Core PV Concepts

CORE PV CONCEPTS
(Johnson & Johnson Consumer, Inc., McNeil Consumer Healthcare Division)
Prepared by:
Bernadette C. Sarmiento, MD
Medical Safety Physician
OBJECTIVES
• Know the definitions of terminology used for side effects
• Better grasp on the definitions of different drug safety terms
• Familiarize with concepts used in risk terminology
• Memorize the core concepts used in PV assessment and causality

• CIOMS III/V threshold criteria (aid in determining causal association)
• SNIP criteria (prioritization of potential safety signals)
© 2020 ClinChoice – Confidential and All Rights Reserved 2

TERMS USED FOR SIDE EFFECTS
TERM DEFINITION RELEVANCE
Side effect Unintended effect occurring at normal dose related to the pharmacological Lay-man’s term to describe adverse event
(SE) properties
Adverse event Any untoward medicinal occurrence in a patient or clinical trial subject Standard definition of AE
(AE) administered a medicinal product which does not necessarily have a causal
relationship with this treatment Important thing to remember here is that it is
associated with the use of the product; however, it is
An AE can therefore be any unfavorable and unintended sign (eg, abnormal not necessarily causally related to the medicinal
laboratory finding), symptom, or disease temporally associated with the use product (eg, patient took a medicine and fell of a horse
of a medicinal product, whether or not considered related to the medicinal accidentally and broke his leg. Breaking his leg would
product be considered an AE even though it is not related to the
medicine)
Serious adverse An adverse event which results in death, is life-threatening, requires in- In addition, medical judgment should be used to assess
effect patient hospitalization or prolongation of existing hospitalization, results in an AE as serious due to its medical importance.
(SAE) persistent or significant disability or incapacity, or is a congenital
anomaly/birth defect The Important Medical Event (IMD) list aims to
facilitate the seriousness classification of suspected
ADRs
The seriousness criterion “Life-threatening” in this

context refers to a reaction in which the patient was at
risk of death at the time of the reaction; it does not
refer to a reaction that hypothetically might have
© 2020 ClinChoice – Confidential and All Rights Reserved caused death if more severe 3
Adverse drug A response to a medicinal product which is noxious and unintended Note how ADR differs from AE
reaction
(ADR) “Response” in this context means that a causal relationship between a When we use the word “reaction,” we assign at least a
medicinal product and an adverse event is at least a reasonable possibility reasonable possibility of a causal relationship, whereas
the term AE does not imply a causal relationship
Adverse reactions may arise from use of the product within or outside the
terms of the marketing authorization or from occupational exposure
Conditions of use outside the MA include off-label use, overdose, misuse,

abuse, and medication errors
Serious adverse An adverse reaction which results in death, is life-threatening, requires in- Same subtle difference as AE and ADR
reaction patient hospitalization or prolongation of existing hospitalization, results in
(SAR) persistent or significant disability or incapacity, or is a congenital Any suspected transmission via a medicinal product of
anomaly/birth defect. an infectious agent is also considered a SAR
“Reaction” means that a causal relationship between the medicinal product

and the AE is at least a reasonable possibility
Unexpected adverse An adverse reaction, the nature, severity or outcome of which is not Any event that is not expected, in accordance with the
reaction consistent with the applicable product information label (USPI in US and SmPC in Europe), is considered an
unexpected event.
Importantly, if an event is listed in the label, but occurs

at a higher severity or with a worse outcome than the
© 2020 ClinChoice – Confidential and All Rights Reserved event listed in the label, is also considered unexpected.4
Suspected A serious ADR whose nature or severity is unexpected based on the The same considerations as previously stated in
unexpected serious applicable product information unexpected adverse reaction
adverse reaction
(SUSAR) This term only refers to serious events
Abuse Persistent or sporadic, intentional excessive use of medicinal product, which Although being a condition of use outside the MA,
is accompanied by harmful physical or psychological effects abuse can lead to ADRs
Medication error An unintended failure in the drug treatment process that leads to, or has the This term is related to the way a drug is taken or
(ME) potential to lead to harm to the patient administered, rather than to the effect it causes. A
drug could be wrongly prescribed by a HCP, wrongly
A failure in the drug treatment process does not refer to lack of efficacy of dispensed by a nurse/caregiver, or administered
the drug, rather to human or process mediated failures incorrectly by a caregiver or a patient
Although being a condition of use outside the MA, ME

can lead to ADRs
EMA guidance “Good practice guide on recording,

coding, reporting and assessment of medication errors”
points out that ME may occur at all stages of the drug
treatment process (eg, prescribing, storage, dispensing,
preparation, administration)

Misuse Situations where the medicinal product is Although being a condition of use outside the MA, misuse can lead to ADRs
intentionally and inappropriately used not in
accordance with the terms of the MA
Off-label use Situations where a medicinal product is intentionally When drugs are approved by regulators, they get specific approval to use it for
used for a medical purpose not in accordance with a certain indication or population or dose, only. However, sometimes it is
the terms of the MA noticed that the drug is intentionally prescribed for a medical purpose it is
not explicitly indicated for
Examples:
• Medicine used for disease or medical condition that it is not
approved to treat
• Medicine administration through different route or method of
administration
• Medicine used with different dose (posology)
• Medicine used in different group of patients (population)
Although being a condition of use outside the MA, off-label use can lead to
ADRs
The element of “intention” differentiates some of the off-label uses from the
ME at prescriber level (eg, MD prescribes/administers a drug by unauthorized
route of administration → off-label use; MD unintentionally
prescribes/administers a drug by unauthorized route of administration → ME)
Overdose Administration of a quantity of a medicinal product As described, there is a maximum permissible dose for every medicinal
given per administration or cumulatively which is product. When it is administered above the maximum recommended dose it
above the maximum recommended dose according to is considered as an overdose
the authorized product information
Although being a condition of use outside the MA, overdose can lead to ADRs
Clinical judgment should always be applied

DRUG SAFETY CONCEPTS
Causal relationship According to the WHO, the causal relationship between an To determine the causal relationship (ie, to assess whether the drug
adverse event and a suspected drug can be: caused the AE/ADR), several medical aspects are evaluated
• certain
• probable/likely Elements to assess the causal relationship are drug’s half-life, pathological
• possible mechanisms, temporal relationship of event to drug administration,
• unlikely dechallenge and rechallenge, concomitant diseases and/or concomitant
• conditional/unclassified use of other medicines, previous experience with the drug, and possible
• unassessable/unclassifiable alternative explanations for the event
Causal assessment is determined based on temporal

relationship, alternative explanation, and (if possible)
dechallenge and rechallenge
Critical terms The WHO marked some terms as “Critical Terms.” The WHO list of Critical Terms may serve as a basis for medical judgment
of AEs (ie, to assess whether AEs should be considered serious due to their
These terms either refer to or might be indicative of medical importance)
serious disease states, and warrant special attention,
because of their possible association with the risk of
serious illness that may lead to more decisive action than
reports on other terms

Important medical The EudraVigilance Expert Working Group has coordinated the IME list can be used to facilitate seriousness assessment of
event development of an IME terms list based on the Medical Dictionary for AEs
(IME) Regulatory Activities (MedDRA).
This IME list aims to facilitate the classification of suspected adverse

reactions, the analysis of aggregated data and the assessment of ICSRs
in the framework of the day-to-day PV activities
The IME list is intended for guidance purposes only and is available on
the EMA website and regularly updated in line with the latest
MedDRA version
Designated medical DMEs are serious and rare medical events that are often causally DMEs are serious, rare and often causally associated with
event (DME) associated with drugs across multiple pharmacological/therapeutic drugs. Therefore, even small number of reports of such
classes event can trigger a signal and require special attention
An organization may maintain such list, to prioritize cases of

such event for safety review
EMA maintains a list MedDRA PTs that identifies DMEs. The

content of the EMA DME list is not definitive and may
change as EMA gathers further experience with its use

Dechallenge The clinical decision to withdraw or discontinue a drug Dechallenge (and rechallenge) play an important role in ascertaining a
to monitor the effect on an AE causal relationship
Dechallenge means that a drug that is suspected of causing the event is

withdrawn
A dechallenge is positive when after removal of the drug the AE subsides

or disappears
A dechallenge is negative when the event persists even after removal of

the drug (ie, causal relationship is unlikely)
Rechallenge The point at which a drug is given again to a patient In the instance you have a positive dechallenge (AE subsides or disappears
after its previous withdrawal after your remove the drug), reintroducing the drug represents a
rechallenge
A positive rechallenge (ie, the AE reappears when treatment is restarted),

strongly suggests a causal relationship
Efficacy The ability of a drug to produce the intended effect as
determined by scientific methods (eg, pre-clinical and in
clinical research conditions)

Seriousness vs severity The term “severe” must not be confused with “serious” Understanding the difference between seriousness and severity
is critical to correctly report and evaluate AEs
In the English language, “severe” is used to describe the intensity
(severity) of a specific event (mild, moderate, severe); the event
itself, however, may be of relatively minor medical significance
(eg, severe headache)
Seriousness (not severity) is based on patient/event outcome or

action criteria, and serves as a guide for defining regulatory
reporting obligations
Temporal relationship Temporal relationship is considered positive if the event occurred Is the timeframe between treatment and occurrence of the AE
during the use of the drug and/or within a plausible range based compatible with the drug’s half-life? (eg, an allergic reaction
on the half-life of the drug. Categories for temporal relationship usually occurs shortly after being exposed to that substance →
are this indicated a positive temporal relationship)
• positive
• suggestive On the other had, if an event occurs days after exposure to a
• compatible drug with a short half-life, there is a very weak or a negative
• weak temporal relationship
• negative
The temporal relationship is assessed based on drug kinetics,

toxicity mechanisms, involved organ, and the physiopathology of
the event
Sentinel case Cases for which there is strong evidence of a potential association During review of cases, identification of 3 sentinel cases usually
between the exposure to medicinal product and the occurrence of halts the investigation on the drug-event of interest
an AE without confounding factors

RISK TERMINOLOGY
Identified risk Definition according to GVP Annex I (Rev3): Identified risks can arise from signal evaluation and are
An untoward occurrence for which there is adequate evidence of described and classified in the PSUR/PBRER
an association with the medicinal product of interest
Identified risks have usually been observed in clinical trials or in
Explanatory wording provided in GVP module V (Rev 2): clinical practice and are described in the RSI. The causal
Undesirable clinical outcomes for which there is sufficient relationship is already documented
scientific evidence that they are caused by the medicinal product
Potential risk Definition according to GVP Annex I (Rev3): Potential risks have not necessarily been observed in clinical
An untoward occurrence for which there is some basIs for trials or in the clinical practice; however, pre-clinical or clinical
suspicion of an association with the medicinal product of interest considerations point to a possible causal association to the
but where this association has not been confirmed medicinal product
Explanatory wording provided in GVP module V (Rev 2): Potential risks can be identified from signal evaluation and are
Undesirable clinical outcomes for which there is scientific described and classified in the PSUR/PBRER
evidence to suspect the possibility of a causal relationship with
the medical product, but where there is currently insufficient
evidence to conclude that this association is causal

RISK TERMINOLOGY
Missing information Definition according to GVP Annex I (Rev3): Missing information is identified, characterized, and monitored
(Critical) gaps in knowledge about a medicinal product, related to in the RMP, and the PSUR/PBRER
safety or use in particular patient populations, which could be
clinically significant Typical examples of missing information are the use of a
medicinal product during pregnancy and breastfeeding, or in the
Explanatory wording provided in GVP module V (Rev 2): pediatric population, if there are no adequate clinical studies in
Gaps in knowledge about the safety of a medicinal product for these patients
certain anticipated utilization (eg, long-term use) or for use in
particular patient populations, for which there is insufficient The decision on whether the lack of safety information in a
knowledge to determine whether the safety profile differs form specific population is critical (ie, missing information) is based on
that characterized so far clinical consideration
Risks related to the Any risk relating to the quality, safety, or efficacy of the medicinal The risks related to the use of a medicinal product are
use of a medicinal product as regards patients’ health or public health and any risk investigated, identified, characterized, monitored, and
product of undesirable effects on the environment minimized throughout the life-cycle of a drug
Risk can be identified from signal evaluation and described and

classified in the PSUR/PBRER
New important risks trigger an RMP update

RISK TERMINOLOGY
Benefit-risk balance An evaluation of the positive therapeutic effects of the medicinal The benefit-risk balance of a medicinal product is continuously
product in relation to the risks (ie, any risk relating to the quality, monitored through PV activities and periodic safety reports (eg,
safety, or efficacy of the medicinal product as regards patients’ PSUR/PBRER, DSUR)
health or public health)
Safety concern An important identified risk, important potential risk or missing The safety concerns of a medicinal product are identified,
information characterized, and monitored in the DSUR, RMP, and
PSUR/PBRER
Signal Information arising from one or multiple source, including Signals are continuously monitored and evaluated by the
observations and experiments, which suggests a new potentially Company
causal association, or a new aspect of a known association
between an intervention and an event or set of related events, New signals which emerge, remain ongoing, or are closed during
either adverse or beneficial, that is judged to be of sufficient the reporting period are presented in the PSUR/ PBRER
likelihood to justify further investigation

CIOMS III/V THRESHOLD CRITERIA
I. ACCORDING TO THE SOURCE
Ia. Evidence from Individual Cases
Positive rechallenge
Definitive case (ie, clearly defined specific case histories)
Time to onset plausible
Positive dechallenge
Lack of confounding factors in the spontaneously reported cases
Amount and duration of exposure plausible (appropriate)
Corroboration of the accuracy y of case histories
Cases clear-cut, easily evaluated
Lack of alternative explanation
Co-medication unlikely to play a role
It is reported to occur in such as healthy children, or no other confounding risk factor is present

I. ACCORDING TO THE SOURCE
Ib. Evidence from Clinical Trials/Studies
Positive outcome in targeted studies
Statistically significant difference
Corroborative evidence from various studies
Relative increase in frequency over placebo
Evidence from trials rather than spontaneous reports
Evidence from observational post-market safety studies
Consistent trend in studies
Studies are well-designed
Although there is no other corroborative evidence, there is no contrary evidence
Positive dose response

II. SUPPORTIVE EVIDENCE FOR BOTH ABOVE-STATED SOURCES (ICSR/CLINICAL STUDIES)
Consistency of pattern of presenting symptoms
Consistency of time to onset
Identifiable subgroup at risk
High frequency of reported cases

III. PREVIOUS KNOWLEDGE OF THE AE OR THE DRUG/CLASS, INCLUDING METABOLITES
Recognized consequence of overdosage
PK evidence
Known mechanism
Recognized class effect
Similar findings in animal models
Closeness of drug characteristics to those of other drugs known to cause the ADR
Similar reactions already recognized
Biological plausibility
Event in normal clinical practice is usually drug-related
Drug know to affect same body system in some other way
Low background incidence of event
Positive specific laboratory or in vitro test

SNIP CRITERIA
• A set of criteria to aid in the triage and prioritization of potential safety
signals
Strength of association (positive rechallenge, drug class effect, biologic plausibility
of a causal association, strong reporting association, volume of cases)
Newness of the event (unlisted event, listed events with changed frequency,
severity, or specificity, impacts new population)
Clinical Importance of the event (with greatest impact on patient safety, fatal
outcome or serious medical consequence, Regulatory interest)
Potential for Preventive measures (medication errors, identification of

special/vulnerable population or clinical situation)

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CORE PV CONCEPTS

(Johnson & Johnson Consumer, Inc., McNeil Consumer Healthcare Division)

• Better grasp on the definitions of different drug safety terms

• Familiarize with concepts used in risk terminology

• Memorize the core concepts used in PV assessment and causality

© 2020 ClinChoice – Confidential and All Rights Reserved 2

The seriousness criterion “Life-threatening” in this

Conditions of use outside the MA include off-label use, overdose, misuse,

“Reaction” means that a causal relationship between the medicinal product

Importantly, if an event is listed in the label, but occurs

Although being a condition of use outside the MA, ME

EMA guidance “Good practice guide on recording,

© 2020 ClinChoice – Confidential and All Rights Reserved 5

© 2020 ClinChoice – Confidential and All Rights Reserved 7

Causal assessment is determined based on temporal

© 2020 ClinChoice – Confidential and All Rights Reserved 8

This IME list aims to facilitate the classification of suspected adverse

An organization may maintain such list, to prioritize cases of

EMA maintains a list MedDRA PTs that identifies DMEs. The

© 2020 ClinChoice – Confidential and All Rights Reserved 9

Dechallenge means that a drug that is suspected of causing the event is

A dechallenge is positive when after removal of the drug the AE subsides

A dechallenge is negative when the event persists even after removal of

A positive rechallenge (ie, the AE reappears when treatment is restarted),

© 2020 ClinChoice – Confidential and All Rights Reserved 10

Seriousness (not severity) is based on patient/event outcome or

The temporal relationship is assessed based on drug kinetics,

© 2020 ClinChoice – Confidential and All Rights Reserved 12

© 2020 ClinChoice – Confidential and All Rights Reserved 13

Risk can be identified from signal evaluation and described and

New important risks trigger an RMP update

© 2020 ClinChoice – Confidential and All Rights Reserved 14

© 2020 ClinChoice – Confidential and All Rights Reserved 15

Definitive case (ie, clearly defined specific case histories)

Time to onset plausible

Lack of confounding factors in the spontaneously reported cases

Amount and duration of exposure plausible (appropriate)

Corroboration of the accuracy y of case histories

Cases clear-cut, easily evaluated

Lack of alternative explanation

Co-medication unlikely to play a role

© 2020 ClinChoice – Confidential and All Rights Reserved 16

Positive outcome in targeted studies

Statistically significant difference

Corroborative evidence from various studies

Relative increase in frequency over placebo

Evidence from trials rather than spontaneous reports

Evidence from observational post-market safety studies

Consistent trend in studies

Studies are well-designed

Although there is no other corroborative evidence, there is no contrary evidence

Positive dose response

© 2020 ClinChoice – Confidential and All Rights Reserved 17

Consistency of time to onset

Identifiable subgroup at risk

High frequency of reported cases

© 2020 ClinChoice – Confidential and All Rights Reserved 18

Recognized class effect

Similar findings in animal models

Similar reactions already recognized

Event in normal clinical practice is usually drug-related

Drug know to affect same body system in some other way

Low background incidence of event