As a general rule, claims that a medicinal product is biosimilar effi ciently and to deliver results, a number of outstanding challenges
to a reference product must be substantiated by a direct and remain. Among these is the fact that economies of scale have not
extensive comparability exercise between the two products. The been as easily achieved as anticipated, as well as the continuing
same reference product must be used for all parts of the biosimilar caution exhibited by physicians, particularly as regards the suitability
dossier (quality, safety and effi cacy). Moreover, if the reference of substituting a biosimilar for its reference product.
product has more than one indication, the effi cacy and safety of
Two fundamental issues remain to be resolved: the questions of
the biosimilar must be justifi ed or, if necessary, demonstrated for
substitutability and of interchangeability, two terms which could
each of the claimed indications. In some cases the “therapeutic
be argued to represent the political and scientifi c sides of the same
similarity” shown for one indication may be extrapolated to other
biological coin.
indications. However, there is no general rule and the approval of
the extrapolation is product-specifi c and based on available scientifi c
Determination as to the substitutability of a biosimilar for its
and clinical experience.
reference biological medicinal product previously prescribed to
a patient is, in the view of the national authorities, a fi nancial
The type and amount of preclinical and clinical data required
question fi rmly within their prerogative.
to support authorisation of a biosimilar is not defi ned in
the Community Code. The assessment of an application for
However, the question as to whether two biologic products should
authorisation is made on a case-by-case basis and includes
share the same International Non-proprietary Name (INN), and
determination of precisely the type and amount of data required to
can, thereby, be considered to be scientifi cally interchangeable is
support such an application. The conditions and requirements are
also a matter of debate. The INN identifi es the compound within a
communicated through specifi c EMEA guidelines. Examples of the
family of compounds based on chemistry. It is used for prescribing,
Guideline published by the EMEA include the guidance on Similar
substitution of drugs, reporting of adverse effects, etc. Generics
Biological Medicinal Products, Recombinant Human Erythropoietin,
usually share the same INN as the reference product. Presently,
and Recombinant Human Growth Hormone.
biosimilars and the reference products also share the same INN.
The EMEA produces guidelines, both general and specifi c, on a
Given that, as underlined above, biosimilars are not generics and
variety of topics related to the authorisation of medicinal products
have differences compared with the reference biological product,
in the EU. In general, these guidelines do not have legally binding
there is a continuing debate as to the suitability of their sharing
effect on applicants for marketing authorisations. They are solely
an INN with their reference product and, thus, to be considered
indicative and applicants can, if they feel it appropriate, depart
interchangeable with it.
from these on condition that appropriate justifi cation is provided.
29
Opinions are divided. The innovative industry advocates for a special
However, in the case of biosimilars, compliance with the EMEA’s
INN system of nomenclature for biotechnology products refl ecting
guidelines is made compulsory by the provisions of Article 10 (4)
the inherent differences between products. The biosimilars industry
and Annex I to the Community Code.
and the European Commission oppose the idea, while the World
13 biosimilars, based on three active substances, have been
Health Organization (WHO) currently has no plans to address
approved since the governing provisions of the Community Code
the matter.
entered into force in October 2006. These include:
The issues of substitutability and interchangability continue to
• the recombinant human growth hormones Omnitrope overlap in the EU. On one hand, in some EU member states
(somatropin) and Valtropin (somatropin); authorities consider determination of the suitability of substituting
one biologic for another to be a matter of economics. Other EU
• the erythropoietins Binocrit (epoetin alfa), Epoetin Alfa Hexal
member states acknowledge an absence of data concerning health
(epoetin alfa), Abseamed (epoetin alfa), Silapo (epoetin zeta) and
risks that may be related to the substitution of biosimilars for their
Retacrit (epoetin zeta);
reference products. They have, consequently, adopted national
• the granulocyte-colony stimulating factors TevaGastrim
legislation either excluding substitution of innovative biologics by
(fi lgastrim), Ratiogastrim (fi lgastrim), Biograstim (fi lgastrim) and
biosimilars, as is the case in France and Italy, or placing restrictions
Filgastrim Hexal (fi lgastrim);
on such substitution, as is the case in the UK.
• Zarzio (fi lgrastim) and Filgastrim Hexal (fi lgrastim).
The European Biopharmaceutical Enterprises (EBE) has requested
Two applications for marketing authorisation were rejected and
that the European Commission and the EMEA issue guidance on the
three were withdrawn.
matter and clarify the concepts of “similarity”, “interchangeability”
and “substitution”. The EBE considers this to be crucial for industry
Outstanding issues
and the healthcare professionals. The Commission and the EMEA
It can be argued that biosimilars have not had the impact on the seem disinclined, however, to provide such guidance. They view the
EU market that biosimilar manufacturers had hoped and biologics issue as beyond the scope of EU legislation, considering decisions
manufacturers had feared. While the EU legal framework on concerning the question of the interchangeability of a biosimilar
biosimilars and its practical implementation appear to function and its reference product to lie with a patient’s treating physician.
Scrip World Pharmaceutical News Supplement August 2009
cphi.com | icsexpo.com | p-mec.com | bioph-online.com
wherepharmameets.com | scripnews.com
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