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Bird & Bird LLP
Engel & Novitt, LLP
Finnegan, Henderson, Farabow, Garrett & Dunner, LLP
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Biosimilars Europe
AIPLA Webinar-8 December, 2010
Liz Fuller,
Partner
[email protected]
Overview
● 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
Antibodies
● Summary
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Generics: Chemicals vs Biologics
● Chemical products are created by mixing together well-defined
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
• Omnitrop-Sandoz (reference Genotropin)
• Binocrit, Abseamed, Epoietin Alfa Hexal-Sandoz (reference
Eprex)
• Silapro-Stada (reference Eprex)
• Retacrit-Hospira (reference Eprex)
• Valtropin-BioPartners (reference Genotropin)
• Filgrastim-Sandoz/Hexal (reference Neupogen)
● EU rejections
Alpheon-interferon α-2a and interferon β-BioPartners
Insulin Human Marvel-Marvel LifeSciences-withdrawn
● US-Omnitrop-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-by-case basis
• In US, legal pathways created in Biologics Act in
March 2010-Guidances forthcoming
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Biopharmaceuticals: Biogenerics, Biosimilars and
Follow-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-on
biologic” are used by the FDA.
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Relevance of this lack of “identicality”
● Immunogenicity-significant danger to patients
● Very difficult to develop products from a different cell line-only
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.,
Eprex)
● 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 multidetermined (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
registration.
● 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 caseEprex 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)-mandatory that they obtain regulatory approval
at the EMEA (European Medicines Agency-London)
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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 2005-2007
● Various Product-specific CHMP Guidelines (G-CSF,
Somatropin, human soluble insulin, Erythropoietins, alpha
interferon and LMW heparins (draft))
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Amendment to Directive 2001/83
(2003/27/EC)
Article 10.4
“Where a biological medicinal product which is similar 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
guidelines. 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:
non-clinical and clinical issues (EMEA/CPMP/42832/05)
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Non-clinical development for biosimilar
mAbs
● Scientific Advice strongly recommended
● Risk-based approach to be evaluated on a case-by-case basis in
the choice and extent of in vitro and in vivo studies
● Determination as to whether in vivo studies are required will
depend on the availability of a relevant animal model-large
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-human
primate.
● If the conduct of the in vitro studies raises no specific safety
concerns, it is possible that no in vivo animal studies will be
required.
© Bird & Bird LLP 2010
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
used.
● Dose-concentration-response studies will always be required
● Specific considerations for extrapolation to additional oncological
indications.
● Focus of exercise is to demonstrate similar efficacy and safety relative
to the reference product, not to patient benefit, per se
© Bird & Bird LLP 2010
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
© Bird & Bird LLP 2010
Thank you
Liz Fuller
Partner
[email protected]
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