Expectedness/Unexpectedness Assessment_Katalyst HLS

Training for Drug Safety Associates, Drug Safety Specialists, Senior Drug
Safety Specialists, Medical and Drug Safety Managers, Medical
Monitors and Drug Safety Physicians
1
Katalyst Healthcares & Life Sciences
Expectedness/Unexpectedness Assessment
│ GLOBAL REACH │ THERAPEUTIC EXPERTISE │ EXPERIENCED PROJECT TEAMS │
│ ACCELERATED STUDY START-UP LPI │ MANAGEMENT OF TECHNOLOGY INTEGRATION │
02/24/17

Objectives for
Expectedness/Unexpectedness
Training
 Understanding frequently used
terms
 Defining Expectedness &
Unexpectedness
 Defining the importance of
Expectedness & Unexpectedness
Assessment
 Using Reference Safety
Information as a resource for
Assessment
 Expectedness & Unexpectedness
Assessment
 Showing examples of
 Determining Expectedness using
the Investigator Brochure
 Determining Expectedness using
the SmPC
 General Assessment of
Expectedness vs.
Unexpectedness
 Helpful CIOMS Rules
 Good Practice Rules for
Pharmacovigilance Projects

Frequently Used Terms and Definitions
 Adverse Event (AE): Any untoward medical occurrence in a patient or clinical
investigation subject administered a pharmaceutical product and which does
not necessarily have to have a causal relationship with this treatment.
 Adverse Drug Reaction (ADR): All noxious and unintended responses to a
medicinal product related to any dose should be considered an ADR.
 Serious Adverse Event/Experience/Reaction (SAE): is any untoward medical
occurrence that at any dose results in death, is life-threatening, requires
inpatient hospitalization or prolongation of existing hospitalization, results in
persistent or significant disability/incapacity or, is a congenital anomaly/birth
defect.
 Expected ADR: is one for which its nature or severity is consistent with that
included in the appropriate RSI such as the IB or CCSI for an unapproved
product or a package insert or a SmCP for an approved product.
 Unexpected ADR: an adverse reaction, the nature or severity of which is not
consistent with the appropriate RSI such as the IB or CCSI for an unapproved
product or a package insert or a SmCP for an approved product.

 Expectedness means the AE whether serious or not is already listed in the
IB or SmPC.
 Unexpectedness: the AE whether serious or not is not listed in the IB or
SmPC.
 Labeled/Unlabeled: For a product with an approved marketing
application, any reaction which is not mentioned in the official product
information is unlabeled. If it is included, it is termed labeled. Official
product information refers to SmPCs, package inserts, or product data
sheets.
 Listedness/Unlistedness: any reaction which is not included in the
Company Core Safety Information within a company’s core data sheet
for a marketed product is unlisted. If it is included it is termed listed.
 Marketing Authorization Holder (MA): is the pharmaceutical
sponsor/client holding the investigational drug.

 Reference Safety Information (RSI): is information in the form of an Investigator Brochure or CCSI for investigational
drugs that have not been approved or pre-marketed drugs. RSI can also be a IB, SmPC, package insert and
product insert and these apply to drugs that have been approved or post-marketing drugs.
 Investigator Brochure (IB): a compilation of the clinical and nonclinical data on the investigational product(s) that
are relevant to the study of the product (s) in human subjects.
 Package Insert/Product Insert (PI): is a document provided with a prescription medication to provide addition
information about the drug.
 Summary of Product Characteristics (SmPC): is a definitive statement, agreed by a manufacturer and the
European Communities, of facts and recommendations regarding the prescription use of a medical product
approved for marketing. The SmPC is used by healthcare professionals, such as doctors, nurses and pharmacists,
and explains how to use and prescribe a medicine. (This document is the same as the package insert in the US.)
 Company Core Safety Information (CCSI): a clinical safety reference of all relevant safety information contained in
the company core data sheet prepared by the MAH and that the MAH requires to be listed in all countries where
the company markets the drug, except when local regulatory authority specifically requires a modification. It is the
reference information by which listed and unlisted are determined for the purpose of periodic reporting for
marketed products, but not by which expected and unexpected are determined for expedited reporting
 Company Core Data Sheet (CCDS): a document prepared by the manufacturer, containing all relevant safety
information, such as adverse drug reactions, which the manufacturer requires to be listed for the drug in all
countries where the drug is marketed. It is the reference document by which labeled and unlabelled are
determined for the purpose of international ADR reporting. Also referred to as CCSI.
 According to ICH E2C(R1), the CCDS covers material related to safety, indications, dosing, pharmacology,
and other information concerning the product.
 Development of Core Safety Information (DCSI): an independent section of an IB identical in structure to the CCSI
that contains a summary of all relevant safety information that is described in more detail within the main body of
the IB. It is the reference safety document that determines whether an ADR is listed or unlisted.

What is Expectedness/Unexpectedness &
What is Expectedness?
- Expectedness refers to the AE being
previously observed and documented in
Reference Safety Information (i.e. IB,
SmPC, Package Insert, CCSI).
What is not Expectedness?
- Expected does not mean that the AE
could have been anticipated, e.g., from
the known pharmacological properties
of the medicine.
- Expected does not refer to what may
occur in the course of the treated
disease such as in the case of disease
progression and/or lack of effect.
What is Unexpectedness?
- Unexpectedness refers to AE not being
observed or documented in the
Reference Safety Information.
What is Unexpectedness Assessment?
- Unexpectedness assessment is
deciphering whether the reported
adverse event is different in its nature,
severity, specificity or usual outcome
relative to the term/description used in
Reference Safety Information. This is
determining unexpectedness.
- An AE will be unexpected in the
regulatory sense unless it is mentioned
in the appropriate RSI, even if it is a
medical occurrence expected for the
disease being treated.
What is Expectedness Assessment?
- Expectedness assessment is deciding
whether the adverse event presented is
listed (expected) or not listed
(unexpected) in the appropriate
section of the Reference Safety
Information.

Why is Expectedness/Unexpectedness Assessment Important?
- It defines whether a reported AE is expected or
unexpected.
and
- It determines expedited reporting requirements.
NOTE: Expectedness/Unexpectedness assessment
must take place once a case is validated.

What resources to use for
 Reference Safety Information (RSI) documents should be used in
the determination of expectedness.
 Much safety information may be contained in various sections of
the RSI – this may create confusion or ambiguity about what should
or should not be considered ‘expected’.
 The CIOMS V working group advises that expectedness should be based
on inclusion of an AE in the AE/ADR section of the RSI.
 Even if an AE/ADR is mentioned in the clinical pharmacology,
contraindications, warnings, precautions, or other sections of the RSI, it
should also be included in the AE/ADR section, which is the
comprehensive repository of expected AEs/ADRs.

What resources to use for
Examples of RSI documents for
investigational medicinal
products:
 Investigator Brochure (IB)
 Development Core Safety
Information (DCSI) in an IB
Examples of RSI documents for marketed
medicinal products:
 Company Core Safety Information
(CCSI)
 Company Core Data Sheet (CCDS)
 Official local data sheet
 In the US, it is the Package Insert
 In the EU it is the EU SmPC or local
SmPCs
E. g. In the US the package Insert can be accessed at http://dailymed.nlm.nih.gov/dailymed/about.cfm or
at http://www.nlm.nih.gov/medlineplus/medicines.html
For recent approved medicines in the EMEA, SmPCs can be accessed at the EMEA site
http://www.emea.europa.eu/htms/human/epar/a.htm
Local UK SmPCs can be accessed at http://emc.medicines.org.uk/

How to Assess Expectedness/Unexpectedness
(2 Levels of Decision Making)
1st
Question
 Is the AE/ADR mentioned in
the appropriate section of
the reference safety
information (RSI)? Any
reaction not mentioned is
supposedly new and
therefore unexpected.
 If the actual term is not listed
in the RSI – is a synonym
listed?
2nd
Question
 Based on the medical information
contained in the case report, is the AE
different regarding its nature, severity,
specificity or usual outcome relative to
the term or description used in the RSI?
 More difficult – requires well
documented cases.
 If sufficient information is absent – the
AE should be regarded as unexpected
(i.e. SAE starts out as expected b/c
listed in RSI but follow-up sae is
unexpected b/c PI updated the term
as more severe.)

Examples of Expected Adverse Events
1. AEs are expected if their nature, severity, specificity and frequency
are consistent with the information in the relevant Reference Safety
Information (RSI).
2. Generally, further anatomical specification or synonym of a labelled
AE should be considered labelled.
3. AEs associated with specific indications, dose specifications, dose
forms or circumstances are only expected for those specific
conditions (i.e. “situational” expectedness).
4. An overdose, whether intentional or accidental, is expected if listed
in the RSI. AEs associated with an overdose are expected if
described in the overdose section or if listed as expected elsewhere
in the RSI.
• Note: When AE has been reported only in association with an overdose, than
that same AE at ordinary (usual) doses should be considered unexpected.
1. Lack of drug effect is typically treated as expected, with exceptions;
e.g. Oral Contraceptives.

Examples of Unexpected Adverse Events
AEs are generally considered unexpected if:
1. The reported AE is different in nature, or greater in specificity, severity
or frequency than AEs mentioned in the RSI.
2. The reported AE has a fatal outcome, unless the possibility of a fatal
outcome from the AE is stated in the RSI.
3. The reported AE is only cited in data from clinical trials, unless the same
AE has been included in the ADR (Undesirable Effects) section of the
RSI.
4. The reported AE has only been described in Investigator Letters that
are appended to an Investigator’s brochure (IB) and not contained in
the safety attachment on the current approved IB.
Note: Medication Error is generally treated as unexpected unless
specifically stated in the RSI

Determining Expectedness According to
the Investigative Brochure
Events are considered to be expected according to the current
approved IB if:
 Events are found in the Core Safety Information or Development
Core Safety Information (DCSI) section in the current approved IB
under possible sections entitled: Warnings, Precautions,
ADR/Undesirable Effects or Efficacy and Safety. (NOTE: Not all IBs have
these sections)
 Medical judgement must be used to determine expectedness if an
AE is in the Overdose, Discontinuation Effects, Pregnancy section
etc. Note: Medical judgement refers to the principal investigator
and/or the medical monitor.

Determining Expectedness
According to the Investigative
Brochure (cont.)
Other events may be mentioned in the body of the IB, but are NOT considered expected
according to the IB.
For example:
 Events NOT attributable to the product.
 Events mentioned which occurred with placebo or control drugs only.
 Note: Some US pharmaceuticals consider an event expected even if the event ia in the IB clearly
in the placebo group.
 Events associated with animal data only.
 Events of different nature, or greater specificity, severity or frequency than identified in
the IB.
 Events described in Investigator Letters appended to an IB.
 An AE term is considered to be unexpected/unlabelled until the new AE is added to the
appropriate section (s) of the IB. (i.e. The term expectedness can only be used with
current approved version of the IB or IB addendum).

Determining Expectedness According to the Summary
of Product Characteristics (cont.)
Expected AEs identified under any of the
following sections of the SmPC include:
 Special Warnings and Precautions for
Use
 Undesirable Effects
 Interaction
 Drug Interactions are only
considered expected if the
product is listed as an interacting
drug and the associated AE is listed
as occurring as a result of the drug
interaction.
 Medical judgement must be used to
determine expectedness if an AE is in
the Overdose, Discontinuation Effects,
Pregnancy section etc.
Unexpected Adverse Events according to
the SmPC include:
 Events associated with animal data
only.
 Events of greater specificity, severity or
frequency than specified.
 Events associated with specific
indications, dose specifications or
circumstances are only expected for
those specific conditions.
 Class labelling which does not mention
the specific product being marketed.

General Assessments (when expectedness seems
unexpected vs. when unexpectedness seems expected.
 A laboratory value that is representative of the definition of the diagnosis
(labelled in the RSI) is expected, for example, if the expected term is
thrombocytopenia then decreased platelet count is expected.
 While PI is reporting decrease platelet count but RSI says thrombocytopenia, it
is expected even though the terms are different but the meaning is the same.
 Diagnoses are not equivalent to lab values for example,: if the
expected term is raised liver enzymes (meaning if the RSI states exactly
this), then hepatitis (diagnosis) is not expected because it is not listed in
the RSI.
 Only a medic can provide a diagnosis.
 Symptoms/signs listed in the RSI are expected but diagnoses not listed in
the RSI equals unexpected.

Helpful CIOMS Rules
Helpful CIOMS Rules:
These are meant to be guidelines and the
Sponsor/Marketing Authorization Holder has their own
rules, the sponsor rules should be followed.

Helpful CIOMS Rules[1]
 Further anatomical specification of a labelled AE does NOT make it
unlabelled:
 E.g., fibrosis of upper left lobe is equivalent to lung fibrosis
 However: if arteritis is expected, temporal arteritis should be considered
unexpected due to the associated additional risks and poorer prognosis
 Extra histological specification does NOT make, per se, a labelled AE
unlabeled:
 E.g., liver biopsy shows hepatic necrosis [labelled] with the presence of
eosinophiles [not mentioned in labelling]
 However: e.g., cerebral thrombo-embolism or cerebral vasculitis would
be unexpected [by virtue of greater specifity] if the labelling only listed
cerebral vascular accidents.
 Interstitial nephritis should be considered unexpected when only acute
renal failure is expected.

Helpful CIOMS Rules [2] cont.
 If a labelled AE is not normally accompanied by an additional sign
or symptom, AE should NOT be considered labelled:
 E.g., if the labelling mentions gastrointestinal irritation, then
‘gastrointestinal irritation associated with melena’ would be
unlabelled.
 Mention of any additional symptom or sign usually associated with
an already labelled AE does NOT merit upgrading the event to
unlabelled:
 E.g., labelling mentions thrombocytopenia, then a report on
‘thrombocytopenia associated with petechia’ would be labelled;
 E.g., labelling mentions pseudomembraneous colitis, then a
report on ‘pseudomembraneous colitis with dehydration would
be labelled;

 CIOMS rule: In general, the medical view is that if a labelled AE is
often life-threatening or often results in death, a fatal outcome in a
particular case does NOT make the AE unlabeled, even if death is
NOT mentioned in the labelling as possible outcome:
 E.g., myocardial infarction is mentioned, but fatal myocardial
infarction is not.
 However, as a policy decision, company adopted the overall
conservative approach for world-wide reporting, that all fatal
outcomes are assessed as unexpected, unless explicitly
mentioned in the RSI.

 If a reported AE is significantly more severe than the labelled AE, it
should be considered unlabeled:
 E.g., circulatory collapse would be unlabelled when hypotension
is labelled
 E.g., death from hepatic necrosis would be unlabelled when
hepatic failure is labelled
 Rash does cover morbiliform rash, but not Steven Johnson
Syndrome
 Fulminant hepatitis should not be considered expected if only
‘liver injury’ is mentioned

 If an AE is not medically more important than a labelled AE, the case
need not be considered unlabelled:
 E.g., vertigo, when dizziness is labelled;
 E.g., raised liver function test when hepatitis is labelled
 Death from a condition diagnosed prior to treatment is NOT a
reportable event – in fact, it is not an event at all !
 E.g., death in pre-existing bronchogenic carcinoma
 Exception: exacerbation of the pre-existing condition following
treatment leading to death

 AE with causality disclaimer – are considered expected (including
those listed in a frequency table).
 E.g., "The following adverse events have been reported in
association with the drug, but a causal relationship has not been
established”
 However: if the AE disclaimer states that the events have been
reported but not been considered drug-related (negative
causality statement), then the AE should be assessed as
unexpected

 An unlabelled diagnosis which relates to a group of symptoms or
signs which are labelled, the new case is not in itself labelled:
 E.g., anaphylaxis is unlabelled, even if hypotension, wheezing
and urticaria are all labelled (DIAGNOSIS must be stated in the
label to make it expected)
 If a DIAGNOSIS is labelled, then the signs and symptoms which
comprise the diagnosis are also considered to be labelled.
 E.g., anaphylaxis is labelled, then hypotension, wheezing and
urticaria together would be considered to be labelled

 HOWEVER: Even though a diagnosis or syndrome is expected, if
the usually accompanying signs and symptoms are reported in
the absence of a clear diagnosis (i.e., as one or more isolated
signs and symptoms), those terms should not be considered as
expected unless already in the RSI. It is impossible to ascertain
that their appearance alone or together necessarily reflects a
mechanism similar to that of a labelled diagnosis (e.g., isolated
nausea, or asthenia, or gastralgia, when liver injury is labelled;
isolated pallor, or hypotension or pruritus when anaphylactic
reaction is labelled).
 If the label lists an AE which is specified to be transient, but it persists
in the new case, the case is unlabeled and should be reported:
 E.g., prolonged elevated liver function tests, when labelling states
transient elevated liver function tests

 If an AE/ADR has been reported only in association with an
overdose, then that same AE/ADR at usual doses should be
considered unexpected.
 If an AE/ADR occurs in a different indication, it is assessed
unlabelled unless it is described in the adverse events section
applicable for a specific indication or patient population.
 If an AE/ADR follows a different route/formulation of drug
administration, the event labelled for one presentation cannot be
considered labelled for another presentation.

 Drug exposure during pregnancy: Abortion, stillbirth, congenital
abnormalities and maternal/new-born hazards are considered
unlabelled unless explicitly specified in the RSI.
 Pregnancy/drug exposure in utero or normal babies are considered
labelled.
 Note: Pregnancy, drug exposure in utero, and delivery of a healthy
newborn are no adverse events per se!
 Drug abuse, drug dependence, maladministration: unlabelled
unless explicitly specified in the relevant sections of the RSI.
 Lack of efficacy and resulting signs or symptoms are considered
labelled events. However, if treatment directly exacerbates the
treated condition then exacerbation is considered unlabelled
unless specifically mentioned in the RSI.
 If an AE/ADR is due to a specific drug-drug interaction, it is
considered labelled but only in the context of the drug-drug
interaction.

 Death as an Outcome:
 Unless the RSI specifies a fatal outcome, then the case should be
considered as unexpected as long as there was an association between
the adverse reaction and the fatality
 A fatal outcome to a suspected ADR should not be mentioned in the RSI
unless it has been reported to occur and is thought to be causally
related to the ADR.
 In the absence of special circumstances, once the fatal outcome is itself
expected (labelled/listed), reports involving fatal outcomes should be
handled as for any other serious suspected ADR in accord with
appropriate regulatory requirements.

Good Practice Rules for PV Projects
 Identify relevant RSI documents
 Identify relevant safety sections within RSI documents
 Discuss with client the basis for expectedness/unexpectedness
assessments or any areas of ‘Special interest’ for the product.
 Develop internal project specific guidance following the general
rules as stated in this presentation
 Document project specific expectedness/unexpectedness rules
and reach consensus with client
 Include in project specific documentation

Sources:
 CIOMS V – Current Challenges in Pharmacovigilance:
Pragmatic Approaches. CIOMS Geneva, 2001.
 CIOMS VI – Management of Safety Information from
Clinical Trials. CIOMS Geneva, 2005.

Expectedness/Unexpectedness Assessment_Katalyst HLS

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