LEGISLATION/REGULATORY
EU regulatory framework
for biosimilars
The regulatory policy for biosimilars is outlined mainly in general and product class-specific
guidelines issued by the European Medicines Agency, addressing quality, non-clinical and
clinical issues
Paolo Rocco PhD
Silvia Franzè PhD
Francesca Selmin PhD
Department of
Pharmaceutical Sciences,
Università degli Studi di
Milano, Italy
When patent and data protection of
a medicinal product have expired, new
manufacturers might choose to market a copy of the
product. Because the copy of a biologic medicinal
product can only be demonstrated to be similar, but
not identical, to the one previously authorised, it is
defined as a biosimilar. 1
Marketing authorisations and biosimilars
The requirements for the marketing authorisation
(MA) of a biosimilar medicinal product include
the demonstration of the similar nature to the
reference product in terms of quality, efficacy and
safety (biosimilarity). Biosimilarity is demonstrated
through an in-depth comparison of physical,
chemical and in vitro biological characteristics,
and comparative non-clinical and clinical studies,
which together comprise the comparability
exercise. 2
As for any complex drug, the physicochemical
characteristics of a biologic are influenced greatly
by the manufacturing process, and they cannot
be exactly duplicated when producing a copy, or
necessarily even maintained when a change in
manufacturing occurs. 1 Even without changes in the
manufacturing process, batch-to-batch variability is
to be expected and should be monitored. Moreover,
biologics cannot be completely characterised using
available analytical methods, and bioequivalence is
not enough to guarantee therapeutic equivalence
because the pharmacodynamics can be different. 3
The conclusions of a comparability exercise are valid
for a given time only; thus, it would be preferable
to demonstrate the similarity over the whole
product lifecycle with regard to the effects on the
biosimilar’s characteristics, such as therapeutic
equivalence. For this reason, the assessment of
therapeutic equivalence should not end with the
MA, but should be managed for the entire lifecycle
of the product. 4-6
The assessment of therapeutic equivalence
influences the way a medicinal product is managed,
namely the policies on interchangeability and
substitution, and the possibility of pharmacist
and clinician intervention at the dispensing level.
Moreover, a substitution programme can be
introduced by the public administration on the basis
of interchangeability.
Regulatory issues
Interchangeability is a scientific concept directly
related to intrinsic drug characteristics, and it
follows from therapeutic equivalence. Due to its
complexity, the assessment of interchangeability
requires the scientific knowledge that only
regulatory agencies possess at an institutional level.
Unlike generics, which are interchangeable by
definition, biosimilars are not interchangeable per
se. The policy of the European Medicines Agency
(EMA) comprises a mandatory comparability exercise
to grant a MA for biosimilars, but the regulatory
guidelines do not include recommendations
on interchangeability because all decisions are
regulated at the national level.
The term ‘substitution’ could be used to indicate
the prescription of a biosimilar to naive patients,
or the switch, made by the prescribing physician,
between two medicinal products. Because in
these cases the prescriber’s choice is not limited
to interchangeable products, this term is better
avoided, and only used with the meaning of
‘automatic substitution’ at the dispensing level.
The term ‘substitution’ should be avoided even
when, due to the payer’s policies, physicians
might be forced to prescribe a biosimilar instead
of the reference product; the term ‘constrained
prescription’ could be used instead. 7
In the EU, the policy of automatic substitution
is left to local authorities, which can introduce it
based on a demonstration of interchangeability,
even though many countries do not allow automatic
substitution at the dispensing level. 7 Even in
countries where it might be allowed, automatic
substitution at the dispensing level makes traceability
more difficult to deal with, as it can imply the loss
of essential information for this class of medicines
and might compromise traceability during the
product’s lifecycle and its identification in the
pharmacovigilance report. While this is accepted in
the case of small molecule generics, it might raise
concerns when extended to biologics.
The publication of the results from NOR-SWITCH,
a randomised, non-inferiority, double-blinded,
Phase IV trial addressing the issue of switching from
the reference infliximab to a biosimilar in stable
patients, has shed some light on a highly debated
topic. The conclusions of the study can be seen as
reassuring for prescribing physicians, at least in the
case of infliximab. 8
From a product liability perspective, ‘failure
to warn’ or ‘design defect’ liabilities cannot be
considered ascribable to the generic MA holder.
Indeed, the generic must have the same labelling
as the originator. Redesign or label modification,
intended to improve the risk–benefit ratio, are not
possible for generics, because the generic drug
is required to have the same active ingredients,
route of administration, dosage form, strength,
and labelling as the reference (21 U.S.C. 355(j)).
As a consequence, the extent to which a generic
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