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CHAPTER

1
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The Theory
and Definitions
of Drug Safety —
Pharmacovigilance

W
hat is an adverse event (AE)? A Pharmacovigilance terminology and related initialisms are
somewhat confusing; commonly used terms are explained
serious AE (SAE)? An adverse below. Table 1 contains a list of associated initialisms. For
drug reaction (ADR)? A sus- a more extensive listing of initialisms used in pharma-
pected, unexpected, serious adverse covigilance, see the Acronyms section of this manual.
reaction (SUSAR)? A suspected, expected, The “official” and accepted definitions in most
serious adverse reaction? What do countries are based on the International Conference on
Harmonization (ICH) E2A Guideline and are given in
expected, unexpected, listed and unlisted the following sections. Note that the ICH changed its
mean? name to International Council for Harmonization of
Technical Requirements for Pharmaceuticals for Human
Note: Unless otherwise noted, the words “drug” Use in 2015. They still refer to it as ICH.
or “drug product” or “medicinal product” should
be taken in this book to include “biologics” and Adverse Event (AE) — ICH
“vaccines”, too.
Any untoward medical occurrence in a patient or clini-
cal investigation subject administered a pharmaceutical
product and which does not necessarily have to have a
  The Theory causal relationship with this treatment (ICH E2A).
There have been many variants on the terms and defi- Any unfavorable and unintended sign (including an
nitions used to talk about safety issues over the years. abnormal laboratory finding, for example), symptom,

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use of a medicinal product, whether or not considered

Table 1. Selected Initialisms and Acronyms
related to the medicinal product (EMA, Good Phar-
Used in this Manual
macovigilance Practices Annex I Definitions) (http://
Initialism Interpretation
www.ema.europa.eu/docs/en_GB/document_library/
AE Adverse Event, sometimes Adverse Drug Event
(ADE) or, for FDA, also means Adverse
Scientific_guideline/2013/05/WC500143294.pdf).
Experience In the context of pharmacovigilance and outside
API Active Pharmaceutical Ingredient a clinical trial, any untoward medical occurrence in a
AR Adverse Reaction, sometimes Adverse Drug patient to whom a medicinal product is administered
Reaction (ADR) and which does not necessarily have a causal relation-
CCSI Company Core Safety Information ship with this treatment.
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CFR Code of Federal Regulations, for US

DCSI Development Core Safety Information
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GVP Good Pharmacovigilance Practice, for Post- Adverse Event/Experience

marketing in the EU (AE) — FDA
ICH International Council for Harmonization of
Technical Requirements for Pharmaceuticals for The FDA uses the term adverse event/experience and
Human Use (formerly International Conference on defines it as follows:
Harmonization)
IME
SAE
Important Medical Event
Serious Adverse Event
ƒ For post-marketing cases: Any AE associated
with the use of a drug in humans, whether or not
SAR Suspected Adverse Reaction, sometimes Serious considered drug-related, including the following: An
Adverse Reaction
AE occurring in the case of the use of a drug prod-
SADR Serious Adverse Drug Reaction, sometimes
uct in professional practice; an AE occurring from
Suspected Adverse Drug Reaction, neither of which
is currently in common use drug overdose whether accidental or intentional;
SUSAR Serious Unexpected Suspected Adverse
an AE occurring from drug abuse; an AE occurring
Reaction, used in the EU trials and outside from drug withdrawal; and any failure of expected
the US; similar in concept to FDA’s Suspected pharmacological action (21CFR314.80(a)).
Unexpected Serious Adverse Reaction (no
initialism for FDA)
ƒ For clinical trial cases: Any untoward medical
occurrence associated with the use of a drug in
NSAE Non-serious Adverse Event humans, whether or not considered drug-related.
NSAR Non-serious Adverse Reaction
In practice, most people use the term “AE” to refer
to any “bad thing” that occurs during the use of a
drug without implying that the bad thing is due to
or disease temporally associated with the use of any the drug. The bad thing may be due to the drug
dose of a medicinal product, whether or not considered substance, excipients, packaging, storage issues or
related to the medicinal product (ICH E2A). other problems and may or may not be due to the
active ingredient.

Adverse Event (AE) — EMA Adverse Reaction (AR)

Any untoward medical occurrence in a patient or clinical Synonyms: Adverse drug reaction (ADR), Suspected
trial subject administered a medicinal product and which adverse (drug) reaction or serious adverse reaction
does not necessarily have to have a causal relationship (SAR), Adverse effect, Undesirable effect (see EMA GVP
with this treatment (Article 2(m) of Directive 2001/20/ Module Annex 1 Definitions).
EC). An AE can therefore be any unfavorable and unin-
tended sign (e.g., an abnormal laboratory finding), ƒ For pre-approval (i.e., not yet marketed, experi-
mental) products, the definition is as follows:
symptom, or disease temporally associated with the

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The Theory and Definitions of Drug Safety — Pharmacovigilance   3

“All noxious and unintended responses to a medic- ƒ IsResults in death,

inal product related to any dose should be consid- ƒ Note: The term life-threatening in the definition of
life-threatening,
ered adverse drug reactions.” This means “that a serious refers to an event in which the patient was at
causal relationship between a medicinal product
and an adverse event is at least a reasonable pos- risk of death at the time of the event; it does not refer
sibility, i.e., the relationship cannot be ruled out.” to an event that hypothetically might have caused
(ICH E2A) death if it were more severe.
ƒ· For post-approval (i.e., marketed) products, the ƒ Requires inpatient hospitalization or prolongation
of existing hospitalization,
definition is as follows:

“A response to a drug which is noxious and unin-

ƒ Results in persistent or significant disability/inca-
pacity, or
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tended and which occurs at doses normally used in

man for prophylaxis, diagnosis, or therapy of dis- ƒ Is a congenital anomaly/birth defect.
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ease or for modification of physiological function.”

Medical and scientific judgment should be exer-
(ICH E2A)
cised in deciding whether expedited reporting is
appropriate in other situations, such as important
EMA (GVP Module Annex I Definitions):
medical events (IMEs) that may not be immedi-
A response to a medicinal product which is noxious
ately life-threatening or result in death or hospi-
and unintended. Response in this context means that
talization but may jeopardize the patient or may
a causal relationship between a medicinal product
require intervention to prevent one of the other
and an AE is at least a reasonable possibility (see GVP
outcomes listed in the definition above. These
Annex I). An adverse reaction, in contrast to an AE,
should also usually be considered serious.
is characterized by the fact that a causal relationship
between a medicinal product and an occurrence is sus- Examples of such events are intensive treatment
pected. For regulatory reporting purposes, if an event in an emergency room or at home for allergic
is spontaneously reported, even if the relationship is bronchospasm; blood dyscrasias or convul-
unknown or unstated by the healthcare professional or sions that do not result in hospitalization; or
consumer as the primary source, it meets the definition development of drug dependency or drug abuse
of an adverse reaction. (ICH E2A).
Therefore, all spontaneous reports notified by The EMA considers any suspected transmission
healthcare professionals or consumers are considered via a medicinal product of an infection agent to
suspected adverse reactions, since they convey the be a serious adverse reaction.
suspicions of the primary source, unless the primary
source specifically states that they believe the event Note that an event or reaction may meet one or more
to be unrelated or that a causal relationship can be of the criteria for seriousness simultaneously. Only one
excluded. is needed, however, to consider the event or reaction to
be serious. For an individual case safety report (ICSR)
to be serious, it takes only one serious AE out of all the
AEs present. To be a non-serious ICSR, all the AEs must
Serious Adverse Event and Serious
be non-serious.
Adverse Reaction (SAE/SAR)
FDA’s definition of a serious event or reaction for
A key difference between an “AE” and an “AR” is the clinical trials (21CFR312.32(a)) is as follows:
concept of causality. An “event” is merely something
“bad” that occurs, but a “reaction” captures the concept An AE or suspected adverse reaction is con-
of a relationship between the event and drug exposure. sidered ‘‘serious’’ if, in the view of either the
A serious AE (experience) or serious AR is any investigator or sponsor, it results in any of the
untoward medical occurrence that at any dose: following outcomes: Death, a life-threatening

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AE, inpatient hospitalization or prolongation means there is evidence to suggest a causal relationship
of existing hospitalization, a persistent or sig- between the drug and the AE. Suspected adverse reac-
nificant incapacity or substantial disruption of tion implies a lesser degree of certainty about causality
the ability to conduct normal life functions, or than adverse reaction, which means any AE caused by
a congenital anomaly/birth defect. Important a drug.
medical events that may not result in death, be
The point here is the word suspected, which means
life-threatening, or require hospitalization may
some level of causality with the drug in question, is
be considered serious when, based upon appro-
present. It may be serious or non-serious.
priate medical judgment, they may jeopardize
the patient or subject and may require medical
or surgical intervention to prevent one of the Serious, Unexpected, Suspected
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outcomes listed in this definition. Examples

Adverse Reaction (SUSAR)
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of such medical events include allergic bron-

chospasm requiring intensive treatment in an EMA uses this phrase for an SAR in a clinical trial that
emergency room or at home, blood dyscrasias is serious, not listed (i.e., unexpected) in the reference
or convulsions that do not result in inpatient safety information, e.g., investigator brochure, and
hospitalization, or the development of drug suspected to be due to the drug in question. See the
dependency or drug abuse. definitions for serious and unexpected. The FDA does
not use this definition or initialism formally for cases,
FDA’s definition of a suspected adverse reaction for
though the concept is similar to SUSAR; FDA wording
clinical trials is as follows:
for this concept is “Suspected, Unexpected, Serious
Adverse Reaction”. Such an SAR will ordinarily trig-
Any adverse event for which there is a reason- ger an expedited report in the EU and consideration
able possibility that the drug caused the adverse of expedited reporting to FDA (see below). The acro-
event. For the purposes of IND safety reporting, nym “SUSAR” is only applied to clinical trial data, i.e.,
‘‘reasonable possibility’’ means there is evidence it does not apply to spontaneous reports in the post-
to suggest a causal relationship between the marketing phase.
drug and the adverse event. Suspected adverse
reaction implies a lesser degree of certainty
about causality than adverse reaction, which Serious, Expected, Suspected
means any adverse event caused by a drug.
Adverse Reaction
EMA uses this phrase for an SAR in a clinical trial that
Non-serious Adverse Event and is serious, listed (i.e., expected) in the reference safety
Non-serious Adverse Reaction information, e.g., investigator brochure, and suspected
(NSAE/NSAR) to be due to the drug in question. See the definitions
for serious and expected. The FDA does not define this
An event or reaction is non-serious when it does not phrase in 21CFR312.32(a) or use this phrase formally
meet any of the criteria for seriousness. for cases, though application of the concept is similar
and relevant.

Suspected Adverse (Drug) Reaction

(SAR/SADR) — FDA Unexpected Adverse
Event — FDA
This includes any AE for which there is a reasonable
possibility that the drug caused the AE. For the pur- Pre-marketing: “Unexpected” as applied to clin-
poses of IND safety reporting, “reasonable possibility” ical trials is defined by FDA in 21CFR312.32(a):

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The Theory and Definitions of Drug Safety — Pharmacovigilance   5

An AE or suspected adverse reaction is considered which are mentioned in the SmPC but which are not
“unexpected” if it is not listed in the investigator bro- specifically described as occurring with this product.
chure or is not listed at the specificity or severity that For products authorized nationally, the relevant SmPC
has been observed, or if an investigator brochure is is that approved by the Competent Authority in the
not required or available, is not consistent with the Member State to whom the reaction is being reported
risk information described in the general investiga- (often in the local language). For centrally authorized
tional plan or elsewhere in the current application, as products, the relevant SmPC is the SmPC authorized
amended. For example, under this definition, hepatic by the European Commission. During the time period
necrosis would be unexpected (by virtue of greater between a CHMP Opinion in favor of granting a mar-
severity) if the investigator brochure referred only to keting authorization and the Commission Decision to
elevated hepatic enzymes or hepatitis. Similarly, cere- grant a marketing authorization, the relevant SmPC is
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bral thromboembolism and cerebral vasculitis would the SmPC annexed to the CHMP Opinion (EMA GVP
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be unexpected (by virtue of greater specificity) if the Module Annex I definitions).

investigator brochure listed only cerebral vascular
These adverse reactions, when the SmPC is used as
accidents. “Unexpected”, as used in this definition,
the reference document, are referred to as unlabeled.
also refers to AEs or suspected adverse reactions that
This is quite different from unlisted (see below).
are mentioned in the investigator brochure as occur-
ring with a class of drugs or as anticipated from the Note: For products registered in the EU, the EU
pharmacological properties of the drug, but are not SmPC is the single document to consider, even for clin-
specifically mentioned as occurring with the particu- ical trial ICSRs; the investigator brochure is the refer-
lar drug under investigation. ence document for clinical trial ICSRs, but only if the
product is not registered.
Post-approval (Marketed) Products: This
takes account of any adverse drug experience that is
not included in the current labeling (Package Insert or
Summary of Product Characteristics (SmPC)) for the
Unlisted Adverse Reaction — EMA
drug product. This includes events that may be symp- An adverse reaction that is not specifically included as
tomatically and pathophysiologically related to an event a suspected adverse effect in the Company Core Safety
listed in the labeling, but differ from the event because Information (CCSI). This includes an adverse reaction
of greater severity or specificity. FDA provides an exam- whose nature, severity, specificity or outcome is not con-
ple in 21CFR314.80(a): Hepatic necrosis would be sistent with the information in the CCSI. It also includes
unexpected (by virtue of greater severity) if the labeling class-related reactions which are mentioned in the CCSI
only referred to elevated hepatic enzymes or hepatitis. but which are not specifically described as occurring
AEs that are considered “class-related” (i.e., with this product (GVP Annex IV, ICH-E2C(R2).
allegedly seen with all products in this class of drugs)
and are mentioned in the labeling (Package Insert or
SmPC) or investigator brochure but are not specifically Expected (Listed versus Labeled)
described as occurring with this product are considered
As opposed to “unexpected”, “expected” refers to an
unexpected.
event that is noted in the investigator brochure or label-
ing (Package Insert or SmPC). One complication is that
Unexpected Adverse two different reference documents (labels) are available
Reaction — EMA for marketed drugs for expectedness. One is the regu-
lator-approved prescribing information (e.g., Package
An adverse reaction, the nature, severity or outcome of Insert or SmPC, etc.), which may vary from jurisdic-
which is not consistent with the Summary of Product tion to jurisdiction, and the other is the company’s
Characteristics (SmPC) (Article 1(13) of Directive core safety information (CCSI). The latter is provided
2001/83/EC67). This includes class-related reactions to regulators, but it is a company-driven document

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that does not ordinarily need approval by regulators. An AR is an AE in which there is “reasonable possi-
Usually, these are quite similar if not identical, but bility” of a causal relationship between the drug and the
not always. The CCSI contains the company position AE. Some interpret this to mean that the relationship
on the minimum safety information that should be in cannot be ruled out. This is probably too extreme as it
every regulator-approved label wherever the product is implies that unless causality can be absolutely, positively
authorized for marketing. An event/reaction not found ruled out, it is “possibly related” or that there is a “rea-
in the CCSI may be included in the regular-approved sonable possibility” of causality. FDA in its guidance on
label, but not vice-versa. If the event/reaction is not IND Safety Reporting of December 2012 (https://www.
found in the SmPC, it is considered unlabeled. If it is fda.gov/downloads/drugs/guidancecomplianceregula-
not found in the core labeling, i.e., the product’s CCSI, toryinformation/guidances/ucm227351.pdf) discussed
it is unlisted. If it is not found in the PI or SmPC, this at length and indicated that they do not want to see
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etc. it is unlabeled. The CCSI is used to determine cases reported as expedited IND reports if there is “not
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“listedness” for periodic aggregate reports in the post- enough evidence to suggest that there was a reasonable
marketing phase. possibility that the drug caused the AE”. This is done
to increase the likelihood that the information sent to
Thus, an event in the United States is expected or
FDA will be “interpretable and will meaningfully con-
unexpected depending on whether it is found in the ref-
tribute to the developing safety profile of the investi-
erence safety information (RSI): the investigator’s bro-
gational drug and improve the overall quality of safety
chure for unapproved products or the FDA-approved
reporting”. The notion of causality is discussed in much
labeling for marketed products. In the European Union,
greater detail in Chapter 22. Thus, an AE possibly or
it is the same for unapproved products, but for marketed
probably due to the drug is an ADR or AR.
products, an unexpected event/reaction may be unla-
beled (not in the SmPC) or unlisted (not in the CCSI). These terms are being replaced in practice by SAR,
which emphasizes the suspicion that the drug is a pos-
sible cause of the bad thing or is the possible cause of
the bad thing. Following logically from this, we now
  The Practice have the phrase suspected, unexpected, serious
In practice, these definitions are rather murky and adverse reaction. The addition of the words “serious”
confusing. They also change periodically. For a good and “unexpected” to the SAR term represents the crite-
summary of post-marketing pharmacovigilance defini- ria for submission as expedited reports to government
tions used in the EU (and often elsewhere), see the health agencies in many countries of serious reactions
GVP Annex I Definitions, referenced above. This is a from clinical trials. This phrase is very similar in mean-
comprehensive document with definitions from the ing to the acronym SUSAR that is used for expedited
EMA. They are very similar to the FDA definitions. clinical trial reports in the EU.

AEs are unintended “bad things” that occur when Suspected, expected, serious adverse reactions usu-
taking a drug (or biologic or vaccine, etc.). They may ally do not have to be submitted as expedited reports
or may not be due to the drug itself (the “active moi- to governmental agencies. They are usually submitted
ety”, or “active pharmacological ingredient” (API)), periodically (e.g., yearly) or at the end of the study
the formulation, excipients in the product (e.g., the in the final study report. However, some regulatory
inactive ingredients, fillers), the packaging (e.g., leach- jurisdictions require submission of all “serious” SARs,
ing of products from a container into the liquid drug regardless of expectedness, if there is a reasonable pos-
product), a contaminant, manufacturing problems, the sibility of a causal relationship with the product.
underlying disease, or some other unknown cause or Expectedness represents an often highly subjective
causes. Thus, an AE does not imply that the drug (i.e., area. An event or reaction is expected if it is found in
the active component) necessarily caused the bad thing the product reference document (IB for clinical trials or
to occur. the post-marketing labeling for approved drugs). More

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The Theory and Definitions of Drug Safety — Pharmacovigilance   7

specific or more severe events or reactions, however, disability/incapacity, birth defect) and related (“rea-
are considered to be unexpected. Thus, if “pneumonia” sonable possibility” that the AE is due to the drug)
is in the brochure or product labeling and the patient and unexpected (not in the IB or only included in the
has “streptococcal pneumonia”, this is considered class labeling section) are expeditable in the clinical
unexpected because the “streptococcal” designation trial setting.
is more specific. Similarly, “fatal pneumonia” is con-
Another nuance is the responsibility for the cau-
sidered unexpected if only pneumonia is labeled (see
sality determination for clinical trial reports: FDA
Chapter 22).
has assigned this responsibility to the sponsor (only),
The bottom line here is that there are multiple whereas elsewhere, either the sponsor or the inves-
definitions and variants floating around. They all more tigator judgment applies. In general, one should be
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or less add up to the same cases being “expeditable” in conservative in applying the definitions, and if one
the United States, European Union, and elsewhere in has to discuss or debate whether something is serious
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many, but not all situations. There are nuanced differ- and/or related and/or unexpected, then it is. That is,
ences in the definitions of related/unrelated, but fun- if there is any doubt about any of these three defini-
damentally what they come down to is that cases that tions, choose the more conservative approach (seri-
are serious (death, life-threatening, hospitalization, ous, related, unexpected).

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