PMDA February 2009

Peter Richardson, EMEA

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 Biosimilars

Implementation

Guidelines
å
Experience

Future Developments
 Overview of presentation

z Rationale / Introduction

z EMEA Guidelines

z Vision

z Experience

z Conclusion
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 The EU Road to Biosimilars

z Review of Pharmaceutical Legislation *

» Opportunity to assess EU needs
z Novel approach – “Abridged biologicals”
» Recognising variability in biological products.
z Scientific principles : Comparability
» Experience of innovators making changes
z Comparability applied to biosimilars
» Reduce non-clinical & clinical data
* Regulation EC/726/2004 + amended Directive 2001/83EC 4
 Rationale - biosimilar evolution

z Development of comparability concept

» History of changes to various products

z New Pharmaceutical Legislation

» (Directive 2001/83/EC, as amended: Article 10.4)

z “additional data, in particular, the

toxicological and clinical profile shall be
provided.”

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 Rationale for Guidelines
z Guidelines need to address:

» Types of Product / Classes Applicable

» Quality / Safety / Efficacy / Pharmacovigilance
» Sufficient detail with flexibility
(Balance of “case-by-case” v recipe)

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 Biosimilars evolve from generics
z Regulatory perspective - What is a biosimilar ?

» Previous Generic Definition - NOT sufficient

» * “The provisions of Article 10(1)(a)(iii) [i.e. for generic

medicinal products] may not be sufficient in the case of
biological medicinal products. If the information required
in the case of essentially similar products (generics)
does not permit the demonstration of the similar nature
of two biological medicinal products, additional data, in
particular, the toxicological and clinical profile shall be
provided.”
* Section 4, Part II, Annex 1 (Dir. 2001/83/EC)
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 Biosimilars are not generics
z Regulatory perspective – “Biogeneric” ??
» Is a generic biological possible?
» In THEORY – YES
» In PRACTICE – may be possible where
molecule is fully characterised (depends on
complexity).
» RESULT – SBMP (Similar Biological
Medicinal Product). Informally: “biosimilar”

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 Biosimilar Legislation

z New legislation* defined legal base for SBMP:

» Where there are differences (particularly) in raw

materials or manufacturing processes of biosimilar
and reference product, then results of appropriate
pre-clinical tests or clinical trials relating to these
conditions must be provided.

* Article 10(4) of Directive 2001/83/EC, as amended

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Dossier requirements for biosimilars

Module 1 - Normal Requirements

Module 2 - Normal Requirements

Integrated CE
(Comparability Exercise)

Quality, Module 3 - FULL + CE

Non-clinical, Module 4 - Reduced + CE

Clinical, Module 5 - Reduced + CE

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Dossier requirements for biosimilars

CTD Module Originator Biosimilar

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Cross
reference

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Cross
reference
Cross reference – class specific Comparability exercise – product specific
Safety and Efficacy Quality, Safety and Efficacy

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 Overview of Centralised Procedure
- Biosimilar Timetable (Full MAA)

D.1 D.120 D.121 D.210 D.276

Opinion
Primary Clock Secondary Post
Pre-submission Stop
Evaluation Evaluation Authorisation
Decision

LoQ Answers
Response
Scientific Rap/Co-Rap Assessment -Ph.Vigilance
Advice Day 80 -Variations
Assessment D. 180 -Extensions
Rap/Co-Rap Reports Hearing? -Renewal

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 EPAR - European Public Assessment Report
= CHMP AR after deletion of commercially confidential information

Patient All readers

friendly summary
available in all All authorised
22 languages
All readers
presentations

available in English Package Leaflet Patients

Summary of Product
Characteristics
Health professionals

Scientific assessment Labelling Pharmacists/patients

(CHMP report)
Authorisation: Scientific community
Scientific Basis Health professionals

Steps taken for the assessment Anyone interested

of the product
Steps taken after granting Anyone interested
the Marketing Authorisation

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EPARs – EMEA homepage

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 Overview of presentation

z Rationale / Introduction

z EMEA Guidelines

z Vision

z Experience

z Conclusion
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 Preparing the network

z Legislation refers to Guideline

» General principles ( “ overarching” )
z EMEA tasks
» Coordination by Secretariat / BMWP / BWP
z Consult with stakeholders
» Workshop – Paris 2005 / comments during drafting
z Asessor training
» EMEA, October 2007 (app. 50 assessors)
» Immunogenicity workshop 2007

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 Biosimilar Guidelines – Summary (2006)
User guide Overarching Guideline (CHMP/437/04).
“Guideline on Similar Biological Medicinal Products”
Defines key concepts / principles (information reference)

Quality
Quality Issues
(general)
Non-
clinical

(Non)-clinical Clinical
(general)

Insulin GCSF Somatropin Epoetin Others…

Class specific Non- Non- Non- Non- Non-

clinical clinical clinical clinical clinical

Clinical Clinical Clinical Clinical Clinical

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 Biosimilar – Guidelines
z Overarching guideline

z Quality guideline o
z (non)-clinical guideline on SBMP

z Product-class specific guidelines on SBMP -

(non)-clinical

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 Overarching Guideline
z Guideline on Similar Biological Medicinal Products.
CHMP/437/04 (CHMP Adopted).
z Main points:
» Outline concepts and basic principles
– Biological, Biotech. (rDNA), Immunological &
Blood / plasma derived products
» Considerations: analytical methods, processes,
clinical and regulatory experience.
» Choice of Reference Product
(EU Reference for comparability exercise)

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 Quality guideline
z Specific for rDNA derived proteins
z Main issues
» state-of-art analytical methods to
characterise both similar and reference
products
» Manufacturing process should be well
developed
» Avoid changes, i.e. additional Comparability
Exercises during development

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 (Non)-Clinical Guideline
z Guideline on general principles
» Clinical equivalence
» Safety studies
» Immunogenicity
» (Pharmacovigilance)

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 Biosimilar Guidelines – Summary (2009)
Overarching Guideline (CHMP/437/04).
Defines philosophy
“Guideline on Similar Biological Medicinal Products”
and principles

Biotechnology- derived proteins

Quality

General guidelines Non-

clinical
Under Development
Clinical

Under review
Insulin Somatropin filgrastim Epoetin IFN-α LMMH

Annex guidelines -
specific data Non- Non- Non- Non- Non- Non-
requirements clinical clinical clinical clinical clinical clinical

Clinical Clinical Clinical Clinical Clinical Clinical

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 BMWP + BWP
z Current Highlights
» Company briefing meetings
» Scientific advice / MAAs
» Guidance
–Finalise LMMH / interferon alfa
–Revise epoetin guideline
–Different expression systems
» Workshop on Monoclonals – 2009

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 Overview of presentation

z Rationale / Introduction

z EMEA Guidelines

z Vision

z Experience

z Conclusion
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 Current applicability - Biosimilars
z Biotechnology-derived: recombinant proteins
» Product complexity – major factor
» Data requirements not always the same
» Case-by-case approach partly applicable

z Applications to other biologicals

» Not ruled out
» Ability to characterise becomes critical

z Aims for future

» Extend to other biologicals – mAbs ?
» Reduce data requirements where possible
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 Spectrum of Complexity
Science

Chemicals Recombinant DNA Blood- Immunologicals Advanced

technology derived therapy

Legislation

Generic Biosimilar Full

(essentially similar) Dossier
* Future Developments ? 26
 Overview of presentation

z Rationale / Introduction

z EMEA Guidelines

z Vision

z Experience

z Conclusion
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 EU Experience - MAAs
15 MAA Procedures
Determined - January 2009
Somatropin (2)
11 Products
Filgrastim (4)
(9MAHs)
Epoetin (5)

Interferon-alfa (1) + 2 Positive opinions for

filgrastim
Insulin (3)
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 Reasons for MAA success

z Pay attention to quality requirements

» State of the art techniques
» Justify differences

z Request (and adhere to) Sci. Advice

» SA still helpful when guidance available

z Demonstrate comparability
» Well developed process
» Care with in-licensing
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 Scientific Advice

Biosimilar Scientific Advice

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Numberof applications

15
Follow up advice
First advice
10

0
2003 2004 2005 2006 2007 2008
Year
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 Overview of presentation

z Rationale / Introduction

z EMEA Guidelines

z Vision

z Experience

z Conclusion
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 Conclusions

z Promote early meetings with EMEA

» Legal / Regulatory

z Scientific Advice
» Comparability / Complexity / Study Design

z Continued growth in interest in biosimilars

» International : Health Canada, Japan, Others
» USA – legislative proposals
» WHO guidance under development
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