Fuller - Biosimilars Europe


5 Δεκ 2012 (πριν από 8 χρόνια και 8 μήνες)

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Biosimilars Europe

AIPLA Webinar
8 December, 2010

Liz Fuller,



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Chemicals vs. Biologics
bioequivalence and comparability

Authorisations to date

Biosimilars in Europe
Legal basis for authorisation

What's New
Draft Guidelines out for Biosimilars of Monoclonal


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Generics: Chemicals vs Biologics

Chemical products are created by mixing together well
chemicals under controlled circumstances. The resultant
product can be analysed in a laboratory to determine that it is
identical to that of an originator/innovator. Therefore easy to
compare to reference product for bioequivalence.

Biological products are alive (e.g., vaccines, mAbs, recombinant
proteins). They are created by engineering living cells to
produce the desired protein or antibody. As the living cells are
unique, the products so produced can never be absolutely
identical to that of an originator/innovator.

“Biological medicinal products can be defined therefore largely
by reference to their method of manufacture.”

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Biosimilars to date

EU approvals

Sandoz (reference Genotropin)

Binocrit, Abseamed, Epoietin Alfa Hexal
Sandoz (reference

Stada (reference Eprex)

Hospira (reference Eprex)

BioPartners (reference Genotropin)

Sandoz/Hexal (reference Neupogen)

EU rejections

2a and interferon

Insulin Human Marvel
Marvel LifeSciences

Sandoz (reference Genotropin)

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So why are Biosimilars important?

Biosimilars have strongest growth in the pharma sector, and are
not priced as are other “generics”

They are an extremely expensive category of products used to
treat very serious indications

Many other products under development by: BioPartners,
Merck BioVentures, Sandoz, Bioceuticals, Biogenerix, Ambrx, et
al. Other major pharma companies have indicated they will
enter this market.

Regulatory environment and legal status in flux

in EU, on a case
case basis

In US, legal pathways created in Biologics Act in
March 2010
Guidances forthcoming

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Biopharmaceuticals: Biogenerics, Biosimilars and
on Biologics

Biological pharmaceuticals manufactured by biotechnology
methods, i.e., involving the use of living organisms (cells,
bacteria, yeast)

Biopharmaceuticals are defined by their manufacturing
processes. If they originate in different cell lines, they are
distinct, i.e.,
not bioequivalent
. As such, there is
technically no such thing

as a biogeneric, though the
term is often used.

It is however, possible to demonstrate comparability to the
originator’s product, the term “biosimilar” is used in
Europe, while the terms biosimilar and “follow
biologic” are used by the FDA.

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Relevance of this lack of “identicality”

significant danger to patients

Very difficult to develop products from a different cell line
very large sophisticated companies can manufacture and
support biotech development.

Very minor changes in the manufacturing process can result in
profound differences in safety and efficacy of the product (e.g.,

Extensive post
marketing surveillance is required, and effects
“substitutability” by physicians and pharmacists (US), problem
with INN

Perhaps particularly relevant in case of mAbs
due to multi
determined (and sometimes poorly understood) efficacy

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Eprex and PRCA

J & J (Ortho Biotech/Janssen
Cilag) altered its manufacturing process
(and presentation) of erythropoietin marketed in the EU, Eprex.

On the market for 10 years, and in 2002, PRCA (pure red cell aplasia)
was identified in patients with CRF and/or CRI that had received
Eprex SC. MA in that indication suspended in EU for nearly 4 years.

There were over 65 variations in the EU to the original Eprex

Significance is that problems of the RMP effect profoundly effect
subsequent developments and regulatory strategies (specific exception
made for Binocrit from the EPO development guideline in this case
Eprex was not used as a comparator in SC studies in renal anaemia
patients and therefore no second randomised, parallel group clinical
trial could be conducted).

Regulatory Authorities far more strict on safety issues and also in
imposing post
marketing obligations.

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Pharmaceutical Regulation in Europe

Most chemical products
National Regulatory Authorities
either individually or through DCP or MRP

Biotech products

(e.g., recombinants, mAbs, transgenic
products), orphan medicinal products and products for the
treatment of certain types of disease (e.g., autoimmune, cancer
and diabetes)

that they obtain regulatory approval
at the EMEA (European Medicines Agency

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Biosimilar MA Route
EU Legal Basis

Amendments to Annex I of Directive 2001/83 (2003/63/EC)

CPMP Guidance Notes (2003)

Amendments to text of Directive 2001/83 (2004/27/EC)

Various CHMP Guidelines in 2005

Various Product
specific CHMP Guidelines (G
Somatropin, human soluble insulin, Erythropoietins, alpha
interferon and LMW heparins (draft))

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Amendment to Directive 2001/83

Article 10.4

“Where a biological medicinal product which is

to a
reference biological product does not meet the conditions in the
definition of generic medicinal products, owing to, in particular,
differences relating to raw materials or differences in
manufacturing processes of the biological medicinal product
and the reference biological medicinal product,
the results of
appropriate pre
clinical tests or clinical trials relating to these
conditions must be provided

The type and quantity of
supplementary data to be provided must comply with the
relevant criteria stated in Annex I and the related detailed
The results of other tests and trials from the
reference medicinal product’s dossier shall not be provided

In force as from 30 October 2005.

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Draft Guideline on biosimilar medicines
containing monoclonal antibodies

Released for Consultation 26 November 2010 until 31 May 2010

Addresses Non
clinical, Clinical and Post
marketing issues
(both PV and post
marketing clinical requirements)

Quality issues are not addressed
rather the reader is referred to
existing Guidances EC/CHMP/49348/05 (which is soon to be
revised) and CHMP/BWP/15753/07

To be read in conjunction with the general guidelines set forth in
the "Guideline on similar biological medicinal products
containing biotechnology

derived proteins as active substance:
clinical and clinical issues (EMEA/CPMP/42832/05)

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clinical development for biosimilar

Scientific Advice strongly recommended

based approach to be evaluated on a case
case basis in
the choice and extent of
in vitro

in vivo


Determination as to whether
in vivo
studies are required will
depend on the availability of a relevant animal model
comparative tox studies in non
human primates are not
recommended, though, due to the specificity of mAbs, the
relevant species for tox studies is in most cases a a non

If the conduct of the
in vitro
studies raises no specific safety
concerns, it is possible that no
in vivo

animal studies will be

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Clinical development of biosimilar mAbs

Again, close collaboration with EMEA through scientific advice is
strongly recommended.

A comparative PK study in a sufficiently sensitive and homogeneous
population forms an integral part of biosimilar mAb development,
usually in a parallel
group design due to the long half
life of mAbs and
potential interference of immunogenicity.

PK data can be used to extrapolate data on both safety and efficacy to
other indications
generally most sensitive to immunogenicity must be

response studies will always be required

Specific considerations for extrapolation to additional oncological

Focus of exercise is to demonstrate similar efficacy and safety relative
to the reference product, not to patient benefit,
per se

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Biologic patents to expire
according to BIO

Humira (Abbot) 2016

Neulasta (Amgen) 2015

Aranesp (Amgen) 2014

Enbrel (Amgen) 2012

Myozyme (Genzyme) 2016

Fabrazyme (Genzyme) 2015

Herceptin (Roche) 2018

Avastin (Roche) 2018

Rituxan (Roche) 2018

Lucentis (Roche) 2018

Erbitux (Eli Lilly) 2017

Remicade (J & J) 2014

Synagis (AZ) 2018

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Questions and answers

Thank you

Liz Fuller



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