Standard Operating Procedure

SOP 340729

Atlas Number / Version: 340729-01

SmartSolve Number / Edition: PDL-14800 Edition 1.00

Title: Safety Case Management

Supersedes Atlas Number /

Replaces: SOP308949, SOP220464-12
Version:

Supersedes SmartSolve
Replaces: PDL-14474, PDL-14475, PDL-14477
Number / Version:

Atlas Document Owner: Sylvie Tomczyk

SmartSolve Document Owner: Diane Kwok

Revisions to this document must be made in association with both the SmartSolve
and Atlas owners and align with the current edition/version in the respective system.

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Standard Operating Procedure
SOP 340729

Table of Contents
1 Purpose and Scope....................................................................................................... 3
2 Responsibilities ............................................................................................................. 4
2.1 Global Case Management ...................................................................................... 4
2.1.1 Global PV Book-In Team ................................................................................. 4
2.1.2 Global PV Triage and Skilled Data Entry Team ............................................... 4
2.1.3 Global PV Case Manager ................................................................................ 4
2.1.4 Global PVQC Reviewer ................................................................................... 4
2.1.5 Global PV Medical Reviewer............................................................................ 5
2.2 Seqirus PV ............................................................................................................. 5
2.3 Local Safety Contacts ............................................................................................ 5
2.4 Seqirus Quality Oversight within PVRM ................................................................. 5
2.5 Seqirus Interfacing Departments ............................................................................ 5
3 Execution ...................................................................................................................... 6
3.1 Perform Case Receipt / Intake / Book-in of Cases ................................................. 7
3.2 Evaluate Clinical SAE for SUSAR status and Perform Inline Unblinding ................ 9
3.3 Triage and Skilled Data Entry ............................................................................... 10
3.4 Perform Quality Control of Cases ......................................................................... 10
3.5 Conduct Medical Review & Assessment of Cases ............................................... 11
3.6 Submit/Distribute the ICSR ................................................................................... 12
3.7 Perform Follow-Up................................................................................................ 13
3.8 General Guidance ................................................................................................ 13
3.8.1 Timelines........................................................................................................ 13
3.8.2 Clinical Trial Adverse Event Cases ................................................................ 14
3.8.3 Processing of SAEs ....................................................................................... 16
4 Abbreviations and Definitions ...................................................................................... 16
4.1 Abbreviations ........................................................................................................ 16
4.2 Definitions ............................................................................................................. 18
5 References .................................................................................................................. 21
5.1 Standards, Regulations, and Guidelines .............................................................. 21
5.2 Reference Documents .......................................................................................... 22
6 Attachments ................................................................................................................ 23
7 Change History ........................................................................................................... 23

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Standard Operating Procedure
SOP 340729

1 Purpose and Scope

The purpose of this Standard Operating Procedure (SOP) is to provide an overview of

the Individual Case Safety Report (ICSR) handling process. This procedure describes
the activities required in order to ensure that safety case reports received by Seqirus
from any source (such as spontaneous from either Patients/Consumers or Health Care
Professionals), Clinical Trial interventional studies, non-interventional studies,
Investigator-led studies, literature, and Organized Data Collection Systems (ODCs)
anywhere in the world are handled, exchanged, and reported to relevant parties in
accordance with applicable regulatory requirements and Seqirus quality standards.

Relevant parties include but are not limited to: Health Authorities (HAs), Institutional
Review Boards/Ethics Committees (IRB/EC), license partners, and others as
appropriate to meet global and local regulatory and contractual obligations.

This procedure applies to all Seqirus personnel responsible for or involved in the receipt,
triage, data entry, quality control review, medical assessment, reporting, follow up,
closure and archival of reports of adverse events (AEs) and serious adverse events
(SAEs), including pregnancy, medication error and other relevant safety information (see
Definitions Section 4.2) related to Seqirus sponsored and supported clinical trials in all
phases (I-IV) of development (including those conducted by a Contract Research
Organization (CRO) or by a third party), non-interventional studies, named patient and
compassionate use, and unsolicited/spontaneous post marketing reporting (published
and unpublished) from Seqirus approved products, including where license partners are
the source.

This scope includes the handling and management of all safety AEs/SAEs (solicited,
spontaneous, and clinical) received by Seqirus that enter the case processing workflow
through the Local Safety Contacts (LSCs) (local CROs, distributors and local
Pharmacovigilance (PV) functions) as well as those received globally at Seqirus central
processing sites.

Although PV operations will be performed by a global third party CRO (referred to as

Global Case Management), Seqirus PV will maintain full oversight on the end-to-end
processes to ensure quality and compliance with internal case processing and reporting
timelines to HAs, national RAs and license partners, outlined in applicable agreements.

Processes such as aggregate reporting, literature screening, risk management, signal

detection and tracking are beyond the scope of this SOP. This SOP also does not cover
handling of adverse events involving Seqirus in-licensed products.

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Standard Operating Procedure
SOP 340729

2 Responsibilities

The following summarizes roles and responsibilities of the parties involved within this
process:

2.1 Global Case Management (Global third party CRO)

2.1.1 Global PV Book-In Team

The role of the CRO Global PV Book-in Team includes end-to-end processing of all
global cases received from any source. This encompasses checking of case validity,
performing duplicate check in database, attaching scan of source documents, archiving
source documents, and contacting local parties for local case narratives (if necessary).

2.1.2 Global PV Triage and Skilled Data Entry Team

The role of the experienced Global PV Triage and Skilled Data Entry Team includes
triage, coding, full data entry of case information and case narrative, initial assessment
on seriousness, listedness (whether event is expected/unexpected based on whether
event is included/not included in the current labeling for the product), causality (causal
relationship between the drug and adverse event) and identification of Adverse Events
of Special Interest (AESI).

2.1.3 Global PV Case Manager

The role of the Global PV Manager includes case unblinding (clinical and post-
marketing), distribution of case safety reports, and determination of case follow-up that
is needed.

2.1.4 Global PVQC Reviewer

The role of the Global PVQC Reviewer includes the performance of in-line risk-based
quality control, identification of case corrections and tracking the outcome of QC on a
tracking tool outside of the system. The third party PVQC reviewer will also provide to
Seqirus Quality Oversight a sample of random safety cases for offline QC.

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Standard Operating Procedure
SOP 340729

2.1.5 Global PV Medical Reviewer

The role of the Global PV Medical Reviewer includes online medical assessment of
serious cases cases including confirming the seriousness, causality and listedness
assessment, review of medDRA coding and case narrative and finalization of the
company comment. The medical reviewer should also review any case follow up queries
required for serious cases. The medical reviewer check if any QA investigations are
required.

2.2 Seqirus PV

The role of Seqirus PV is to maintain full oversight of the CRO end-to-end process for
handling and processing of solicited and unsolicited safety AEs/SAEs from all sources to
ensure quality and compliance with internal case processing and reporting timelines to
HAs, and license partners.

2.3 Local Safety Contacts (local CRO’s, distributors, Seqirus local teams)

The role of the Local Safety Contacts is to be the contact point for adverse event
reporting in their respective territories and serve as conduit of AE/SAE information from
external sources into the central Global PV organization and processing sites. All
AE/SAE reports received will be sent via email to the central Global AE mailbox for
processing (AE.reporting@Seqirus.com ).

2.4 Seqirus Quality Oversight within PVRM (Pharmacovigilance & Risk Management)

Seqirus Quality Oversight will conduct offline QC of source against case data for key
fields on a 10% sample of cases on a weekly basis.

2.5 Seqirus Interfacing Departments

The Clinical Development Department is responsible to ensure SUSARs (Suspected

Unexpected Serious Adverse Reaction ) are submitted to Clinical Investigators and
EC’s, IRBs, as required.

The Regulatory Affairs Department or LSC are responsible to create submission

packages as per local/national requirements where necessary (e.g. SUSARs for the
United States FDA as well as other national Health Authorities).

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Standard Operating Procedure
SOP 340729

QA Investigation is performed according to SOP340754 (PDL-14786): Processes and

Responsibilities Relating to QA Investigations and the PV department checks if QA
investigation is required. Cases requiring QA batch investigation criteria based on
medical review will be requested by PV to the applicable Site Quality Unit for
investigation.

3 Execution

For the purposes of regulatory reporting, Day 0 starts on receipt of the four elements of
a valid report (i.e., an identifiable patient, an identifiable medicinal and/or pharmaceutical
product, an identifiable reporter, and an adverse event) by any Seqirus employee or
designee or licensed partner. Every effort should be made to obtain the necessary
information within the required timeframe.

All Seqirus staff members are to report all safety relevant information to the
AE.reporting@Seqirus.com Global AE/SAE intake mailbox for Seqirus within 24 hours of
becoming aware of the information.

All information related to Product Technical Complaints (PTCs) should be sent to PTC
manager or delegate.

The following safety relevant information must be collected regardless of whether it is

associated with an adverse event or not:
• Medication error (this refers to an unintentional error in the prescribing, dispensing,
or administration of a medicinal product by either a healthcare professional or a
patient/consumer, e.g. use of expired product, incorrect route of administration,
incomplete dose applied)
• Misuse/Abuse
• Overdose (i.e. administration of a higher dose of drug/vaccine than described in the
package insert)
• Drug dependency
• Drug interactions
• PTCs including product quality defect or counterfeit/falsified product, with a related
suspected adverse reaction(s)
• Unexpected therapeutic effect
• Transmission/suspected transmission of an infectious agent

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Standard Operating Procedure
SOP 340729

• Off-label use (e.g. use in an unlicensed/unapproved indication or in the wrong age

group, vaccine administered to a child which is not approved/licensed for children)
• Possible Lack of Efficacy (LOE)/suspected drug/vaccination failure (e.g. the
occurrence of an infection in someone who received the vaccine to be protected
against that infection)
• Drug exposure via mother/father (exposure during conception, pregnancy,
childbirth, breastfeeding)
• Vaccine administered to a pregnant or breast-feeding woman (drug exposure during
lactation).
• Any kind of interaction following the administration of a medicinal product (e.g.
drug/vaccine or food/vaccine interaction)
• Medicinal product administered despite the presence of contraindications (e.g.
known allergens to any component of the vaccine)
• Occupational exposure
The execution process is categorized by 5 steps including case receipt/intake/book-in,
triage and skilled data entry, quality check/control, medical review, and submission and
distribution.

3.1 Perform Case Receipt / Intake / Book-in of Cases

Step # Role Activity

Local Safety Contacts /
3.1.1
Global PV Book-In Team
Global PV Book-In Team
3.1.2
Local Safety Contacts/
Global PV Book-In Team
3.1.3
Receive case information from solicited and
unsolicited sources
If E2B case from HAs, review and accept case and
perform duplicate check.
For all other cases/non E2B cases:
• Send acknowledgement back to reporter
• Ensure minimal case information is available
• If minimal case information is missing, request
this from the reporter
• Translate into English, if required

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Standard Operating Procedure
SOP 340729

Global PV Book-In Team If case is a CT SAE, notify Seqirus BRMP (Benefit

3.1.4 Risk Management Physician) with source
documents via email for them to evaluate and
confirm if SUSAR:
• If not a SUSAR, process case as a SAR (Serious
Adverse Reaction).
• If case is a SUSAR, proceed with unblinding as
per SOP 340730 (PDL-14801): Unblinding of
Suspected Unexpected Serious Adverse
Reactions (SUSARs) and process as a SUSAR
Global PV Book-In Team Perform duplicate check, book-in the case
3.1.5 (according to the Seqirus Database User Manual)
• If initial case, book-in with available minimal case
information
• If follow-up, enter follow up information into the
initial case
• If invalid case (minimal information is not
available), book-in as ainvalid case.

Note: Book-in refers to the creation of the case in the

safety database as an initial case or as follow-up
information to an existing case.
Global PV Book-In Team Scan source documents and attach in safety
3.1.6 database.

Document any additional follow-up needs in the

safety database.

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Standard Operating Procedure
SOP 340729

3.2 Evaluate Clinical SAE for SUSAR status and Perform Inline Unblinding

Step # Role Activity

Seqirus BRMP Review/Evaluate and Confirm if the case is a SUSAR
3.2.1
If the case is a SUSAR,
• Follow SOP 340730 (PDL-14801) - Unblinding
of Suspected Unexpected Serious Adverse
Reactions (SUSARs)
• If an Analysis of Similar Events (ASIME) is
required for reporting to the FDA, follow
SOP340731 (PDL-14783) - Guideline for the
Analysis of Similar Events

Note: If the report is a SUSAR and also Fatal/Life-

threatening (F/LT), notification must be sent to
Regulatory Affairs due to a shorter timeframe of
submission

If the case is not a SUSAR, notify Case management

that unblinding is not required and continue to have
them process the case as a Serious Adverse
Reaction (SAR)

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Standard Operating Procedure
SOP 340729

3.3 Triage and Skilled Data Entry

Step # Role Activity

Global PV Triage and • For all booked-in cases, process the case in the
3.3.1 Skilled Data Entry safety database in accordance with the SOP 340737
(PDL-14792) - Case processing standards for
Seqirus.
• Perform MedDRA Coding, WHO Coding, Company
drug coding
• Enter preliminary assessments for seriousness,
listedness, and causality
• Create Case Narrative
• Evaluate if follow up is needed
Global PV Triage and • If case is serious, add any follow-up queries to the
3.3.2 Skilled Data Entry collection
• If case is non-serious, send out follow-up request and
track the follow-up in the safety database

3.4 Perform Quality Control of Cases

Step # Role Activity

Global PV QC Perform Inline Quality Control of ICSRs.
3.4.1 Reviewer • Inline sampling and variable sample are summarized
in attached table (Attachment 1)
Global PV QC Compare details of the ICSR source documentation
3.4.2 Reviewer against the case details entered in database ensuring
that the correct information has been transcribed.
Check the case assessments and correct if required.
Global PV QC Correct any errors within the case in database
3.4.3 Reviewer Document the QC result in QC tracking tool

Offline QC Activities include:

• Global PV Quality Reviewers - provide Seqirus Quality Oversight a 10% sample of
cases on a weekly basis.
• Seqirus Quality Oversight – review the aggregate line listings on a weekly basis to
ensure the case information has been captured correctly when processing ICSRs.

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Standard Operating Procedure
SOP 340729

3.5 Conduct Medical Review & Assessment of Cases

Step # Role Activity

Global PV Medical For serious cases, complete the medical review as per
3.5.1 Reviewer SOP 340763 (PDL-14805): Medical Evaluation Guideline.
Global PV Medical Determine if additional information needed, and add to
3.5.2 Reviewer follow up request as necessary.
Global PV Medical Review if QA Investigation is required:
3.5.3 Reviewer Refer to SOP340754 (PDL-14786): Processes and
Responsibilities Relating to QA Investigations.
Global PV Medical If a key event has been identified during case medical
3.5.4 Reviewer review, refer to SOP340734 (PDL-14804): Key Events
Procedure

Offline Activities include:

• Global PV Medical Reviewer – on a weekly basis generate a line listing for all
received cases for offline medical review. Conduct off-line medical review utilizing
listings.

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Standard Operating Procedure
SOP 340729

3.6 Submit/Distribute the ICSR

Step # Role Activity

Seqirus PV Auto schedule reports for generation based on reporting rules
3.6.1 Safety • Generate E2B
database • Generate CIOMS
• Generate CT CIOMS
• Generate VAERS

Transmit reports that are setup for auto transmission via email
or electronic gateway to HAs/LSCs/Distributors/LPs based on
reporting rules as appropriate
Global PV Monitor status of auto transmitted reports and address any
3.6.2 Case Manager issues as necessary.
Local Safety For reports submitted by Local Safety Contacts, upon receipt of
3.6.3 Contacts (i.e. the ICSR:
local CROs, • Create submission package per local specific requirements,
distributors or if necessary
Seqirus local • Create submission package per local requirements as
teams) necessary
• Submit ICSR report to HAs as per applicable local
regulations
• Provide submission date/non-submission reason, late
reason if necessary, RCA, and CAPA to Seqirus monthly
Global PV For expedited ICSR reports for cases from interventional CTs,
3.6.4 Case Manager distribute to the following based on reporting destination
• Regulatory Affairs
• Clinical Department

Seqirus For expedited ICSR reports for cases from interventional CTs:
3.6.5 Regulatory • Prepare/create submission package per local requirements
Affairs as necessary
• Submit to local HAs
Seqirus Clinical For expedited ICSR reports for cases from interventional CTs:
3.6.6 Department • Prepare/create submission package per local requirements
as necessary
• Ensure submission to Investigators, Ethics Committees, and
IRBs, as appropriate

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Standard Operating Procedure
SOP 340729

3.7 Perform Follow-Up

Step # Role Activity

Global PV – Triage Determine and draft follow up queries in step
3.7.1 and Skilled Data 3.3.
Entry All information regarding ICSR is important
however particular effort should be made to
obtain the following information from reporters:
• Minimum ICSR criteria
• Trade name and Batch number of
suspect drug
• Medical confirmation for consumer report
• Event outcome

Global Medical In step 3.5, confirm follow up queries and add

3.7.2 Reviewer any medical queries as required
Global PV Case Post case processing cycle, send follow up
3.7.3 Manager queries to reporter/LSC as required. Send any
applicable questionnaires if required.
Track the follow up attempts in the Safety
database
Global PV Case Perform daily review of follow-up open action
3.7.4 Manager items:

3.8 For details on follow-up attempts based on case type, see Attachment 3 General
Guidance

3.8.1 Timelines

The start date for expedited reporting is the clock start date (see Definitions Section 4.2)
which is Day zero (0) of the process.

The overall timelines for global ICSR processing and reporting follow the internationally
agreed standards in calendar days:
• Suspected unexpected serious adverse reactions that are fatal or life threatening by
calendar day 7
• Suspected unexpected serious adverse reactions by calendar day 15
• Non-serious ICSRs (that require expedited reporting) by calendar day 90
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Standard Operating Procedure
SOP 340729

Based on the clock start date and depending on the ICSR characteristics, the ICSRs are
processed according to defined timelines (Attachment 2). Initial as well as follow up
reports are handled with the same timelines described in this SOP.

ICSRs should generally be processed as soon as possible, but no later than within the
timelines stated in Attachment 2. Timelines for the sub-processes are a general
guidance only in order to keep overall compliance.

Notes:
• Timelines for local submission may vary according to local regulatory requirements
• The timelines for processing of license partner ICSRs or ICSRs which have to be
sent to license partners may vary due to the arrangements documented in the
individual PV Agreement.
• The timelines for processing invalid ICSRs should be the same as for non-serious
ICSRs

3.8.2 Clinical Trial Adverse Event Cases

Serious Adverse Events (SAEs)

All SAE occurring at any time after a subject has signed the informed consent until the
end of the follow-up period must be handled via the process outlined in this SOP. All
diagnoses, symptom(s), sign(s) or finding(s) that have a start date after signing the
informed consent must be recorded in the clinical database as AEs/SAEs. This also
includes:
• All events with a start date during a wash out or run in period.
• A condition that was present before signing the informed consent and worsens after
signing the informed consent must also be recorded as an AE/SAE.
SAEs with an onset date after the end of the follow-up period of an interventional study
are not actively gathered. However, if such SAEs are reported to Seqirus or affiliate,
they must be forwarded to Global PV and entered into the database.

Non-Serious Adverse Events

• For an event that is reported as non-serious but is potentially considered medically
significant by the company based on characteristics of the event, the investigator’s
opinion will be considered for seriousness assessment.

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Standard Operating Procedure
SOP 340729

• For such cases the Medical Reviewer will consult the product responsible Seqirus
Benefit Risk Management Physician (BMRP) and Clinical Development Physician to
jointly decide if the case should be upgraded to serious. If there is disagreement,
the Head of PVRM and Clinical Development Therapeutic Head will be consulted
for a decision.
• If there is further disagreement, the final adjudication will be made by the Head of
Pharmacovigilance & Risk Management (PVRM). If the company decides to
upgrade the case, the investigator should be queried for possible upgrading of
event to serious, or to confirm the event as non-serious. Should the company
concur with the investigator that the event is non-serious, the investigator does not
need to be queried. All non-serious AEs reported by the Investigator must be
entered into the Clinical database (non-serious clinical cases are not entered into
the PV database).

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Standard Operating Procedure
SOP 340729

3.8.3 Processing of SAEs includes:

• All SAEs (initials and follow-ups) that occur during clinical trials must be reported to
PV within 24 hours of the Investigator becoming aware that an event meeting
reporting requirements has occurred, regardless of causality.
• All SAEs are to be assessed regardless of whether they occurred after the
administration of a drug/trial vaccine, comparatorproduct, placebo, or if no treatment
was administered.
• All SAEs reported after study completion are recorded in the PV Safety Database
according to the clinical protocol and reported per pertinent Regulatory
requirements (expedited or periodic).
• The Investigator must provide an assessment of causality for every SAE. In the
event that an Investigator assessment of causality is not provided, or an additional
diagnosis is extracted from other information provided by the Investigator, PV will
apply a conservative approach and consider the event/case as related for reporting
purposes. If the medical assessment of the Investigator and the Company differ,
more information will be requested form the Investigator. If no consensus can be
reached, the Company will apply a conservative approach and will consider the
event/case as related for reporting purposes. However, the causality assessment
from both the Company and the Investigator will be provided with the report

4 Abbreviations and Definitions

4.1 Abbreviations

Acronym Description
ADR Adverse Drug Reaction
AE Adverse Event (synonym: adverse experience)
AESI Adverse Event of Special Interest
ASIME/AOSE Analysis/Assessment of Similar Events
BRMP Benefit Risk-Management Physician
CIOMS Council for International Organizations of Medical Sciences
CRO Contract Research Organization
CT Clinical Trial
E2B Electronic Transmission of Individual Case Safety Report
EC Ethic Committee
EDD Estimated Due Date of Delivery
EMA European Medicines Agency
EU-QPPV European Qualified Person Responsible for Pharmacovigilance

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Standard Operating Procedure
SOP 340729

Acronym Description
FDA Food and Drug Administration
FLT Fatal Life Threatening
HA Health Authority
IB Investigator Brochure
ICSR Individual Case Safety Report
IMP Investigational Medicinal Product
IND Investigational New Drug
INL Investigator Notification Letter
IRB Institutional Review Board
LOE Lack of Efficacy
LP License Partner
LSC Local Safety Contact (local CRO, Distributors, Seqirus local team)
MRD Manufacturer’s Receipt Date
ODC Organized Data Collection Systems
PSUR Periodic Safety Update Report
PTC Product Technical Complaint
PV Pharmacovigilance
PVRM Pharmacovigilance and Risk Management Department
QA Quality Assurance
RCA Root cause analysis
SAE Serious Adverse Event
SAR Serious Adverse Reaction
SOP Standard Operating Procedure
SUSAR Suspected Unexpected Serious Adverse Reaction
VAERS Vaccine Adverse Event Reporting System

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Standard Operating Procedure
SOP 340729

4.2 Definitions

Term Definition
Adverse Event Any untoward medical occurrence in a patient or clinical trial
(AE) subject administered a medicinal product and which does not
Synonym: necessarily have to have a causal relationship with this treatment.
Adverse An adverse event can therefore be any unfavorable and
experience unintended sign (e.g. 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.
For the purpose of this SOP the term adverse event is used as
synonym for adverse experience and adverse reaction.
Adverse A response to a medicinal product which is noxious and
Reaction unintended. Response in this context means that a causal
Synonyms: relationship between a medicinal product and an adverse event is
Adverse Drug at least a reasonable possibility. Adverse reactions may arise
Reaction from use of the product within or outside the terms of the terms of
(ADR), the marketing authorization or from occupational exposure.
suspected Conditions of use outside the marketing authorization include
adverse (drug) overdose, misuse, abuse and medication errors.
reaction
ASIME Analysis of Similar Events is required for SUSARs in trials
conducted under an IND for the US FDA
CIOMS I Form Form developed by CIOMS to provide a standardized format for
the exchange/reporting of suspected adverse reactions to any
medical product
Clinical Trial Any investigation in human subjects intended to discover or verify
(CT) the clinical, pharmacological and/or other pharmacodynamics
effects of one or more investigational medicinal product(s), and/or
to identify any adverse reactions to one or more investigational
medicinal product(s) and/or to study absorption, distribution,
metabolism and excretion of one or more investigational
medicinal product(s) with the objective of ascertaining its (their)
safety and/or efficacy.

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Standard Operating Procedure
SOP 340729

Term Definition
Clock Start This date defines the start date for expedited reporting (day 0 of
Date the process). It is the calendar date that a Seqirus employee,
license partner or agent receives the minimum information to
validate a case or receives follow up information.

The clock start date for ICSRs received from license partners is
the date when the License partner was informed about the ICSR.
E2B E2B is the international standard for transmitting medicine
adverse event reports specified by the International Conference
on Harmonisation (ICH) of Technical Requirements for
Registration of Pharmaceuticals for Human Use.
Individual Case Individual Case Safety Report (ICSR), format and content for the
Safety Report reporting of one or several suspected adverse reactions to a
(ICSR) medicinal product that occur in a single patient at a specific point
of time. A valid individual case safety report for expedited
reporting shall include at least an identifiable reporter, an
identifiable patient, at least one suspect adverse reaction and a
suspect medicinal product.
Investigator A notification to Investigators participating in the project of any
Notification Serious Adverse Event (experience) which is “unexpected” and
Letter (INL) “suspected” (SUSAR – suspected Unexpected Serious Adverse
Reaction) or any findings that suggest a significant risk to the
patient. All participating Investigators must be notified either on
an expedited basis and/or by six monthly periodic listing as per
national regulations and local procedures.
Minimum For the purpose of reporting cases of suspected adverse
criteria for reactions, the minimum data elements for a case are: an
reporting identifiable reporter, an identifiable patient, an adverse reaction
and a suspect medicinal product.
Off-label use Situations where a medicinal product is intentionally used for a
medical purpose not in accordance with the authorized product
information. Off-label use includes use in non-authorized
pediatric age categories. Unless specifically requested, it does not
include outside the EU in an indication authorized in that territory
which is not authorized in the EU.

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Standard Operating Procedure
SOP 340729

Term Definition
Product A report of a visual, organoleptic, qualitative, quantitative, or
Technical functional defect.
Complaint
(PTC)
Serious An event which results in death, is life-threatening, requires in-
Adverse patient hospitalization or prolongation of existing hospitalization,
Reaction results in persistent or significant disability or incapacity, is a
(SAR)/Serious congenital anomaly/birth defect, is medically significant. Any
Adverse Event suspected transmission of infectious agent via the medicinal
(SAE) product is always serious. Lack of efficacy is serious for vaccines
and products in acutely life-threatening conditions.
Solicited Organized data collection systems, which include clinical trials,
sources of registries, post-authorization named patents use programs, other
ICSR patient support and disease management programs, surveys of
patients or healthcare providers or information gathering on
efficacy or patient compliance. For the purpose of safety
reporting, solicited reports should not be considered spontaneous
but classified as individual case safety reports from studies and
therefore should have an appropriate causality assessment by a
healthcare professional or the marketing authorization holder.
Unsolicited/Spo An unsolicited communication by a healthcare professional or
ntaneous consumer to a company, regulatory authority or other organization
Report (i.e. the World Health Organization, a regional center, a poison
Synonym: control center) that describes one or more adverse reactions in a
Spontaneous patient who was given one or more medicinal products and that
Notification does not derive from a study or any organized data collection
scheme.

Stimulated reporting can occur in certain situations, such as direct

healthcare professional communication (DHCP), a publication in
the press or questioning of healthcare professionals by company
representatives, and adverse reaction reports arising from these
situations are considered spontaneous reports, provided the
report meets the definition above. Reporting can also be
stimulated by invitation from patients’ or consumers’ organizations
to their members. Reporting made in the context of early post-
marketing phase vigilance (EPPV), e.g. in Japan, is also
considered stimulated reporting.

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Standard Operating Procedure
SOP 340729

Term Definition
7-Day Report SUSARs with a seriousness criterion of “Death” and an outcome
“Fatal/Death’ or events which are considered immediately life-
threatening that MUST BE REPORTED to HAs, Investigators, and
ECs/IRBs within 7 calendar days of receipt by the sponsor.
Follow-up reports of initial 7-Day reports must be reviewed under
the same 7-Day timeline.
15-Day Report All other SUSARs and safety issues must be reported to HAs,
Investigators, and ECs/IRBs within 15 calendar days after date of
initial receipt by the sponsor. Follow-up reports of initial 15-Day
reports must be reviewed under the 15-Day timeline.

5 References

5.1 Standards, Regulations, and Guidelines

ICH E2A: Guideline on Clinical Safety Data Management: Definitions and Standards for
Expedited Reporting.

ICH E2D Post-Approval Safety Data management: Definitions and Standards for Safety
Data Reporting.

ICH E6: Guidelines for Good Clinical Practice (Sections 4.11, 5.1, 5.3, 5.5, 5.16, 5.17)

Regulation (EU) 1235/2010, amendment of pharmacovigilance Council Regulation (EC)

726/2004 of the European Parliament and of the Council of 31 March 2004 laying down
Community procedures for the authorization and supervision of medicinal products for
human and veterinary use and establishing a European Medicines Agency (EMA).

Directive 2010/84/EU, amendment of Pharmacovigilance Commission Directive

2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the
Community code relating to medicinal products for human use.

EMA Guideline on GVP), Module VI – Management and reporting of adverse reactions

to medicinal products.

Clinical trials - Regulation EU No 536/2014. http://ec.europa.eu/health/human-

use/clinical-trials/regulation_en

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Standard Operating Procedure
SOP 340729

Code of Federal Regulations (CFR), Title 21, Volume 5, Revised as of April 1, 2016,
21CFR312.32, IND Safety Reports.

http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=312.32

Code of Federal Regulations (CFR), Title 21, Volume 5, Revised as of April 1, 2016,
21CFR 314.80, Applications For FDA Approval To Market A New Drug,

https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?fr=314.80

Code of Federal Regulations (CFR), Title 21, Volume 7, Revised as of April 1, 2016,
21CFR 600.80, Postmarketing Reporting of Adverse Experiences.

http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?fr=600.80

5.2 Reference Documents

• Seqirus Business Process Design Overview, Client 3700, Version: 01.00

• Seqirus Quality Policy – Product Surveillance and Controls Version 1.0 (SQPC-
00009)
• SOP340752 (PDL-14811): Signal Management Process
• SOP340754 (PDL-14786): Processes and Responsibilities Relating to QA
Investigations
• SOP340731 (PDL-14783): Guideline for the Analysis of Similar Events (ASIME)
• SOP340734 (PDL-14804): Key Events Procedure
• SOP340754 (PDL-14786): Processes and Responsibilities Relating to QA
Investigations
• SOP 340730 (PDL-14801): Unblinding of Suspected Unexpected Serious Adverse
Reactions (SUSARs)
• SOP 340763 (PDL-14805): Medical Evaluation Guideline
• SOP340734 (PDL-14804): Key Events Procedure
• SOP340737 (PDL-14792): Case Processing Standards for Seqirus
• WI – QC Tracking Tool for Seqirus
• Adverse Event Report Form
• QA Investigation Request Form

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Standard Operating Procedure
SOP 340729

6 Attachments

Attachment 1 - Inline QC Sampling and Variable Sample Table

Attachment 2 - Internal ICSR Handling Timelines

Attachment 3 - Follow-Up Attempts

Attachment 4 - Adverse Events Received from Legal Department

7 Change History
Step Changes Made Change Justification
Changes made throughout the
Integration of legacy bioCSL and
document to integrate legacy bioCSL
All Novartis Influenza Vaccines PV
and Novartis Influenza Vaccines
systems.
processes

Regulatory Commitments
Version DR / CC / CAPA # Change History
N/A N/A N/A

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Standard Operating Procedure
SOP 340729

Attachment 1

Inline QC Sampling and Variable Sample Table

Inline QC Sampling and Variable Sample Table:

Seriousness Listedness QC Sampling (%)

Serious Unlisted 100

Serious Listed 65

Non-Serious Unlisted 20

Non-Serious Listed 5

* 100% of AESI will be subject to QC

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Standard Operating Procedure
SOP 340729

Attachment 2

Internal ICSR Handling Timelines

Responsible Process Step ICSR qualifying ICSR qualifying All other ICSRs
as 7-day report as 15-day
report

Global PV –
Receipt By day 1 By day 2 By day 2
Book-in Team

Global PV –
Intake/Book-in By day 2 By day 3 By day 3
Book-in Team

Global PV –
Triage and
Triage and
Skilled Data By day 3 By day 6 By day 6
Skilled Data
Entry
Entry Team

Global PV - QC
QC By day 3 By day 8 By day 8
Reviewer
Global PV -
Medical Medical Review By day 4 By day 10 By day 10
Reviewers
Global PV –
Distribution By day 5 By day 11 By day 11
Case Manager
Local Safety
Contacts (i.e.
local CROs,
distributors or
If required prior
Seqirus local Submission By day 7 By day 15
to due date
teams); Seqirus
Regulatory
Affairs, Clinical
for CT SUSARs

Note: day refers to calendar days

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Standard Operating Procedure
SOP 340729

Attachment 3

Follow-Up Attempts

Serious FLT
Non-Serious Adverse
Serious Adverse Drug Exposure
AE/AR or Event
Event (SAE)/SAR During
Invalid Case (SAE/SAR)
Case Reports Pregnancy
Reports Case
Reports

Minimum
number of
1 3 3 3
follow-ups
required

Within 15 days Within 24 Within 15 calendar Within 15 days

Timeframe
from MRD hours of MRD days from MRD from MRD

EDD + 1 month
Frequency of Up to 4
N/A Up to 4 weeks EDD + 2 month
attempts weeks
EDD + 3 month

Considered After EDD +

4 weeks after 4 weeks after 4 weeks after 3rd
lost to follow- attempts at 1,2,3
initial follow-up 3rd reminder reminder
up months

Refer to SOP 340737 (PDL-14792) - Case Processing Standards for Seqirus for more
detailed processes regarding follow up.

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Standard Operating Procedure
SOP 340729

Attachment 4

Adverse Events received from Legal Department

The Legal Department may learn about an AE/SAE in a patient taking a Company product
in the context of a litigation (controversy before a court; lawsuit), as a result of a claim (e.g.
for damages) that has not yet reached the stage of litigation (non-litigation), or through
other communication.

It is the responsibility of the Legal Department to ensure that any AE/SAE (initial and
follow-up) received is immediately and properly forwarded to Global PV within 24 hours.

In compliance with Regulatory Requirements, legal case reports should be processed and
reported according to Standard Operating Procedures and timeframes.

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