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10 Cobert’s Manual of Drug Safety and Pharmacovigilance
crucial to harmonization, especially when conducting
research and activities on a global scale.
Pharmaceutical and biotechnology companies,
medical device manufacturers, research and develop-
ment organizations, etc. would ideally all follow one
set of standardized definitions as it pertains to prod-
uct development and research. However, what we have
found is that there are slight variations in definitions
of specific terms, documents, and procedures based on
region, product type, or as simple as someone’s past
experience.
For example, the internal document that outlines
the roles and responsibilities of a given CRO, Vendor,
supplier, manufacturer, sponsor, etc., during a clinical
trial can be named a multitude of things, when in reality
they have the same goal and are the same document.
This document has been referred to as a Safety Manage-
ment Plan (SMP), Safety and Medical Monitoring Plan
(SMMP), Safety Reporting Plan (SRP), Safety Operating
Guidelines (SOG), Joint Operating Guidelines (JOG),
and on and on. It is our wish to standardize some of
these definitions amongst the industry as outlined in
this chapter.
Pharmacovigilance terminology and related initial-
isms can be confusing, especially when comparing the
terms between CROs and big/small pharma. Table 1
contains a list of associated initialisms for reference, but
this is certainly not a comprehensive list and will unfor-
tunately differ company to company.
The “official” and accepted definitions in most
countries are based on the International Conference on
Harmonization (ICH) E2A Guideline and are given in
the following sections.
Some agencies, such as the EMA, have also gone
so far as to develop their own lexicon and dictionary
of terms to help close communication gaps due to dif-
fering opinions, language nuances, and definitions
globally. The European Medicines Agency (EMA) has
developed a “Medical terms simplifer,” or a plain lan-
guage description of medical terms related to medicine
use and is available on their website. For pharmacovigi-
lance terms in the EU, and for other countries that have
adopted EU Good Pharmacovigilance Practices (GVPs),
one should refer to the EMA, Guideline on GVP, Annex I
— Definitions. This document is complete, simple to
read, accessible, and truly should not be regarded as for
use only in postmarketing scenarios, but in all aspects
of product development, and is a good reference point
of terms that are relevant to pharmacovigilance, includ-
ing Off-Label Use, Product Quality Complaints, and
Medication errors — terms that are often neglected by
Table 1.
Selected Initialisms and Acronyms Used
in this Manual
Initialism Interpretation
AE Adverse Event, sometimes Adverse Drug Event
(ADE) or, for FDA, also means Adverse
Experience
AESI Adverse event of special interest
API Active Pharmaceutical Ingredient (also application
programming interface)
AR/ADR Adverse Reaction, sometimes Adverse Drug
Reaction (ADR)
CCSI Company Core Safety Information
CFR Code of Federal Regulations, for US
DCSI Development Core Safety Information
GVP Good Pharmacovigilance Practice, for Post-
marketing in the EU
ICH International Council for Harmonization of
Technical Requirements for Pharmaceuticals for
Human Use (formerly International Conference on
Harmonization)
IME Important Medical Event
SAE Serious Adverse Event
SAR Suspected Adverse Reaction, sometimes Serious
Adverse Reaction
SADR Serious Adverse Drug Reaction, sometimes
Suspected Adverse Drug Reaction, neither of which
is currently in common use
SESAR Serious Expected Suspected Adverse Reaction
SUSAR Serious Unexpected Suspected Adverse Reaction,
used in the EU trials and outside the US; similar in
concept to FDA’s Suspected Unexpected Serious
Adverse Reaction (no initialism for FDA)
NSAE Non-serious Adverse Event
NSAR Non-serious Adverse Reaction
Primary definitions relevant to Safety & Pharmacovigilance 11
other areas as being relevant to the pharmacovigilance
system.
Now let’s get down to basics. Each of the terms out-
lined in this chapter are the basic terms one needs to
fully comprehend to survive and operate in this indus-
try. As noted numerous times, however, one will find
a difference in language and points of clarification
depending on the source and region of the definition,
even though ultimately, the intent of the concepts cap-
tured in the definitions is basically the same.
Adverse Event (AE)
The “adverse event”, its seriousness, classification, and
relationship to the product, is what we as researchers
tend to look for in product development, and could
be considered one of the most critical data points that
will be collected and studied for the life of the prod-
uct. There are varying definitions by region as noted
below:
1. Any untoward medical occurrence in a patient
or clinical investigation subject administered a
pharmaceutical product and which does not nec-
essarily have to have a causal relationship with
this treatment (ICH E2A).
2. Any unfavorable and unintended sign (includ-
ing an abnormal laboratory finding, for exam-
ple), symptom, or disease temporally associated
with the use of any dose of a medicinal product,
whether or not considered related to the medic-
inal product (ICH E2A). Any untoward medical
occurrence in a patient or clinical trial subject
administered a medicinal product and which does
not necessarily have to have a causal relationship
with this treatment (Article 2(m) of Directive
2001/20/EC). An AE can therefore be any unfa-
vorable and unintended sign (e.g., an abnormal
laboratory finding), symptom, or disease tem-
porally associated with the use of a medicinal
product, whether or not considered related to the
medicinal product (EMA, Good Pharmacovigi-
lance Practices Annex I Definitions).
In the context of pharmacovigilance and outside
a clinical trial, any untoward medical occurrence in a
patient to whom a medicinal product is administered
and which does not necessarily have a causal relation-
ship with this treatment.
Adverse Event/Experience
(AE) — FDA
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 the drug.
The bad thing may be due to the drug substance, excip-
ients, packaging, storage issues or other problems and
may or may not be due to the active ingredient. There-
fore, AEs are events that coincide with the use of a prod-
uct but may not necessarily be caused by the product.
The FDA uses the term adverse event/experience
and defines it as follows:
For post-marketing cases: Any AE associated with
the use of a drug in humans, whether or not considered
drug-related, including the following: An AE occur-
ring in the case of the use of a drug product in profes-
sional practice; an AE occurring from drug overdose
whether accidental or intentional; an AE occurring
from drug abuse; an AE occurring from drug with-
drawal; and any failure of expected pharmacological
action (21CFR314.80(a)).
For clinical trial cases: Any untoward medical
occurrence associated with the use of a drug in humans,
whether or not considered drug-related.
Adverse Reaction (AR)
A key difference between an “AE” and an “AR” is the
concept of causality. An “event” is merely some-
thing “bad” that occurs, but a “reaction” captures the
concept of a relationship between the event and drug
exposure.
An Adverse Reaction (AR) refers to an AE that
has occurred during the use of a product AND has an
12 Cobert’s Manual of Drug Safety and Pharmacovigilance
associated relationship, or causal relationship with the
use of that product. These events would be classified
as having at least a possible causal relationship with a
product according to most definitions, and these types of
events should be clearly defined in protocols and com-
pany definitions for clarification amongst team members.
Synonyms: Adverse drug reaction (ADR), Suspected
adverse (drug) reaction or serious adverse reaction
(SAR), Adverse effect, Undesirable effect (see EMA GVP
Module Annex 1 Definitions).
1. For pre-approval (i.e., not yet marketed, experi-
mental) products, the definition is as follows:
“All noxious and unintended responses to a
medicinal product related to any dose should be
considered adverse drug reactions.” This means
“that a causal relationship between a medicinal
product and an adverse event is at least a rea-
sonable possibility, i.e., the relationship cannot
be ruled out.” (ICH E2A)
2. For post-approval (i.e., marketed) products, the
definition is as follows:
“A response to a drug which is noxious and unin-
tended and which occurs at doses normally used
in man for prophylaxis, diagnosis, or therapy of
disease or for modification of physiological func-
tion.” (ICH E2A)
3. EMA (GVP Module Annex I Definitions):
A response to a medicinal product which is
noxious and unintended. Response in this con-
text means that a causal relationship between a
medicinal product and an AE is at least a rea-
sonable possibility (see GVP Annex I). An
adverse reaction, in contrast to an AE, is char-
acterized by the fact that a causal relationship
between a medicinal product and an occurrence
is suspected.
4. For regulatory reporting purposes, if an event is
spontaneously reported (such as in post-
marketing reports from patients), even if the
relationship is unknown or unstated by the
healthcare professional or consumer as the pri-
mary source, it meets the definition of an
adverse reaction.
Therefore, all spontaneous reports notified by
healthcare professionals or consumers are considered
suspected adverse reactions, since they convey the sus-
picions of the primary source, unless the primary source
specifically states that they believe the event to be unre-
lated or that a causal relationship can be excluded.
Serious Adverse Event and Serious
Adverse Reaction (SAE/SAR)
A key difference between an “AE” and an “AR” is the
concept of causality. An “event” is merely some-
thing “bad” that occurs, but a “reaction” captures the
concept of a relationship between the event and drug
exposure.
A serious AE or AR are events that meet a specific
set of requirements based on definitions echoed globally,
and only varying slightly between devices and drugs.
SAEs/SARs are additional classifications of events that
are heavily scrutinized, reviewed by the sponsors, and
reported to the agencies at varying frequencies due to
their nature of severity and impact to public health.
SAEs and SARs, like other critical events, should be
clearly defined in the protocol and procedures at spon-
sor companies. The definitions should match the local
regulations and internal procedures or be a unified
definition that encompasses the varying regional defi-
nitions (see... this isn’t as easy as Websters Dictionary!)
A serious AE (experience) or serious AR is any
untoward medical occurrence that, at any dose, meets
one, or more, of the following criteria:
1. Results in death,
2. Is life-threatening,
a. Note: The term life-threatening in the defini-
tion of serious refers to an event in which the
patient was at risk of death at the time of the
event; it does not refer to an event that hypo-
thetically might have caused death if it were
more severe.
3. Requires inpatient hospitalization or prolonga-
tion of existing hospitalization,
4. Results in persistent or significant disability/
incapacity,
Primary definitions relevant to Safety & Pharmacovigilance 13
5. Is a congenital anomaly/birth defect,
6. Is an Important Medical Event. (See below)
Medical and scientific judgment should be exercised
in deciding whether expedited reporting is appropriate
in other situations, such as important medical events
(IMEs) that may not be immediately life-threatening or
result in death or hospitalization but may jeopardize
the patient or may require intervention to prevent one
of the other outcomes listed in the definition above.
These should also usually be considered serious. The
EMA has developed a companion document called the
“MedDRA Important Medical Events Term List” that is
readily available to the public (can be found by a simple
search) and should be referenced and used by sponsors
as a guideline for what events are automatically con-
sidered IMEs, and therefore automatically considered
serious.
Examples of such events are intensive treatment in
an emergency room or at home for allergic broncho-
spasm; blood dyscrasias or convulsions that do not
result in hospitalization; or development of drug depen-
dency or drug abuse (ICH E2A).
The EMA considers any suspected transmission via
a medicinal product of an infection agent to be a serious
adverse reaction.
Note that an event or reaction may meet one or more
of the criteria for seriousness simultaneously. Only one
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
be non-serious.
A. FDA’s definition of a serious event or reac-
tion for clinical trials (21CFR312.32(a)) is as
follows:
An AE or suspected adverse reaction is considered ‘‘seri-
ous’’ if, in the view of either the investigator or spon-
sor, it results in any of the following outcomes: Death, a
life-threatening AE, inpatient hospitalization or prolon-
gation of existing hospitalization, a persistent or signifi-
cant incapacity or substantial disruption of the ability to
conduct normal life functions, or a congenital anomaly/
birth defect. Important medical events that may not
result in death, be life-threatening, or require hospital-
ization may be considered serious when, based upon
appropriate medical judgment, they may jeopardize the
patient or subject and may require medical or surgical
intervention to prevent one of the outcomes listed in
this definition. Examples of such medical events include
allergic bronchospasm requiring intensive treatment in
an emergency room or at home, blood dyscrasias or
convulsions that do not result in inpatient hospitaliza-
tion, or the development of drug dependency or drug
abuse.
B. FDA’s definition of a suspected adverse
reaction for clinical trials is as follows:
Any adverse event for which there is a reasonable pos-
sibility that the drug caused the adverse event. For the
purposes of IND safety reporting, ‘‘reasonable possibil-
ity’’ means there is evidence to suggest a causal relation-
ship between the drug and the adverse event. Suspected
adverse reaction implies a lesser degree of certainty
about causality than adverse reaction, which means any
adverse event caused by a drug.
Suspected Adverse (Drug) Reaction
(SADR) — FDA
This includes any AE for which there is a reasonable
possibility that the drug caused the AE. For the pur-
poses of IND safety reporting, “reasonable possibility”
means there is evidence to suggest a causal relationship
between the drug and the AE. Suspected adverse reac-
tion implies a lesser degree of certainty about causality
than adverse reaction, which means any AE caused by
a drug.
The point here is the word suspected, which means
some level of causality with the drug in question, is
present. It may be serious or non-serious.
Serious, Unexpected, Suspected
Adverse Reaction (SUSAR)
Serious, Unexpected, Suspected Adverse Reactions
(SUSARs) are events that are serious (meet one of the
6 main criteria), are unexpected (meaning not listed
14 Cobert’s Manual of Drug Safety and Pharmacovigilance
in the current labeling or known to have previously
occurred in nature or severity), suspected (meaning
there is a suspected or known causal association with the
product), adverse reaction. SUSARs are therefore consid-
ered one of the most critical types of events in research
as they typically garner the most attention and require
a more expeditious reporting timeframe than any other.
EMA uses this phrase for an SAR in a clinical trial
that is serious, not listed (i.e., unexpected) in the refer-
ence safety information, e.g., investigator brochure, and
suspected to be due to the drug in question. See the
definitions for serious and unexpected. The FDA does
not use this definition or initialism formally for cases,
though the concept is similar to SUSAR; FDA wording
for this concept is “Suspected, Unexpected, Serious
Adverse Reaction”. Such an SAR will ordinarily trig-
ger an expedited report in the EU and consideration of
expedited reporting to FDA (see below). The acronym
“SUSAR” is only applied to clinical trial data, i.e., it does
not apply to spontaneous reports in the post-marketing
phase.
Serious, Expected, Suspected
Adverse Reaction (SESAR)
Serious, Expected, Suspected, Adverse Reactions (SES-
ARs) are events that are serious (meet one of the 6 main
criteria), are expected (meaning already listed in cur-
rent labeling or investigator brochure, or known to have
previously occurred in nature or severity), suspected
(meaning there is a suspected or known causal associa-
tion with the product), adverse reactions.
EMA uses this phrase for an SAR in a clinical trial
that is serious, listed (i.e., expected) in the reference
safety information, e.g., investigator brochure, and sus-
pected to be due to the drug in question. See the defini-
tions for serious and expected.
The FDA does not explicitly define or use this ter-
minology however in 21CFR312.32(c(1)(iv) compa-
nies are required to report an “increased rate of occur-
rence of serious suspected adverse reactions. The sponsor
must report any clinically important increase in the rate
of a serious suspected adverse reaction over that listed in
the protocol or investigator brochure.” Therefore, if there
are known reactions listed in the protocol or investi-
gator brochure (aka “expected” events), and their rate
of occurrence increases, sponsors are responsible for
reporting on such increases. We have found that this is
often a forgotten or missed concept within the indus-
try, however this requirement plays a crucial role in the
scientific monitoring and analysis of previously known
data. Processes should also exist that outline how these
types of events will be identified as it will take an aggre-
gate review of cumulative data in order to determine if
there is a clinically significant increase in the previously
observed rate.
A few questions come to mind regarding this pro-
cess; 1) Are there already established rates of occur-
rence? 2) At what point is the cumulative rate of event
occurrence considered “Clinical important”? Does it
have to be a statistically significant increase (i.e. p value
>.05?) 3) Who makes this determination? Is it a com-
mittee or an individual? 4) What is the day 0 when it is
identified? Processes for ICSR processing and reporting
should include language that addresses the above ques-
tions. These questions are only sometimes answered
and, when answered, may vary from place to place.
Unexpected Adverse Event — FDA
Pre-marketing: “Unexpected” as applied to clini-
cal trials is defined by FDA in 21CFR312.32(a): An
AE or suspected adverse reaction is considered “unex-
pected” if it is not listed in the investigator brochure or
is not listed at the specificity or severity that has been
observed, or if an investigator brochure is not required
or available, is not consistent with the risk informa-
tion described in the general investigational plan or
elsewhere in the current application, as amended. For
example, under this definition, hepatic necrosis would
be unexpected (by virtue of greater severity) if the
investigator brochure referred only to elevated hepatic
enzymes or hepatitis. Similarly, cerebral thromboembo-
lism and cerebral vasculitis would be unexpected (by
virtue of greater specificity) if the investigator brochure
listed only cerebral vascular accidents. “Unexpected”,
as used in this definition, also refers to AEs or suspected
adverse reactions that are mentioned in the investiga-
tor brochure as occurring with a class of drugs or as
Primary definitions relevant to Safety & Pharmacovigilance 15
anticipated from the pharmacological properties of the
drug but are not specifically mentioned as occurring
with the particular drug under investigation.
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
drug product. This includes events that may be symp-
tomatically and pathophysiologically related to an event
listed in the labeling but differ from the event because of
greater severity or specificity. FDA provides an example
in 21CFR314.80(a): Hepatic necrosis would be unex-
pected (by virtue of greater severity) if the labeling only
referred to elevated hepatic enzymes or hepatitis.
AEs that are considered “class-related” (i.e.,
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
described as occurring with this product are considered
unexpected.
Unexpected Adverse
Reaction — EMA
An adverse reaction, the nature, severity or outcome
of which is not consistent with the Summary of Prod-
uct Characteristics (SmPC) (Article 1(13) of Directive
2001/83/EC67). This includes class-related reactions
which are mentioned in the SmPC but which are not
specifically described as occurring with this product.
For products authorized nationally, the relevant SmPC
is that approved by the Competent Authority in the
Member State to whom the reaction is being reported
(often in the local language). For centrally authorized
products, the relevant SmPC is the SmPC authorized
by the European Commission. During the time period
between a CHMP Opinion in favor of granting a mar-
keting authorization and the Commission Decision to
grant a marketing authorization, the relevant SmPC is
the SmPC annexed to the CHMP Opinion (EMA GVP
Module Annex I definitions).
These adverse reactions, when the SmPC is used as
the reference document, are referred to as unlabeled.
This is quite different from unlisted (see below).
Note: For products registered in the EU, the EU
SmPC is the single document to consider, even for clin-
ical trial ICSRs; the investigator brochure is the refer-
ence document for clinical trial ICSRs, but only if the
product is not registered.
Unlisted Adverse Reaction — EMA
An adverse reaction that is not specifically included as
a suspected adverse effect in the Company Core Safety
Information (CCSI). This includes an adverse reaction
whose nature, severity, specificity or outcome is not
consistent with the information in the CCSI. It also
includes class-related reactions which are mentioned
in the CCSI but which are not specifically described
as occurring with this product (GVP Annex IV, ICH-
E2C(R2).
Expected (Listed versus Labeled)
As opposed to “unexpected”, “expected” refers to an
event that is noted in the investigator brochure or label-
ing (Package Insert or SmPC). One complication is that
two different reference documents (labels) are avail-
able for marketed drugs for expectedness. One is the
regulator-approved prescribing information (e.g., Pack-
age Insert or SmPC, etc.), which may vary from jurisdic-
tion to jurisdiction, and the other is the company’s core
safety information (CCSI). The latter is provided to reg-
ulators, but it is a company-driven document that does
not ordinarily need approval by regulators. Usually, these
are quite similar if not identical, but not always. The
CCSI contains the company position on the minimum
safety information that should be in every regulator-
approved label wherever the product is authorized for
marketing. An event/reaction not found in the CCSI
may be included in the regular-approved label, but
not vice-versa. If the event/reaction is not found in the
SmPC, it is considered unlabeled. If it is not found in
the core labeling, i.e., the product’s CCSI, it is unlisted.
If it is not found in the PI or SmPC, etc. it is unlabeled.
The CCSI is used to determine “listedness” for periodic
aggregate reports in the post-marketing phase.
Thus, an event in the United States is expected
or unexpected depending on whether it is found in
16 Cobert’s Manual of Drug Safety and Pharmacovigilance
the reference safety information (RSI): the investiga-
tor’s brochure for unapproved products or the FDA-ap-
proved labeling for marketed products. In the European
Union, it is the same for unapproved products, but for
marketed products, an unexpected event/reaction may
be unlabeled (not in the SmPC) or unlisted (not in the
CCSI).
This is confusing terminology. To summarize
“listed” refers to the CCSI; “labeled” refers to the PI or
SmPC.
The Practice
For a good summary of post-marketing pharmacovigi-
lance definitions used in the EU (and often elsewhere),
see the GVP Annex I Definitions, referenced above. This
is a comprehensive document with definitions from the
EMA. They are very similar to the FDA definitions.
AEs are unintended events that occur when taking a
drug (or biologic or vaccine, etc.). They may or may not
be due to the drug itself (the “active moiety”, or “active
pharmacological ingredient” (API)), the formulation,
excipients in the product (e.g., the inactive ingredients,
fillers), the packaging (e.g., leaching of products from
a container into the liquid drug product), a contami-
nant, manufacturing problems, the underlying disease,
or some other unknown cause or causes. Thus, an AE
does not imply that the drug (i.e., the active compo-
nent) necessarily caused the bad thing to occur.
An AR is an AE in which there is “reasonable possi-
bility” of a causal relationship between the drug and the
AE. Some interpret this to mean that the relationship
cannot be ruled out. This is probably too extreme as
it implies that unless causality can be absolutely, posi-
tively ruled out, it is “possibly related” or that there is a
“reasonable possibility” of causality. FDA in its guidance
on IND Safety Reporting discussed this at length and
indicated that they do not want to see cases reported
as expedited IND reports if there is “not enough evi-
dence to suggest that there was a reasonable possibility
that the drug caused the AE”. This is done to increase
the likelihood that the information sent to FDA will be
“interpretable and will meaningfully contribute to the
developing safety profile of the investigational drug and
improve the overall quality of safety reporting”. The
notion of causality is discussed in much greater detail
later in this Manual. Thus, an AE possibly or probably
due to the drug is an ADR or AR.
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
have the phrase suspected, unexpected, serious adverse
reaction. The addition of the words “serious” and
“unexpected” to the SAR term represents the criteria for
submission as expedited reports to government health
agencies in many countries of serious reactions from
clinical trials. This phrase is very similar in meaning to
the acronym SUSAR that is used for expedited clinical
trial reports in the EU.
Suspected, expected, serious adverse reactions usu-
ally do not have to be submitted as expedited reports
to governmental agencies. They are usually submitted
periodically (e.g., yearly) or at the end of the study
in the final study report. However, some regulatory
jurisdictions require submission of all “serious” SARs,
regardless of expectedness, if there is a reasonable pos-
sibility of a causal relationship with the product.
Expectedness represents an often highly subjective
area. An event or reaction is expected if it is found in
the product reference document (IB for clinical trials or
the post-marketing labeling for approved drugs). More
specific or more severe events or reactions, however, are
considered to be unexpected. Thus, if “pneumonia” is
in the brochure or product labeling and the patient has
“streptococcal pneumonia”, this is considered unex-
pected because the “streptococcal” designation is more
specific. Similarly, “fatal pneumonia” is considered
unexpected if only pneumonia is labeled (see Chap-
ter 22).
The bottom line here is that there are multiple defi-
nitions and variants floating around. They all more or
less add up to the same cases being “expeditable” in
the United States, European Union, and elsewhere in
many, but not in all situations. There are nuanced dif-
ferences in the definitions of related/unrelated, but fun-
damentally what they come down to is that cases that
are serious (death, life-threatening, hospitalization, dis-
ability/incapacity, birth defect) and related (“reasonable
https://avxhm.se/blogs/hill0
Primary definitions relevant to Safety & Pharmacovigilance 17
possibility” that the AE is due to the drug) and unex-
pected (not in the IB or only included in the class label-
ing section) are expeditable in the clinical trial setting.
Another nuance is the responsibility for the cau-
sality determination for clinical trial reports: FDA
has assigned this responsibility to the sponsor (only),
whereas elsewhere, either the sponsor or the investiga-
tor judgment applies. A good rule of thumb: In general,
one should be conservative in applying the definitions,
and if one has to discuss or debate whether something
is serious and/or related and/or unexpected, then it is.
That is, if there is any doubt about any of these three
definitions, choose the more conservative approach
(serious, related, unexpected).
Q&A
Q: What can be done to simplify this process?
A: Companies must adopt a uniform dictionary and
process and stick with them. Ideally, all companies
would define which dictionary they will use to oper-
ate and define events from a safety and pharmacovig-
ilance perspective. Would you start a game a Scrabble
without confirming which dictionary would be used to
challenge words? No, so then why would you accept a
varying degree of understanding of terms when it comes
to the evaluation of safety data in order to protect and
monitor human health and outcomes?
Q: How can companies achieve this?
A: Create a policy, SOP, or lexicon, that will be refer-
enced throughout all procedures and training for defini-
tions. Train your employees on these definitions; if your
employees do not have a uniformed understanding of
what it is they are evaluating, what they are looking
for, and what they are monitoring and reporting on, we
will continue to see discrepancies in data analysis and
review.
CHAPTER
19
3
Regulations, Directives,
Guidance, Laws and
Consensus Documents
P
harmacovigilance (PV) is governed
by a large body of requirements.
Some are written and rigid, i.e.,
legally enforceable. Others are writ-
ten but are far less rigid. Others are not
requirements but only guidances or
guidelines, and still others are unwrit-
ten customs and (best or optimal)
practices. Obviously, laws and regu-
lations, as well as their enforcement,
vary from country to country and are
subject to change over time. Difficulty
in effecting change is roughly in this
rank order (beginning with most diffi-
cult and time-consuming): Laws, Reg-
ulations, Regulatory Guidance, and
Consensus Guidelines. The sections
that follow concisely summarize the
obligations in the US and the EU for
drugs and over-the-counter (OTC)
products, but also provide selected
references to assist with remaining
“up to date” on PV requirements.
United States
Legal requirements for drug safety come from multiple
areas. There are laws, regulations, and guidances issued
by the United States’ federal government. These are
the predominant formal requirements governing drug
safety. In the US, a “law” is a written statute, require-
ment, or ordinance that has been passed by a legisla-
ture and then signed into law (where required) by the
executive. That is, a federal law is passed by Congress
in Washington, D.C., and signed by the president. Laws