be attributed [69]:
• Extracellular or intracellular tissue deposition
of the drug or metabolite.
• Specic anatomical location or pattern of
injury.
• Physiological dysfunction or direct tissue
damage that can be proved by physicochemical testing.
• Infection because of administration of a potentially infective agent or because of demonstrable contamination.
Spontaneous reports are also important for
discovering drug–drug and drug–food interactions. The incidence of drug interactions may be
low in the general population since they may
require specic comorbidities and other risk factors in the patients to manifest. This means that
the design of an RCT to assess the risk or reality
of a drug interaction may be prohibitively expensive or large. The best evidence may initially
come from case reports, an inversion of the usual
hierarchy of evidence, although they require a
thorough causality evaluation [70].
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