An agency of the European Union
EU Regulatory Update Peter Richardson Head of Quality Specialised Scientific Disciplines Department, European Medicines Agency
Content
• Re-organisation of the EMA
• Validation guideline – Biological active substances
• Quality by Design
• Variations (Post approval changes)
• Biosimilars
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Re-organisation of the EMA
• Management Positions defined – 16th September
• Focus on how to better:
• support the scientific work of the of the EMA committees;
• share the knowledge and information the Agency holds throughout the EU medicines regulatory network;
• meet the need of the Agency’s stakeholders and partners.
• Therapeutic area Offices lead Product Teams.
• Additional functions – Offices / Services support to procedures and processes.
• Effort to rationalise activities where possible.
• Administrative / procedural aspects separated from scientific – regulatory support.
• Quality Office : further integration of chemicals and biologicals.
• Implementation in progress following redesign of the processes.
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http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2013/09/news_detail_001886.jsp&mid=WC0b01ac058004d5c1
New EMA Structure
Management structure: Divisions / Departments / Offices
Human Medicines Research and Development Support Division,
Human Medicines Evaluation Division,
- Scientific and Regulatory Management Department
- Specialised Scientific disciplines Department
- Quality Office (Chemicals and biologicals)
Procedure Management and Business Support Division
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http://www.ema.europa.eu/ema/index.jsp?curl=pages/about_us/general/general_content_000112.jsp&mid=WC0b01ac0580028c2c
Content
• Re-organisation of the EMA
• Validation guideline – Biological active substances
• Quality by Design
• Variations (Post approval changes)
• Biosimilars
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Concept Paper
Why develop this ?
- active substance focus
● Gaps to be filled: process- and product-related impurity clearance (e.g. host cell proteins, DNA),
column/membrane sanitization and life time, hold time, reprocessing, pooling of intermediates and
selection of batches to be included in evaluation/validation studies.
● Evolution of concepts already outlined in ICH 8 -11 do not provide practical recommendations on the
necessary evaluation/validation studies to be filed on these specific aspects.
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Validation Guideline Workshop
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http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/events/2013/01/event_detail_000693.jsp&mid=WC0b01ac058004d5c3
Workshop - Remarks
Acknowledgement:
K. Ho (ANSM / Roche)
BWP and industry
participants
A. Ganan (EMA)
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Critical Process Parameters:
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Process Verification
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Data overview
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Product Validation
• Draft (QWP) guideline finalised.
• Principles applicable to biologicals.
(addresses continuous process
verification)
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Content
• Re-organisation of the EMA
• Validation guideline – Biological active substances
• Quality by Design
• Variations (Post approval changes)
• Biosimilars
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• FDA – QbD parallel
assessment.
• Focus: chemicals
(affects biologicals).
• Outcomes – Q&A.
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Perjeta - (informal) parallel assessment
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QbD Approach:
QbD Workshop - Jan 2014
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Content
• Re-organisation of the EMA
• Validation guideline – Biological active substances
• Quality by Design
• Variations (Post approval changes)
• Biosimilars
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Variations Regulation
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Procedural guideline
Variation classification guideline
• in force since Jan 2010
• medicinal products authorised via centralized (CP), mutual recognition (MRP) and decentralized
• in force since Nov 2012 • extend the scope -> medicinal products
authorised at national level
• Changes in decision making process for product involving a CP
• EC decision only for type II variations favourable & affecting annexes, acc. to Art 2.3.1(a)
Variation to all MAs in EU subject to the same rules Earlier implementation for most Quality changes for CPs -> as no EC decision needed.
Regulation (EC) No 1234/2008
Regulation (EC) No 712/2012
Revision of classification guideline
Updated guidleine published on EC website on 16th May 2013.
Published in Official Journal of EU. Entered into force on 04 August 2013,
Main Revisions in the guideline:
•New Pharmacovigilance legislation;
•Other changes to reflect experience;
•Outcome of Art. 5 recommendations
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Revision of Classification guideline
Overview of Quality related changes
• New scopes:
– As result of Art 5 (e.g. stability protocol)
– From frequent questions to CA / Clarification purposes
(e.g. WCB storage)
– Align requirements (e.g. consistency between active and product)
– In relation to enhanced development (QbD) (e.g. changes to
change management protocols)
– relevant to biological products e.g. inclusion of finished product
design space, adventitious agents safety, batch control/testing sites.
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Important changes for biologicals -
Classification Guideline
B.I.a.2.c - Change in manufacturing process of the active substance
B.I.a.2.c The change refers to a biological / immunological substance or use of a different chemically derived
substance in the manufacture of a biological/immunological substance, which may have a significant
impact on the quality, safety and efficacy of the medicinal product and is not related to a protocol
B.I.b.2.d Change in test precedure for the active substance
B.I.b.2.d Substantial change to or replacement of a biological/ immunological/ immunochemical test method or
a method using a biological reagent for a biological active substance.
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Variations – Web Link Categorisation Guideline:
http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:C:2013:223:FULL:EN:PDF
Content
• Re-organisation of the EMA
• Validation guideline – Biological active substances
• Quality by Design
• Variations (Post approval changes)
• Biosimilars
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Evolution of Biosimilars in the EU
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2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013
First biosimilars authorised –
Omnitrope and Valtropin
First biosimilar epoetins
authorised
First biosimilar filgrastims authorised
Legislation Guidance
Product evaluation
Directive 2001/83/EC
Directive 2004/27/EC
Overarching guideline
Product-class specific guidelines
Quality guideline Non-clinical/Clinical guideline
First biosimilar mAbs authorised
Directive 2003/63/EC
Guideline Revision /
Update
Biosimilar product experience in EU Marketing Authorisation
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26 MAAs reviewed
18 Positive 1 Negative 7 Withdrawn
14 Valid MAs
2 Withdrawn
28 MAAs submitted
2 MAAs under review
Follitropin alfa (1) Insulin glargine(1)
Somatropin (1) Epoetin (5) Filgrastim (6) Infliximab (2)
Filgrastim (1) Somatropin (1)
Interferon alfa Insulin (6) Epoetin (1)
2 DMP
Filgrastim (1) Follitropin alfa (1)
Guidelines for biosimilars
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Overarching Guideline (CHMP/437/04) “Guideline on Similar Biological Medicinal Products”
Defines principles
Draft GL : May 2013
Quality Guideline Non-clinical/clinical Guideline
General Guidelines on Q/S/E
Final GL 1Q2104
Insulin Somatropin G-CSF Epoetin LMWH IFN-α IFN-β mAbs Follitropin alfa
Class-specific Guidelines: non-clinical/clinical aspects
Overarching Guidelines:
Draft GL : June 2013
2006 Rev 2012
2006 2006 2006 Rev 2010
2009 Rev 2013
2009 2013 2012 2013
30 Jun 2013
31 Jul 2013
Implementation 1 Sep 2013
Biosimilars Workshop
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INN Aspects
• EMA uses INN according to WHO policy
• Biosimilar can use Reference Product INN
• EMA: robust assessment of biosimilarity
• WHO Consultation – 2006 / 2013
• What can be expected from INN ?
• When to use INN ?
• Coding of active substance in biosimilar ?
- TGA / (WHO Draft Policy ?):
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EC: Market access to biosimilars
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• Sep 2010 project launch
• Review availability of biosimilars in EU markets
• Define the necessary conditions for patient access
– Current experience with access and uptake of biosimilars
– Effects and consequences from the uptake of biosimilars
– How to promote uptake of biosimilars
• Deliverables -> 22th April 2013
– Consensus doc: “What you need to know about Biosimilars”
– Information on reimbursement in EEA countries
– Study on “biosimilar market access” prepared by IMS
– Survey conducted by EGA to identify good practices, obstacles related
to biosimilar uptake
http://ec.europa.eu/enterprise/sectors/healthcare/files/docs/biosimilars_report_en.pdf
1st Biosimilar Mab - Remsima
• Remsima (duplicate Inflectra) : first biosimilar mAbs to be approved in Europe. European Commission
Decision – 10th September 2013.
• Active substance: INN infliximab
• Reference product Remicade (authorised 1999).
• Further details – see comprehensive EPAR.
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Remsima Comparability (physicochemical)
33 Table continued in EPAR
Remsima Comparability (bioactivity)
34 Table continued in EPAR
Remsima - Learnings
• Extensive comparability exercise: quality and non-clinical (in-vitro).
This provides robust assurance on clinical performance and the
extrapolation of indications.
• Difference in quality profile - reduced afucosylation, translating into a
lower binding affinity towards specific FcγRIIIa receptors→ lower
ADCC activity ? Resolved by extended testing and consideration of
mechanism of action.
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Thank you
Peter Richardson
Head of Quality
Specialised Medicines Department
European Medicines Agency [email protected] http://www.ema.europa.eu