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Benefit Risk Management and Risk Minimisation
Cecilia Chia Ph.D

Regional Head of GDS, APAC
Merck Serono
Content
Benefit Risk Assessment - Why and What it is
Benefit Risk Assessment Global Frameworks (Descriptive)
Process of Benefit Risk Assessment- Principles and Context
Risk Minimisation - Toolkit
Merck Serono | November 2014
Definitions*
Identified Risk
An untoward occurrence for which there is adequate evidence
of an association with the medicinal product of interest
Examples:
An Adverse Reaction (ADR) adequately demonstrated in
non-clinical studies and confirmed by clinical data
An ADR observed in clinical trials or epidemiological

studies for which the magnitude of the difference compared
with the comparator group, on a parameter of interest
suggests a causal relationship
An ADR suggested by a number of well-documented

spontaneous reports where causality is strongly supported
by temporal relationship and biological plausibility, such as
anaphylactic reactions or application site reactions
In a clinical trial, the comparator may be placebo, active

substance or non-exposure.
*Guideline on good pharmacovigilance practices (GVP) Module V (Rev 1) EMA/838713/2011 Rev 1

3
Definitions*
Potential Risk
An untoward occurrence for which there is some basis for
suspicion of an association with the medicinal product of
interest but where this association has not been confirmed
Examples:
Toxicological findings seen in non-clinical safety studies
which have not been observed or resolved in clinical
studies;
Adverse events (AE) observed in clinical trials or

epidemiological studies for which the magnitude of the
difference, compared with the comparator group on a
parameter of interest raises a suspicion of an association,
but is not large enough to suggest a causal relationship
A signal arising from a spontaneous adverse reaction

reporting system;
An AE known to be associated with other active

substances within the same class or which could be
expected to occur based on the properties of the
medicinal product

4
Definitions*
Important Identified Risk and Important
Potential Risk
An identified risk or potential risk that could have
an impact on the risk-benefit balance of the
product or have implications for public health.
What constitutes an important risk will

depend upon several factors, including the
impact:
On the individual
The seriousness of the risk
The impact on public health
=> Normally, any risk that is likely to be included

in the contraindications or warnings and
precautions section of the product
information should be considered important

5
Definitions*
Principles of Risk Management
The overall aim of risk management is to

ensure that the benefits of a particular
medicinal product exceed the risks by the
greatest achievable margin for the
individual patient and for the target
population as a whole
This can be done either by increasing the

benefits or by reducing the risks
The principles of risk management are

the same regardless of stakeholder or
territory

6
Example of Benefit-Risk/Trade-off Questions

Medicine Feature
Medicine Feature
How long the medicine will keep the
How cancer
long thefrom
medicine
keep the
gettingwill
worse
cancer from getting worse
How to take the medicine
How to take the medicine
Feeling weak or tired
Which Feeling
medicineweak
would
or you
tiredchoose
Stomach problems
if theseStomach
were your
only options?
problems
Sores in mouth or throat
Sores in mouth or throat
Redness or sores on hand and feet
Redness or sores on hand and feet
Risk of lung damage
Which medicine would you choose
if these were your only options?
Risk of liver failure
Which medicine would you choose
if these were your only options?
7
Medicine A
Medicine A
10 months
10 months
Medicine B
Medicine B
5 months
5 months
OD with or without
OD withfood
or without
food
Severe
Severe
O
None
None
Mild-to-moderate
Mild-to-moderate
None
None
No risk
BID without food

BID without food
Mild-to-moderate
Mild-to-moderate
O
Severe
Severe
Severe
Severe
Severe
Severe
5 out of 1000
(0.5%)
O
10 out of 1000
(1.0%)
No risk
The various stakeholders/decision makers

Pharma: Should we
make further
investment in that
medicinal product
in view of a
registration?
Patients: Should I take

this medicinal product
or a comparator?
Authorities: Should we
approve or withdraw that
medicinal product from the
market when it can still be
useful for some patients?
Prescribers: Should
I prescribe this
medicinal product
or a comparator?
Stakeholders in decision-making throughout the

drug development path
Regulatory
approval
Submission
Into man
Preclinical
Drug discovery
toxicology
Healthy volunteers
Phase I
Human
pharmacology
Research
Patients
Phase II
Therapeutic
exploratory
Phase III
Therapeutic
confirmatory
Phase IV
Therapeutic use
Marketing
Clinical Development
Industry
Regulatory Authorities
Investigators
Ethic Committees
Payors
Prescribers
Patients
9
What Benefit-Risk Assessment is (1/2)

An extensive collection and organization/visualization of data,
and the respective value judgments made based on this
collection (preferences or utilities), which are strongly
dependent on the stakeholders perspective
A structured approach with successive steps encompassing
the overall background and context in which the assessment
has to be made
The simultaneous consideration of information pertaining to
multiple effects (favorable (FE) and unfavorable effects (UFE))
and multiple treatment options
10
What Benefit-Risk Assessment is (2/2)

A potential tool for collaborative work across agencies or other
stakeholders
A potential platform for peer review
A tool allowing the comparison between other medicinal
products in the same class
With quantitative methods, a weighing exercise among criteria
and a scoring of options within criteria
Benefit-Risk Assessment may include non medical data, but
this extends the scope to Health Technology assessment (as
done by NICE)
11
What Benefit-Risk (B-R) Assessment is NOT

A B-R Assessment method is not an algorithm to be fed with
data and which would provide an automatic answer; it is a
support to human decision making
B-R Balance Assessment is not based only on objective data
but also on subjective judgments made by the decision maker
Expressing B-R as a ratio is one out of many other methods.
Benefit-Risk balance assessment may be expressed by many
other methods and tools, and have various graphical/visual
representation
12
Content
Benefit Risk Assessment -Why and What it is
Benefit Risk Assessment Global Frameworks (Descriptive)
Process of Benefit Risk Assessment Principles and Context
13
Regulatory Environment is Changing

Multiple Initiatives on Benefit Risk Assessment
Currently not Harmonized
BRAT
EU
Good PV
Practice
FDA BR
Approach
PMDA
Activities
EMA
BR Approach
(Methodology
Project)
IMI
PROTECT
COBRA
(CAN, CH,
Singapore,
AUS)
IMI Innovative Medicines Initiative

PROTECT Pharmacoepidemiological Research on Outcomes of Therapeutics in an
European Consortium
14
SABRE
(Southeast
Asia)
Benefit-Risk Assessment Initiatives

Many B-R Assessment initiatives have been developed; most of them
intend to propose, promote or test various frameworks, methods and
tools. The most relevant ones for Merck Serono/EMD Serono are:
EU
FDA_PDUFA V draft
Plan Feb 2013

www.fda.gov/downloads/ForIndustry/Us
erFees/PrescriptionDrugUserFee/UCM3
29758.pdf
The EMA
Methodology Project
www.ema.europa.eu/ema/index.jsp?cur
l=pages/special_topics/document_listin
g/document_listing_000314.jsp&mid=W
C0b01ac0580665b63
UMBRA (International)
http://cirsci.org/UMB
RA
The PROTECT Work

Package 5
http://www.imi-protect.eu/wp5.shtml
15
1
5
FDA Benefit-Risk Framework

The US Structured Approach to B-R Assessment in Drug
Regulatory Decision Making (draft PDUFA V Implementation Plan)
Proposes a simple framework to be used by all FDA assessors
16
PrOACT
The EU B-R Methodology Project (EMA)proposes the PrOACT-URL
framework
Problem
1. Determine the nature of the problem and its context
EU
2. Frame the problem
3. Establish objectives indicating the overall purposes to be achieved
Objective
4. Identify criteria for favourable and unfavourable effects
Alternatives
5. Identify the options to be evaluated against the criteria
6. Describe how alternatives perform for each of the criteria, i.e.,
Consequences
Trade-off
17
magnitudes of all effects, and desirability or severity, and

incidence of all effects
7. Assess the balance between favourable and
unfavourable effects
URL
EU
Uncertainty
Risk tolerance
Linked decisions
18
8. Report uncertainty associated with favourable and

unfavourable effects
9. Consider how balance between favourable and unfavourable
effects is affected by uncertainty
10. Judge relative importance of decision makers risk
attitude for this product
11. Report how this affected the balance reported in step 9
12. Consider the consistency of this decision with similar

past decisions, and assess whether taking this
decision could impact future decisions
Benefit-Risk Assessment initiatives

The UMBRA initiative: an attempt to combine all other
approaches in a unified 8-step process.
Framing the decision
Identifying benefits and risks
Step 1:
Decision context
Step 7:
Concise
presentation of
results
(visualization)
Step 3:
Refining the value
tree
Step 4:
Relative importance
of benefits and
risks
Step 6:
Evaluating the
uncertainty
Interpretation and recommendations

19
from CIRS
Merck Serono | November (Reference
2014
Step 5:
Evaluating the
options
Assessing benefits and risks
Step 8:
Judgement and
communication
Step 2:
Building the value
tree
PhRMA BRAT (The Pharmaceutical Research and

Manufacturers of America Benefit-Risk Action Team)
20
Commonalities across frameworks

Core B-R process
Define decision
context
Identify
outcomes
Data
evaluation &
summarization
Interpret the
assessment
21
Frameworks demonstrate
Logical soundness
Coherent approach that aids rational thinking & judgment
Consistency
Practicality
Transparency
Systematic, qualitative approaches

Decision aids to structure the evaluation:
Which benefits and risk were considered most relevant?
What was the evidence? How was the evidence
interpreted?
How were the benefits and risks weighed or prioritized?
What can be done to manage and mitigate the risks? To
optimize the benefits?
Content
Benefit Risk Assessment Global Frameworks
22
Problem Statement and Process

(From design to implementation)
Compilation and maintenance of a robust and up-to date benefit-risk
(B/R) profile is key for multiple processes during entire product life cycle
Traditional way:
Processes reactive and often ad hoc
Inconsistency with regard to methods utilized
Lack of clear ownership of process steps
Processes not embedded within a defined governance structure
Output of variable quality
Modern way:
Patients safety focused approach
End-to-end B/R assessment process for the company
Adaptable to various perspectives (regulators, company, prescriber,
patient)
23
Key Steps in Benefit-Risk-Assessment Process

Defined Triggers
New information on B/R (studies, signals)
Application for market authorization / renewal
Request from Health Authorities
Aggregate Reports (PBRER/PSUR/DSUR)
Regular review
Problem
Statement
& Planning
Evidence
Gathering and
Data
Preparation
Analysis
Output: B-R Assessment Core

Document
Context / trigger
Evaluation and summary of benefit
Evaluation and summary of risks
Assessment of benefit versus risk
Conclusions on the BR profile
recommendation of action plan,
Exploration
Conclusion
and
Dissemination
From: IMI-PROTECT Benefit-Risk Group
RECOMMENDATIONS REPORT 2014
Drug Safety
Biostatistics
BRAT*
Clin Develop.
BRAT
Pre-clinic
Reg Affairs
24
*BRAT= Benefit Risk Action Team
Governance
Body
Signal Management, Benefit-Risk Assessment

and Risk Management are linked
Risk
Management
Signal
Management
Benefit-Risk
Assessment
28
Content
Benefit Risk Assessment Global Frameworks
30
Risk Minimization measures

Risk minimization definition:
Interventions intended to prevent or
reduce the occurrence of Adverse
Reactions (ADRs) associated with the
exposure to a medicine
To reduce their severity or impact on the
patient should ADRs occur
Key elements of risk management:
31
Planning and implementing risk

minimisation measures
Assessing their effectiveness

Routine risk minimisation is applicable to all
medicinal products, and involves the use of the
following tools:
Summary of product characteristics (SmPC)
Package leaflet
Labelling
Pack size and design
Legal (prescription) status of the product
Safety concerns of a medicinal product are
normally adequately addressed by routine risk
mininization measures
32

Additional risk minimisation measures :
Optimisation of the safe and effective use of a

medicinal product
Throughout its life cycle
Reducing the burden of adverse reactions or by

optimising benefit, through:
Targeted patient selection
Exclusion and thorough treatment management
(e.g. specific dosing regimen, relevant testing,
patient follow-up)
In medical practice: Supporting the provision of the
right medicine, at the right dose, at the right time,
to the right patient and with the right information
and monitoring
33

Additional risk minimisation measures that may be
considered in addition to the routine measures,
including:
Educational programmes
Controlled access programmes
Other risk minimisation measures
Elements for inclusion in an educational tool could
provide:
Guidance on prescribing, including patient selection,
testing and monitoring
Guidance on the management of such risks (to
healthcare professionals and patients or caregivers)
Guidance on how and where to report adverse reaction
of special interest
34

Educational tools targeting patients
and/or caregivers
To enhance the awareness of patients or
their caregivers
To identify early signs and symptoms of
specific ADRs
Correct administration of the product
To remind the patient about an important
activity
(e.g. a diary for posology or diagnostic procedures
that need to be carried out by the patient)
Patient alert card regarding the patients

current therapy and its important risks
(e.g. potential life-threatening interactions with other
therapies)
35

Examples of requirements that need to be
fulfilled before the product is prescribed
and/or dispensed:
Controlled access program
Specific testing and/or examination of the
patient to ensure compliance with strictly
defined clinical criteria
Prescriber, dispenser and/or patient
documenting their receipt and
understanding of information on:
The serious risk of the product
Explicit procedures for systematic patient
follow-up through enrolment in a specific
data collection system e.g. patient registry
36

Controlled distribution systems
The distribution chain of a medicinal
product are tracked up to the
prescription and/or pharmacy
dispensing the product
Orders and shipments of product
from a single or multiple identified
distribution points to facilitate
traceability of the product
Legislations about the misuse and
abuse of medicines
37

Pregnancy Prevention Programme
A pregnancy prevention programme (PPP) is a set of
interventions aiming to minimise pregnancy
Exposure during treatment with a medicinal product
with known or potential teratogenic effects
The scope of such a programme is to ensure that
female patients are not pregnant when starting therapy
Do not become pregnant during the course and/or
soon after stopping the therapy
Target male patients when use of a medicinal product
by the biological father might have a negative effect on
pregnancy outcome
A PPP combines the use of educational tools with
interventions to control appropriately access to the
product
Prescription limited to a maximum of 30 days supply
38

Direct health care professional communication
(DHPC)
By a marketing authorization holder: Important
information delivered directly to individual healthcare
professionals
By a health authority: Inform HCPs of the need to
take certain actions
DHCP to adapt HCP practices in relation to a
medicinal product
Adapting prescribing decisions
Reporting of ADRs with a medicinal product
39
Thank you
41
Want to Learn More?

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18th 19th November 2015, Singapore

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Area Medical Governance and Pharmacovigilance
Miranda Wang
Head for Country Pharmacovigilance, China
GlaxoSmithKline Pharmaceuticals Limited
Bristol-Myers Squibb
Jean Christophe Delumeau

Head of Pharmacovigilance Asia Pacific and China
Bayer HealthCare / Bayer South-East Asia
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Benefit Risk Management and Risk Minimisation

Cecilia Chia Ph.D

Benefit Risk Assessment - Why and What it is

Benefit Risk Assessment Global Frameworks (Descriptive)

Process of Benefit Risk Assessment- Principles and Context

Risk Minimisation - Toolkit

Merck Serono | November 2014

An ADR observed in clinical trials or epidemiological

An ADR suggested by a number of well-documented

In a clinical trial, the comparator may be placebo, active

*Guideline on good pharmacovigilance practices (GVP) Module V (Rev 1) EMA/838713/2011 Rev 1

Merck Serono | November 2014

Adverse events (AE) observed in clinical trials or

A signal arising from a spontaneous adverse reaction

An AE known to be associated with other active

*Guideline on good pharmacovigilance practices (GVP) Module V (Rev 1) EMA/838713/2011 Rev 1

Merck Serono | November 2014

What constitutes an important risk will

=> Normally, any risk that is likely to be included

*Guideline on good pharmacovigilance practices (GVP) Module V (Rev 1) EMA/838713/2011 Rev 1

Merck Serono | November 2014

The overall aim of risk management is to

This can be done either by increasing the

The principles of risk management are

*Guideline on good pharmacovigilance practices (GVP) Module V (Rev 1) EMA/838713/2011 Rev 1

Merck Serono | November 2014

Example of Benefit-Risk/Trade-off Questions

Merck Serono | November 2014

BID without food

The various stakeholders/decision makers

Patients: Should I take

Merck Serono | November 2014

Stakeholders in decision-making throughout the

Merck Serono | November 2014

What Benefit-Risk Assessment is (1/2)

Merck Serono | November 2014

What Benefit-Risk Assessment is (2/2)

Merck Serono | November 2014

What Benefit-Risk (B-R) Assessment is NOT

Merck Serono | November 2014

Benefit Risk Assessment -Why and What it is

Benefit Risk Assessment Global Frameworks (Descriptive)

Process of Benefit Risk Assessment Principles and Context

Risk Minimisation - Toolkit

Merck Serono | November 2014

Regulatory Environment is Changing

IMI Innovative Medicines Initiative

Merck Serono | November 2014

Benefit-Risk Assessment Initiatives

Plan Feb 2013

The PROTECT Work

Merck Serono | November 2014

FDA Benefit-Risk Framework

Merck Serono | November 2014

1. Determine the nature of the problem and its context

2. Frame the problem

3. Establish objectives indicating the overall purposes to be achieved

4. Identify criteria for favourable and unfavourable effects

5. Identify the options to be evaluated against the criteria

6. Describe how alternatives perform for each of the criteria, i.e.,

Merck Serono | November 2014

magnitudes of all effects, and desirability or severity, and