ICH - E2D Pharmacovigilance and Drug Safety - Pharmaceuticals #peivandpirouzi #training #canada #pirouzi #international #funding #immigrants #refugees #canada #immigration #education

1. Post-Approval Safety Data Management:
Definitions and Standards for Expedited
Reporting
ICH-E2D
Professor Peivand Pirouzi
2010

2. Definition and Terminology
Basic Terms
Adverse Event (AE) (or Adverse Experience)
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.
Any unfavorable and unintended sign (including an
abnormal laboratory finding), symptom, or disease
temporally associated with the use of a medicinal
product, whether or not considered related to the
medicinal product.

3. Definition and Terminology
Basic Terms
Adverse Drug Reaction (ADR)
All noxious and unintended responses to a
medicinal product.
“responses to a medicinal product” means that a
causal relationship between a medicinal product
and an adverse event is at least a reasonable
possibility.

4. Definition and Terminology
Basic Terms
Adverse Drug Reaction (ADR)
A reaction in contrast to an event is characterized
by the fact that a causal relationship between the
drug and the occurrence is suspected.
“if an event is spontaneously reported, even if the
relationship is unknown or unstated, it meets the
definition of an adverse drug reaction.

5. Definition and Terminology
Serious Adverse Event or Adverse Drug Reaction
Serious adverse event / ADR (experience)
Results in death.
Is life-threatening,
Requires inpatient hospitalization or prolongation of
existing hospitalization
Results in persistent or significant
disability/incapacity,
Is a congenital anomaly/birth defect.

6. Definition and Terminology
Basic Terms
Unexpected Adverse Drug Reaction
If AE is not consistent with the term or description
used in the product labeling (Package Insert or
summary of Product Characteristics)
If uncertain whether an ADR is expected or
unexpected, the ADR should be treated as
unexpected.
ADR with fatal outcome should be unexpected unless
the local /regional product labeling states that the
ADR might be associated with a fatal outcome.

7. Definition and Terminology
Basic Terms
Unexpected Adverse Drug Reaction
Drug Class ADRs considers expected if the event is
in the local /regional product labeling of the
specific drug.

8. Definition and Terminology
Basic Terms
Unexpected Adverse Drug Reaction
“Listed or unlisted” terms describe the
expectedness of ADRs in association with the
Development Core Safety Information (DSCI) in
an Investigator’s Brochure.

9. Definition and Terminology
Basic Terms
Unexpected Adverse Drug Reaction
Labeled or unlabeled (Expected or unexpected)
are terms should be used in connection with
official product information for marketed
medicines such as US Package insert, an EU SPC or
other country data sheets.

10. Definition and Terminology
Basic Terms
Healthcare Professional (HP)
A medically – qualified person such as physician,
dentist, pharmacist, nurse, coroner or as
otherwise specified by local regulations.
Consumer
A person who is not a healthcare professional
such as a patient, lawyer, friend, or relative of a
patient.

11. Sources of individual Case Safety Reports
Unsolicited Sources
Spontaneous Reports
Literature
Internet
Other Sources

12. Sources of individual Case Safety Reports
Unsolicited Sources
Spontaneous Reports
A communication by HP or consumer to a company,
Regulatory Authority or other organization.
Describes one or more adverse drug reactions
A patient was given one or more medicinal products
Not reported from a study or any organized data
collection scheme

13. Sources of individual Case Safety Reports
Unsolicited Sources
Spontaneous Reports
e.g.
healthcare professional letter publication in the press
Questioning of HP by company representatives
Consumer adverse reaction reports
Note: If reports received from consumers which do
not qualify for regulatory reporting, the cases
should be retained.

14. Sources of individual Case Safety Reports
Unsolicited Sources
Literature Reports
MAH regularly should review the reference
databases or literatures.
Frequency of the literature searches depends to
local requirements or at least every two weeks.

15. Sources of individual Case Safety Reports
Unsolicited Sources
Literature ADR Reports
Identifiable patient
Report source (a copy of article to sent if
requested)
Expedited reporting time clock starts as soon as
minimum criteria is available
If product source not specified, the MAH should
assume that the product is its product. (the report
should indicate that the specific brand was not identified).

16. Sources of individual Case Safety Reports
Unsolicited Sources
Literature Reports
If multiple products are in the literature, a report
should be submitted only by the applicant whose
product is suspected.
Suspected product which is identified by the
article’s author

17. Sources of individual Case Safety Reports
Unsolicited Sources
Internet report
If MAH become aware of an ADR on a website and
is not managed by MAH, the MAH should review
and determine the reportability of the ADR.

18. Sources of individual Case Safety Reports
Unsolicited Sources
Internet report
 Unsolicited cases should be handled as
spontaneous reports
Verify the reporter refer to existence of a real
person (verify the patient and reporter exist) e.g.
report from email

19. Sources of individual Case Safety Reports
Unsolicited Sources
Other Sources
A non medical sources e.g. the lay press or other
media
Should be handled as a spontaneous report
For reportability, the same criteria should be
applied as for other reports

20. Sources of individual Case Safety Reports
Solicited Sources
 Reports Derived from Organized Data
Collection Systems
Clinical Trials
Registries
Post approval named patient use programs SAP)
Other patient support and disease management
programs
Surveys of patients or healthcare providers

21. Sources of individual Case Safety Reports
Solicited Sources
Reports Derived from Organized Data
Collection Systems
Should not be considered as spontaneous reports.
Should be classified as study reports.
Should have causality assessment by HP or MAH.

22. Sources of individual Case Safety Reports
Contractual Agreements
Marketing of medicines takes place between two
or more company
May market same product in the same or
different counties/region
This can be a complex issue
Define in the agreements, the processes for exchange
of safety information, including timelines and
regulatory reporting
Process to be in place to avoid duplicate of the
reporting

23. Sources of individual Case Safety Reports
Contractual Agreements (cont.d)
Safety personnel to be involved in development of any
agreements
One company to be responsible for literature
screening
MAH is ultimately responsible for regulatory reporting
Minimize the data exchange period between
contracting partners and MAH

24. Sources of individual Case Safety Reports
Regulatory Authority Sources
Individual serious unexpected adverse drug
reaction reports (ISUADR) originating from
foreign regulatory authority to be expedited
reporting to other authorities by MAH
Do not report SADR without new information
to the originating regulatory authority unless
specified by local regulations

25. Standards for Expedited Reporting
What Should be Reported
Serious and unexpected ADRs (15 days)
Serious, Expected ADRs (varies among
countries) (PSUR)

26. Standards for Expedited Reporting
What Should Not be Reported
Non-Serious and Unexpected ADRs
Non-Serious and Expected ADRs
Note: These to be reported in the PSUR
Note: FDA requires everything

27. Standards for Expedited Reporting
What Should Not be Reported
Other observations
Any observation that could change the risk benefit
evaluation of the product to be communicated to
RA in accordance with local regulation as soon as
possible
E.g. lack of efficacy with a drug used in a serious
disease.

28. Standards for Expedited Reporting
What Should Not be Reported
Lack of Efficacy
Evidence of lack of efficacy should be discussed in
the PSUR
Medicinal Products used for the treatment of life-
threatening/serious diseases, vaccines and
contraceptives, the lack of efficacy report should
be considered for expedited reporting.

29. Standards for Expedited Reporting
What Should Not be Reported
Overdose
Collect any information on overdose
Reports with no associated adverse outcome not
to be reported as Adverse Reactions.
SADR are consider subject to expedited reporting,
unless specified by local regulation.
Follow up to ensure the information is as
complete as possible with regard to symptoms,
treatment and outcome.

30. Standards for Expedited Reporting
Minimum Criteria for Reporting
Minimum Criteria for Reporting
An identifiable reporter
An identifiable patient
An adverse reaction
Suspect product

31. Standards for Expedited Reporting
Reporting Time Frames
All Serious, Unexpected ADRs
No later than 15 calendar days.
The date report fulfills minimum criteria
considered day 0

32. Standards for Expedited Reporting
Reporting Time Frames
All Serious ADRs
Time frames varies among countries depending on
source, expectedness and outcome.

33. Standards for Expedited Reporting
Good Case Management Practices
Reports to be
Authentic
Accurate
Complete as possible
Non duplicative

34. Standards for Expedited Reporting
Assessing Patient and Reporter Identifiability
Identifiability
Verify the existence of a patient and a reporter
Apply local data privacy laws
Prevent duplication of the report
 Identifiable Patient
Age or age category (adolescent, adult, elderly)
Gender
Initials
Date of Birth
Name
Patient identification number

35. Standards for Expedited Reporting
Assessing Patient and Reporter Identifiability
Identifiable Reporter
All parties providing the information should be
identifiable

36. Standards for Expedited Reporting
The Role of Narratives
 Objective of Narratives
Summarize all relevant clinical information
Patient characteristics
Therapy details
Medical history
Clinical course of the events
Diagnosis
Outcome
Laboratory evidence
Any other information supports or refutes an ADR

37. Standards for Expedited Reporting
The Role of Narratives
Objective of Narratives
Avoid abbreviations and acronyms (except of
laboratory parameters and units)
Summarize the autopsy or post-mortem finding
Reflect the Terms e.g. adverse event, ADRs,
indication and medical conditions in appropriate
data field

38. Standards for Expedited Reporting
Clinical Case Evaluation
 Medical Review
Ensure correct interpretations of medical information
Review for the quality and completeness
Is a diagnosis possible?
Have the relevant diagnostic procedures been
performed?
Were alternative causes of the reactions (s)
considered?
What additional information is needed?
Use the verbatim term is used by the reporter

39. Standards for Expedited Reporting
Follow-up information
Prioritization of case reports
1.Serious and unexpected
2.Serious and expected
3.Non-serious and unexpected
4.Cases might lead to labeling change

40. Standards for Expedited Reporting
Follow-up information
Obtain the follow up information via
1.Telephone call
2.Site visit
3.Written request (make specific questions by
questioners or specific form)
Note: if information refused by the reporter, a
regulatory authority might be able to help in
obtaining follow up data

41. Standards for Expedited Reporting
How to Report
 CIOMS-I
 It’s important that certain basic data elements be included with any
expedited report, whether in a tabular or narrative presentation.
 MedDRA to be used for coding medical information
 Links:
 Canada Guide book:
 http://www.hc-sc.gc.ca/dhp-mps/medeff/report-declaration/ar-
ei_form-eng.php
 CIOMS Form:
 http://www.hc-sc.gc.ca/dhp-mps/medeff/report-declaration/ar-
ei_form-eng.php