Overcoming the Challenges of Benefit Risk Assessment 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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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

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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

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Type of Financial Interest within last 12 months Name of Commercial Interest

Grants/Research Funding

Stock Shareholder

Consulting Fees

Employee SGS - Life Sciences

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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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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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Starting with literature searches

Internal data provided by MAH

Literature data: search in Embase


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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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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 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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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 [email protected]

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Health & Medicine

Overcoming the Challenges of Benefit Risk Assessment for Established Products