Conducting/Implementing a benefit/ risk assessment can be very challenging for “old” established products. Scientific assessment on benefit/ risk is conducted based on the best evidence available. The main objective of this presentation is to discuss how this approach can be applied for different type of regulatory documents that are to be prepared for established products.

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Overcoming the challenges of
benefit-risk assessment for
established products
DIA 28th Annual EuroMeeting, 6-8 April 2016, Congress
Center Hamburg, Germany
Marion Daverveldt, DVM
Medical Affairs Coordinator
SGS - Life Sciences
© 2015 DIA, Inc. All rights reserved.

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Disclaimer
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Disclosure Statement
I have no real or apparent relevant financial relationships to disclose
I am employed by a regulatory agency, and have nothing to disclose
Please note that DIA is not requesting a numerical amount to be entered for any disclosure, please indicate by
marking the check box, and then providing the company name only for those disclosures you may have.
Will any of the relationships reported in the chart above impact your ability to present an unbiased presentation? Yes No
In accordance with the ACPE requirements, if the disclosure statement is not completed or returned, participation in this activity will be
refused.
Type of Financial Interest within last 12 months Name of Commercial Interest
 Grants/Research Funding
 Stock Shareholder
 Consulting Fees
 Employee SGS - Life Sciences
 Other (Receipt of Intellectual Property
Rights/Patent Holder, Speaker’s Bureau)

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Overview
Introduction
Benefit-risk assessment marketed product
Case study: harmonization of SmPC (Article 30 referral)
Addenda to Clinical Overviews (ACOs), PSURs/PBRERs and
Clinical Overviews supporting Type II variations
Conclusions
Questions
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Introduction
Continuous pharmacovigilance and benefit-risk assessment
marketed product essential for safety of the consumers
Side effects: 5% of all hospitalizations
Nearly 200.000 deaths per year in EU caused by side effects
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Benefit-Risk assessment marketed product (1)
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Benefit-Risk assessment marketed product (2)
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Benefit-Risk assessment marketed product (3)
When a drug is marketed: exposure to patient populations not
investigated in clinical trials and much larger patient populations
Safety issues that did not appear during the development
programme may become only evident once the product is on the
market
Continously evaluation of benefit-risk needed
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Benefit-Risk assesment marketed product (4)
Measurement benefit-risk: never an absolute one: always in
comparison with alternative medicinal products, non-medicinal
modalities, or no treatment
May apply also to different doses or dosage forms of the same
medication, whether for the same or different indications, or even
to a combination of pharmaceutical and other options
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Benefit evaluation
Epidemiology and natural history of the target disease(s)
Purpose of treatment (cure, prophylaxis, etc.)
Summary of efficacy and general toleration data compared with:
- other medical treatments
- surgical treatment or other intervention
- no treatment
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Risk evaluation
Spontaneous/voluntary reporting of cases
Identification of cases through the literature
Postmarketing studies (voluntary or required)
– Observational studies (including automated healthcare databases)
– Randomized clinical trials
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Case Study: Article 30 referral
This type of referral is triggered when Member States have
adopted different decisions over the years for some medicines
(e.g. different indications, contraindications or posology) and
there is a need to harmonise across the EU
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Article 30 Referral
Whenever this binding mechanism is invoked, a scientific
evaluation of the matter is undertaken by the Committee for
Medicinal Products for Human Use (CHMP) of the European
Medicines Agency’s (EMA/Agency)
These referrals lead to an opinion from which the Commission
issues a single decision addressed to all Member States (MS)
which is reported for information to the applicant(s) or marketing
authorisation holder(s) (MAH)
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Article 30 Referral
The referral can only be stopped if MAH(s) withdraw the
concerned marketing authorisations from all EU markets
• This condition applies regardless of whether the procedure was triggered
by the European Commission, a MS or the MAH
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Case Study: Article 30 referral
Translation of the local SmPCs
Comparison tables for all different sections of SmPCs
Review of data for each section
Example: section 4.1: Indications
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section 4.1: Indications
Internal studies
Published studies
Reviews
Meta-analyses
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section 4.1: Indications
Starting with literature searches
Internal data provided by MAH
Literature data: search in Embase
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section 4.1: Indications
Often older trials
Not conducted according to current standards
Diagnostic methods for making diagnosis not as
accurate as nowadays: different indication
Different efficacy parameters across trials
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section 4.1: Indications
Critical evaluation needed
The data of the studies should be described together with the
epidemiology and natural course of the disease
The Benefit-risk of the alternatives should be described also
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Treatment guidelines
The purpose of treatment guidelines is to educate health care
professionals and health care systems about the most effective
treatments available
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Treatment guidelines
Treatment efficacy: the systematic and scientific evaluation of
whether a treatment works.
Clinical utility: the applicability, feasibility, and usefulness of the
intervention in the local or specific setting where it is to be
offered.
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Treatment guidelines
Based on broad and careful consideration of the relevant empirical
literature
Take into consideration the level of methodological rigor and clinical
sophistication of the research supporting the intervention
Guidelines consider clinical opinion, observation, and consensus
among recognized experts
Take into consideration the treatment conditions to which the
intervention has been compared
Consider available evidence regarding patient–treatment matching
Specify the outcomes the intervention is intended to produce, and
evidence should be provided for each outcome
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Summary of the case study: Objectives
Create one harmonized SmPC
Create the supporting documents (Clinical Overview: module 2.5)
Provide all references
Adhere to strict timelines imposed by the Health Authorities
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Summary of the case study: Challenges
Gather all the original internal data that was used for the original
Marketing Authorization Application
Define the correct search criteria to identify all published data without
missing essential trials
Define the correct search criteria for data on epidemiology and natural
course of the disease data and benefit-risk of the alternatives and
treatment guidelines
Critical evaluation of the trials: methodology, endpoints, statistics, etc..
Coordinate and divide the huge amount of data between team
members and still ensure a consistent approach
Adhere to the timelines
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Summary of the case study: Operations - Solutions
Assign a coordinator of the project
Assign enough team members
Assign one person specialized in literature searches
Provide training to the team members (familiarize with the
indications, working mechanism product, alternatives, etc..)
Weekly internal meetings
Weekly meetings with the client
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Summary of the case study: Conclusion
Enough resources required
Communication and regular meetings both internally as with the
client essential!
Team members have to be trained (no juniors)
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Other Regulatory Documents
Addenda to Clinical Overviews (ACOs)
Periodic Safety Update Reports/Periodic Benefit Risk Evaluation
Reports (PSURs/PBRERs)
Clinical Overviews for type II variations
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Conclusions
Benefit-risk assessment marketed (established)
product important
Article 30 SmPC harmonization exercise:
not easy for old products with old studies/ total
evaluation needed with critical review of comparators/
treatment guidelines/years of clinical experience
Other documents: ACOs/ PSURs/PBRERs/COs
supporting type II variations
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Ask
Marion Daverveldt, DVM
SGS - Life Sciences
Marion.Daverveldt@sgs.com
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