• Module 2: summaries of quality, non-clinical and
clinical data;
• Module 3: chemical, pharmaceutical and
biological information (quality);
• Module 4: non-clinical reports (safety);
• Module 5: clinical study reports (efficacy). 12
For biosimilars, the requirements for MA
applications are based on the demonstration of
the similar nature of the two biological products,
based on the comparability exercise. 2 The number
and extent of comparability studies that form the
comparability exercise is outlined in guidelines
issued by the EMA. 10 In the dossier of biosimilars,
comparability studies are required in modules 3, 4
and 5; in the case of generics, non-clinical studies
(module 4) are omitted and the demonstration of
bioequivalence replaces module 5. 1 Indeed,
generics, which are copies of medicinal products
based on active ingredients obtained via a synthetic
pathway, do not require pharmacodynamic
investigations if the pharmacokinetic parameters
can be used to demonstrate that the generic and
reference are essentially the same. By contrast,
because of the complexities of bioproduction,
even minor modifications to manufacturing
processes can yield substantial differences in
pharmacodynamic parameters, so pharmacokinetic
data alone are not sufficient for the demonstration
of biosimilarity.
Conclusions
Biosimilars are a reality of the pharmaceutical
market. EU regulatory policies, mainly established
by guidelines issued by the EMA and revised
periodically, can now draw upon more than a decade
of experience.
Biologics are complex drugs. As such, their
characteristics depend considerably on the
manufacturing process, and their complete
characterisation cannot be achieved by current
analytical methods. The complexity of biologic
medicinal products has clear repercussions
on the assessment of therapeutic equivalence
and, consequently, on interchangeability and
substitution. For this reason, when copies of
biological products are manufactured, they cannot
be considered as small molecule generics. The EMA
has led the way in the development of a regulatory
framework of biosimilars. The EMA has the
scientific competence and the broad view required
to assess the interchangeability of biotechnological
medicinal products. The EMA’s assessment of
interchangeability could then be used as a basis,
by local regulatory agencies, to allow automatic
substitution. The EMA, though, have chosen to leave
decisions on interchangeability of biosimilars to
national authorities. Therefore, it is of paramount
importance to define the pharmacist’s/clinician’s
role in the choice of switching between reference
and biosimilars, especially in hospitals. It is highly
recommended that both the pharmacist and the
prescribing physician decide whether to always
purchase the cheapest biosimilar or which
patients have to be treated with the reference
product, as a precautionary measure to assure
continuity of care.
Where national authorities decide to allow
automatic substitution without the prescriber’s
prior consent, the traceability of the administered
medicinal product should be mandatory, in order to
allow the prescribing physicians to monitor which
medicinal product is actually dispensed to their
patients as specified in good pharmacovigilance
practice guidance.
TABLE 1
Key EMA scientific guidelines on
biosimilars 2,10,11
Overarching biosimilar guidelines
• Similar biological medicinal products
• Similar biological medicinal products containing
biotechnology-derived proteins as active substance:
non-clinical and clinical issues
• Similar biological medicinal products containing
biotechnology-derived proteins as active substance:
quality issues
Product-specific biosimilar guidelines
• Biosimilar medicinal products containing
recombinant granulocyte-colony stimulating factor
(Annex to guideline on similar biological medicinal
products containing biotechnology-derived proteins
as active substance: non-clinical and clinical issues)
• Non-clinical and clinical development of similar
biological medicinal products containing low-
molecular-weight heparins
• Non-clinical and clinical development of similar
biological medicinal products containing recombinant
human insulin and insulin analogues
• Similar biological medicinal products containing
interferon beta
• Similar biological medicinal products containing
monoclonal antibodies: non-clinical and clinical issues
• Similar biological medicinal products containing
recombinant erythropoietins
• Similar biological medicinal products containing
recombinant follicle-stimulating hormone
• Similar medicinal products containing somatropin
(Annex to guideline on similar biological medicinal
products containing biotechnology-derived proteins
as active substance: non-clinical and clinical issues)
• Non-clinical and clinical development of similar
biological medicinal products containing recombinant
interferon alpha or pegylated recombinant interferon
alpha
References
1 Minghetti P et al. Biosimilars
and regulatory authorities.
Nephron Clin Pract 2011;117:
C1–C7.
2 European Medicines
Agency. Guideline on similar
biological medicinal products
(CHMP/437/04 Rev.1) www.
ema.europa.eu/docs/
en_GB/document_library/
Scientific_guideline/2014/10/
WC500176768.pdf (accessed
September 2018).
3 Rocco P et al. Copies of
nonbiological complex drugs:
generic, hybrid or biosimilar?
Drug Discov Today 2018;pii
:S1359-6446(18)30082–5.
4 Schellekens H, Moors E.
Clinical comparability and
European biosimilar regulations.
Nat Biotechnol 2010;28(1):28–31.
5 Schellekens H. Biosimilar
therapeutics – what do we
need to consider? NDT Plus
2009;(Suppl 1):i27–i36.
6 Ebbers HC et al.
Interchangeability,
immunogenicity and biosimilars.
Nat Biotechnol 2012;30(12):
1186–90.
7 Minghetti P, Rocco P,
Schellekens H. The constrained
prescription, interchangeability
and substitution of biosimilars.
Nat Biotechnol 2015;33(7):688–9.
8 Jørgensen KK et al; NOR-
SWITCH study group. Switching
from originator infliximab to
biosimilar CT-P13 compared
with maintained treatment
with originator infliximab
(NOR-SWITCH): a 52-week,
randomised, double-blind,
non-inferiority trial. Lancet
2017;389(10086):2304–16.
9 Rocco, P, Selletti S, Minghetti P.
Biosimilar switching and related
medical liability. J Forensic Leg
Med 2018;55:93–4.
10 European Medicines Agency.
Similar biological medicinal
products. Similar biological
medicinal products containing
biotechnology-derived proteins
as active substance: non-clinical
and clinical issues (EMEA/
CHMP/BMWP/42832/2005 Rev.
1) (2014). www.ema.europa.eu/
docs/en_GB/document_library/
Scientific_guideline/2015/01/
WC500180219.pdf (accessed
September 2018).
11 European Medicines
Agency. Guideline on similar
biological medicinal products
containing biotechnology-derived
proteins as active substance
– quality issues. (EMA/CHMP/
BWP/247713/2012). www.
ema.europa.eu/docs/en_GB/
document_library/Scientific_
guideline/2014/06/WC500167838.
pdf (accessed September 2018).
12 Minghetti P et al. The
regulatory framework of
biosimilars in the European
Union. Drug Discov Today
2012;17(1-2):63–70.
Other guidelines relevant for biosimilars
• Comparability of biotechnology-derived medicinal
products after a change in the manufacturing process
– non-clinical and clinical issues
• ICH Q5E Biotechnological/biological products
subject to changes in their manufacturing process:
comparability of biotechnological/biological products
• I mmunogenicity assessment of biotechnology-
derived therapeutic proteins
• Immunogenicity assessment of monoclonal
antibodies intended for in vivo clinical use
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