Standard Operating Procedure

SOP 340752

Atlas Number / Version: 340752-01

SmartSolve Number / Edition: PDL-14811 Edition 1

Title: Signal Management Process

Supersedes Atlas Number /

Replaces: SOP255442, SOP273291, WI322569, WI322566
Version:

Supersedes SmartSolve
Replaces: PDL-12382
Number / Version:

Atlas Document Owner: Maria Maddalena Lino

SmartSolve Document Owner: Daphne Sawlwin

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Standard Operating Procedure
SOP 340752

Contents

1. Purpose and Scope........................................................................................................ 3

2. Responsibilities .............................................................................................................. 3
3. Execution ....................................................................................................................... 4
3.1 Signal Management Process ................................................................................... 4
4. Abbreviations and Definitions ......................................................................................... 8
5. References ................................................................................................................... 10
6. Attachments ................................................................................................................. 10
7. Change History ............................................................................................................ 10

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Standard Operating Procedure
SOP 340752

1. Purpose and Scope

The purpose of this document is to provide an overview of the Seqirus signal

detection and management process.

This SOP applies to all Seqirus manufactured products, and products for which
Seqirus has responsibility for signal detection and management as defined within
the relevant safety data exchange agreement. It describes the responsibilities and
procedures involved in the signal management process.

This SOP describes the roles, responsibilities and procedures involved in detecting,
validating, prioritizing, further assessing, escalating and tracking of all safety signals
for Seqirus products.

2. Responsibilities

Pharmacovigilance and Risk Management (PVRM) is accountable for overall safety

signal management.

Within PVRM, the Therapeutic Area Safety Heads (TASH) are accountable for the
signal management process within his/her team for the assigned product portfolio.
The assigned Benefit-Risk Management Physician (BRMP ) for a Seqirus product is
responsible for leading the Safety Management Team (SMT) and ensuring that all
potential safety signals (PSS) and signals (both in development and/or marketed
products) are escalated to the Safety Review Team (SRT).

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Standard Operating Procedure
SOP 340752

3. Execution

3.1 Signal Management Process

Signal management is a set of routine pharmacovigilance activities performed to

determine whether there are new risks associated with a Seqirus product or whether
known risks have changed. The signal management process includes signal
detection, validation, assessment, confirmation, prioritization, as well as any related
recommendations, decisions, communications and tracking.

The Signal Management Process is summarised in Attachment 1.

3.1.1 Signal Detection

Signal detection is the process by which relevant internal (e.g. Seqirus safety
database, non-clinical activities, interventional/non-interventional studies, GMP QA)
and external (e.g. searches in medical/scientific literature databases, information
originated from regulatory or health authorities) data sources are proactively
reviewed to identify potential safety signals.

Routine signal detection comprises both a quantitative and a qualitative aspect

through the following processes at a minimum:
• Daily e-mail notifications of Key Events for relevant products
• Weekly reviews of Individual Case Safety Reports (ICSRs) and Adverse Events
of Special Interest (AESI)
• Review of published literature
• Monthly /Periodic review of aggregated spontaneous data from the global
safety database in the form of review of ICSRs or statistical analyses, or
combination of both
• Review of clinical trial safety data at specific time points, as appropriate, which
may coincide with the data availability for Data Safety Monitoring Board
(DSMB) review, interim analyses, for final analysis.
• Ad-hoc review of safety data outside of the scheduled aggregate review (e.g.
enquiry from Competent Authority, competitor information, literature articles).

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Standard Operating Procedure
SOP 340752

3.1.2 Signal Validation

Upon detection of a safety signal or disproportionality by the relevant BRMP, the

signal must be evaluated to determine if it can be considered as validated or not.

The validation of a signal usually involves the review of readily available existing
data in order to determine whether the available data support a potentially causal
association between the signal and the product. When evaluating the detected
signal, relevant information such as strength of evidence from the ICSRs (such as
biological plausibility, measures of disproportionality and quality of the data), clinical
relevance (seriousness and severity) and previously known association (known or
labelled adverse reactions), as well as the novelty of the event should be
considered. If the evidence supports a causal relationship, the signal should be
considered validated and then undergo further assessment/evaluation to either
confirm or refute the signal (See section 3.1.4).

If it is felt that additional data or information is needed to be in a position to consider

the signal as validated or not, this should be achieved in a manner that enables
rapid validation and escalation of signals, particularly those with a potential
important public health impact and/or those that may significantly affect the risk-
benefit profile of Seqirus’ products. All signals, validated or not (closed) are tracked.

All validated signals are discussed in the relevant section of the PSUR.

3.1.3 Signal prioritization

A key element of the signal management process is to promptly identify High Impact
Signals (those with a potentially important impact on patient, public health and/or on
the risk-benefit balance of Seqirus’ products). Therefore, every detected signal must
be evaluated in terms of its potential impact and prioritized accordingly. Where
appropriate/possible, the prioritization process should take into consideration the
following:
• The severity, seriousness, outcome and reversibility of the adverse reaction
(signal) and the potential for prevention;
• The extent of exposure and the estimated frequency of the adverse reaction;
• The public health impact, including the extent of utilization of the product in both
the general population and in special populations (e.g. pregnant women,
children or the elderly) and the patterns of medicinal product utilization (e.g. off-
label use or misuse);

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Standard Operating Procedure
SOP 340752

• Increased frequency or severity of a known adverse reaction;

• Whether the signal is likely to apply to other substances of the same class of
products.

3.1.4 Signal Assessment

Signal assessment is the process of further evaluating a validated signal in order to

either to confirm or refute a causal association/relationship. It consists of an
assessment of data from all the available sources (including non-clinical, clinical
data, PASS, literature).

BRMP undertakes a signal assessment with support from Clinical Safety Scientist
(CSS), as needed. The results of which is:
• Signal is refuted (closing the signal)
• Signal is not confirmed but requires further monitoring to determine whether the
new data (ICSRs or scientific literature) are supportive of a causal relationship
• Signal is confirmed.

The outcome of signal assessment is presented to the SMT by the BRMP.

Should there be a disagreement from cross-functional members, the BRMP

escalates to the SRT.

3.1.5 Signal Escalation and Communication

All validated signals are communicated, both internally and externally, as

appropriate. The EU QPPV must be made aware of all validated signals (both High
and Low Impact Signals). Depending on the circumstances (i.e. a High or Low
Impact Signal), other internal and external recipients may need to be informed.

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Standard Operating Procedure
SOP 340752

3.1.5.1 Signal escalation

As indicated above, all signals must be assessed in terms of their potential impact
and be prioritized and escalated accordingly. Escalation is divided into two
categories: expedited (High Impact Signals/Urgent Safety Issues) and routine (for
Low Impact Signals), and the steps and responsibilities involved for each are
detailed below and in Attachment 2.

For signals which are confirmed and deemed to have implications for public health
and the risk-benefit profile of a product (e.g. High Impact Signals), immediate
escalation to the Seqirus Global Safety Committee (GSC) via GSC Chair. For these
instances, further work on signal assessment, if appropriate, is done in parallel to
GSC being informed. GSC determines appropriate actions, communication to
internal and external stakeholders. The recommended timelines for escalation are
provided below:
Prioritization Responsible Initiator
Intended Audience Timeline
Category for Escalation
Highest priority from
High Impact Signal; Assigned BRMP (SMT the time high impact
GSC
expedited Chair) signal is confirmed and
ratified by the SRT
Communicated at next
Low Impact Signal; Assigned BRMP (SMT PVRM, EU-QPPV, SMT after low impact
routine Chair) GSC Chair, and SMT signal is confirmed and
ratified by the SRT

3.1.6 Recommendations for Action

Signal assessment results in a recommendation that either no further action is

required at that point in time or further action is needed.

Although the formulation of a recommendation for action normally takes place in a

logical sequence at the end of signal assessment, based on the extent of the
information known at that point in time, the need for action, and the exchange of
information, should be considered through the entire signal management process.

Recommendations for action may include, but are not limited to the following:
• Periodic review of the signal through PSURs
• Signal to be re-reviewed after a specific additional period of exposure (in time
or number of persons)
• Event to be added to the list of Adverse Event of Special Interest (AESI) for
ongoing monitoring (watch list)
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Standard Operating Procedure
SOP 340752

• Update of Company Core Safety Information (CSI) and associated labeling

documents e.g. CCDS, Investigator Brochure (IB) and local labels
• Update Risk Management Plan (RMP) to include additional pharmacovigilance
activities (e.g. Post-Authorization Safety Study or other investigations) or risk
minimization activities
• Referral to Quality Assurance and/or Regulatory Affairs for further action (e.g.
product recall or variation of the marketing authorization)

3.1.7 Signal Tracking

Every PSS/signal identified must be tracked.

4. Abbreviations and Definitions

AESI Adverse Event of Special Interest

BRMP Benefit Risk Management Physician who performs signal

detection, directs evaluations and approves drug safety
reviews. In addition, the BRMP provides an expert opinion
on potential risk on human safety with regards to GMP-
related deviations or Product Technical Complaints.

CSI Core Safety Information

CSS Clinical Safety Scientist

CCDS Company Core Data Sheet

DSMB Data Safety Monitoring Board

EU-QPPV EU Qualified Person Responsible for Pharmacovigilance

GMP QA Good Manufacturing Practice Quality Assurance

GSC Seqirus Global Safety Committee

ICSR Individual Case Safety Report

IB Investigator Brochure

PSUR Periodic Safety Update Report

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Standard Operating Procedure
SOP 340752

PSS Potential Safety Signal

PVRM Pharmacovigilance and Risk Management

RMP Risk Management Plan

Signal Information arising from one or multiple sources, which

suggests a new potentially causal association, or a new
aspect of a known association between a product and an
event or set of related events, that is judged to be of
sufficient likelihood to justify verificatory action

SMT Safety Management Team: an internal company cross-

functional team set up by product or therapeutic area
responsible for the planning of all safety relevant activities
and timely review, evaluation and communication of safety
data related to a product throughout its lifecycle. The SMT
is led by the SMT Chair who is the BRMP assigned to a
particular product.

SRT Safety Review Team: Experienced physicians within the

PVRM who provide expert strategic and medical oversight
of the signal management process for Seqirus products.
Collectively, the SRT are highly experienced in plausibility
assessment of safety signals and also provide expert
advice regarding how signals are evaluated and
subsequently escalated and communicated.

TASH Therapeutic Area Safety Head: A senior Physician who

provides guidance and expertise to a group of BRMPs and
clinical safety scientists in applying sound medical
judgment for analysis and interpretation of safety data for
signal detection and initiation of safety risk management
activities including safety specification, PV planning and
risk minimization/mitigation.

Urgent Safety Issue (also referred to as a High Impact signal); a safety

issue/signal with an important public health impact and/or
which may significantly affect the risk-benefit profile of a
product. Note: by default, all urgent safety issues/High
Impact signal must be escalated to the GSC.

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Standard Operating Procedure
SOP 340752

5. References

• Charter for the Seqirus Safety Review Team

• Charter for the Seqirus Safety Management Team

6. Attachments

• Attachment 1 – Signal Management Process

• Attachment 2 – Scheme for low and high priority signals

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

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

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Standard Operating Procedure
SOP 340752

Attachment 1 – Signal Management Process

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Standard Operating Procedure
SOP 340752

Attachment 2 – Scheme for low and high priority signals

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