DEVELOPMENT
Concepts and principles:
Development in depth
In this article, key concepts and principles in the evaluation and approval of biosimilars are explained
Olga Delgado Sanchez
PharmD
Head of Pharmacy
Department, Coordinator
of Pharmacy, Health
Products and Medicines
Policy, University Hospital
Son Espases, Palma de
Mallorca, Spain
The European Medicines Agency (EMA) defines
a biosimilar as a biologic medicine that is
similar to an original medicine that has already been
authorised for use in terms of quality characteristics,
biological activity, safety, and efficacy. 1,2
Core concepts in the development of biosimilars
include:
• Extrapolation
• Comparability
• Immunogenicity
• Interchangeability/risk assessment
• Timelines.
Extrapolation
Extrapolation is a key issue of biosimilar
development and relates to extending the findings
from one set of conditions to another, such as
extending and applying the safety and efficacy data
from clinical studies regarding one indication
(medical condition) to another indication, or
extending data from clinical studies in one
population (for example, adults) to another (for
example, children). Extrapolation concerns four
different aspects – efficacy, safety, immunogenicity
and interchangeability – and might relate to the
indication, population or both.
Much debate has centred on which data are
required to grant an approval for the extrapolated
indications of the reference product. 1,3 In clinical
testing, regulators want to confirm the similarity
of the molecules in disease indications; they do not
TABLE 1
Rationale for indication
extrapolation
• Extrapolation is possible based on the overall
evidence of comparability provided from the
comparability exercise and with adequate justification
• If pivotal evidence for comparability is based on
pharmacodynamics and different mechanisms
of action (or uncertainty exists) for the claimed
indications, then applicants should provide relevant
data to support extrapolation to all claimed clinical
indications
• Extrapolations should be supported with a
comprehensive discussion of available literature
including the involved antigen receptor(s) and
mechanism(s) of action
want to reassess the clinical benefit of the drug per
se. European guidance states that, if adequately
justified, biosimilars can receive all authorised
indications of the reference product, even though
comparative clinical data are only provided for
a subset of those authorised indications. 3–6
Extrapolation is possible based on the overall
evidence of comparability provided from the
comparability exercise and with adequate
justification. If pivotal evidence for comparability
is based on pharmacodynamics, and different
mechanisms of action are relevant (or uncertainty
exists) for the claimed indications, then relevant
data to support extrapolation for all the clinical
indications claimed are required. Applications
for extrapolations should also be supported by
comprehensive discussion of the available literature,
including the involved antigen receptor(s) and
mechanism(s) of action.
The scientific justification of extrapolation
should address:
• mechanism of action
• biodistribution
• immunogenicity
• expected toxicities in each patient population.
Additionally, any other factor that might affect
the safety, efficacy, or immunogenicity of the
product in each (approved or claimed) indication
should be addressed. Supporting clinical data
in a sensitive and representative population
are therefore critical to justify extrapolation to
other indications. This is a crucial consideration,
because if clinical trials were to be conducted
in each indication, the breadth of biosimilar
development programmes would effectively negate
the advantages of an abbreviated approval pathway
based on developing a product that is highly
similar to a reference product with an established
risk–benefit profile. 7 Table 1 shows rationale
for extrapolation as indicated by the European
Medicines Agency (EMA).
Understanding the manufacturing process
To better understand the reasoning behind the
approval process allowing for the extrapolation of
indications, the biosimilar manufacturing process
must be fully understood (for further details refer to
to the article on manufacturing in this handbook).
Biosimilars are systematically engineered to
match the reference product in both structure and
function. Process optimisation toward similarity and
precise control during manufacturing to maintain
similarity are important to ensure the quality of
biosimilars, as is employing suitable test systems,
especially those yielding the best results for
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