This document provides guidance on assessing whether adverse reactions are expected or unexpected based on the applicable reference safety information. It defines expectedness at both the event and case levels. An event is considered unexpected if it is more specific, severe, serious, or accompanied by additional signs/symptoms than described in the reference safety information. The appropriate reference safety information to refer to depends on whether the product is in the premarketing or postmarketing phase. The document also provides examples and clarification on expectedness in various situations like drug interactions, medication errors, product quality issues, pregnancies, and overdoses.

1. Labelling Assessment

2. Unexpected adverse reaction
 ICH definition: An “unexpected” adverse reaction is the
one, the nature or severity of which is not consistent with
the applicable product information (Reference safety
information (RSI)).
 Various RSI include:
1. CCDS: company core data sheet
2. USPI: United states product information
3. SPC: summary of product characteristics
4. PM: product monograph
5. IB: Investigator’s brochure

3. Unexpected adverse reaction
 FDA definition (21CFR314.80): Any adverse drug experience
that is not listed in the current labeling for the drug
product.
 This includes events that may be symptomatically and
pathophysiologically related to an event listed in the
labeling, but differ from the event because of greater
severity or specificity.

4. Expectedness assessment is done
at two levels
 Event level: each event will be assessed individually.
 Case level: overall expectedness. If one or more events is
deemed unexpected, the case will be assessed as
“unexpected”. The case level assessment will determine
regulatory reporting.

5. Which RSI to refer to?
 Postmarketing (NDA): CCDS (Core)
SPC,PM or USPI (local)
 Premarketing(IND): IB.

6. Expectedness and specificity
An event more specific than described
in the RSI would be considered
“unexpected”.
Example: If retinopathy is in the label, and now you see a case of
diabetic retinopathy, which is not in the label—the event would be
considered unexpected.

7. Expectedness and severity
An event more severe than described
in the RSI would be considered
“unexpected”.
Example: Circulatory collapse is considered unexpected when
hypotension is labelled.

8. Expectedness and seriousness
 An event more serious than described in the RSI would be
considered “unexpected”.
Example: ‘Hepatitis’ is listed in the RSI, but the reported event is
‘fulminant hepatitis’ then it becomes unexpected.

9. Expectedness & additional
signs & symptoms
 If a diagnosis is listed in the RSI as an ‘expected’ adverse
reaction, the signs and symptoms that comprise the
diagnosis are also ‘expected’.
 The signs and symptoms need not be specifically listed.
 However, if one or more reported events are not a
recognized sign or symptom of the diagnosis, these events
would be classified as unexpected’.

10. Continued……
• Example: If anaphylactic reaction is labelled, then a report of a
patient who experienced hypotension, wheezing, and urticaria
together would be considered as an expected event.

11. Expectedness and fatal
outcomes
 Unless the RSI specifies a fatal outcome, the case should be
considered as ‘unexpected’ as long as there is an
association between the AE and the fatality.
Example: Agranulocytosis is listed in the RSI. A report is
received of a patient who developed fatal agranulocytosis.
Agranulocytosis would be considered ‘unexpected’ in this
instance.

12. Expectedness and LOE
 Lack of efficacy (LOE) – Is an ‘expected’ event.
 However this may not be a case in cases where the
indication is a life threatening condition.

13. Expectedness and medication
error
 ‘Medications error’ as an event is assessed generally as
unexpected.

14. Expectedness and PQI
 Product quality issue (PQI) – is an expected event.
Example: In case there is any problem with the bottle
opening, taste or odor of the product, any formulation
problem then it is considered as a PQI.

15. Expectedness in pregnancy
cases
* ‘Pregnancy’ as an event is unassessable: hence the labels
will be NA (Not applicable).
* Any event along with pregnancy will be assessed as per the
normal labeling guidelines.

16. Expectedness and overdose
 If in an overdose case the AE is listed in the ‘adverse
events/reactions’ or ‘undesirable events/reactions’ or
‘overdose section’ then it is expected in overdose case also.
 However if the event is listed under ‘overdose’ section of RSI
and the case is not an overdose case then the event is
unexpected.

17. Expectedness and drug
interaction
* Expectedness in case of drug interactions will be considered
based on individual drug interactions and the class effect
should not be considered.
Example: Events are listed under drug interaction of
alprazolam and microlides, but the reported event has
occurred in a patient with alprazolam and azithromycin
interaction then it will be considered unexpected.

18. Expectedness and cross LLT’s
 If two different event are having the same PT then if either
of them is mentioned in the RSI the other becomes
expected.
i.e:
 If event ‘A’ and ‘B’ have the same PT say ‘C’. Then if in the
RSI event ‘A’ is listed but event ‘B’ is unlisted then 'B’ also
becomes expected.

19.  Check for different spelling:
E.g.:
1. Anaemia – anemia
2. Diarrhoea – diarrhea
3. Oedema – edema
4. Colour – color
Hence try to search with common letters.
e.g.: search with ‘emia’, ‘diarr’, ‘edema’ and ‘col’ respectively.

20. Quiz ?
 1. Example:
The prescribing information lists “hives,
hypotension, wheezing, and angioedema”
A patient is reported to have experienced
anaphylaxis.
Would you consider anaphylaxis as an
expected event?

21.  Answer:
 No
 Guideline:
 An adverse event must be expressly
mentioned for it to be considered
“expected”

22. Example:
“Pneumonia” is listed in the prescribing
information and a patient’s x-ray shows
pulmonary infiltrates
Would you consider pulmonary infiltrates
expected?

23. Answer:
No
Guideline:
 Pulmonary infiltrates should not be
considered “expected” as this could be
indicative of other diagnoses