www.biopharminternational.com October 2021 eBook BioPharm International 15
vide comprehensive guidance for man-
ufacturers, sponsors, and marketing
authorization holders to clarif y the
requirements and guide product devel-
opment," she states.
Biosimi la r products t hat seek a
marketing authorization in the EU
must follow the centralized procedure
for regulatory approval, where there
is a single application, evaluation, and
author ization throughout the EU,
says Lancaster. However, the regu-
latory framework applied to generic
medicines was deemed to be unsuit-
able for biosimilars, he adds. "In con-
trast to small-molecule generic drugs,
biosimi la rs a re more diff icu lt and
expensive to manufacture because of
the complexity and sensitivity of the
manufact uring processes involved.
A dd it ion a l l y, t he p a r t ic u l a r c e l l
line from which the reference prod-
uct is derived may not be available
to a biosimilar manufacturer," says
Lancaster. " Inev itably, biosimi la rs
will not be identical to the reference
medicinal product."
As a result, there was a revision to
the regulatory framework, acknowl-
edging that the existing regime was
not suitable for biologica l medici-
nal products (5), Lancaster explains.
"Consequently, in addition to using
pharmaceutical, chemical, and biolog-
ical data to demonstrate biosimilar-
ity, bioequivalence and bioavailability
data was also required," he says. "In
addition, the type and amount of addi-
tional data required would be deter-
mined on a case-by-case basis, taking
into account the specific characteristics
of each individual medicinal product."
However, it soon became clear that
the well-established use pathway was
not appropriate for biosimilar medi-
cines Lancaster notes. "Ultimately, this
led to further revisions of the frame-
work which introduced a specific reg-
ulatory pathway for the approval of
biosimilars" (6).
"EMA's scientif ic framework [for
biosi m i l a r s] is reg u l a rly up d ate d
a nd mon itor e d to r ef le c t ne c e s-
s a r y c h a n g e s ," c o n f i r m s M a r i e
Manley, par tner, head of UK Life
Sciences Practice at Sidley Austin.
"Importantly, however, no relevant
adverse differences have been iden-
tif ied by the EU monitoring system
bet ween biosimi la rs and reference
m e d i c i n e s . O v e r a l l , t h e E M A's
ef for ts a im to foster a reg u lator y
env ironment where biosimilars are
as safe and effective as their reference
medicines. This [environment] neces-
sitates comprehensive comparability
studies with reference medicines to
ensure that there are no divergences
in safety, efficacy, or quality."
Cu r rent g u idel ines for biosimi-
lars in the EU were made under the
2001 Directive and came into effect
i n 2 015 (7 ), a s issued by E M A's
Committee for Medicinal Products
for Human Use (CH MP), Manley
note s. " T he g u idel i ne s prov ide a
framework for companies produc-
ing biosimilars based on reference
med icines that have been g ranted
Eu ropea n E conom ic A rea (EE A)
m a r k e t i n g a ut h o r i z a t ion , w h i l s t
further, more detailed information
is available from EEA Reg u lator y
Authorities," she says. "Specific guid-
ance exists for quality issues as well
as clinical and non-clinical issues for
biosimilars whose active substances
are biotechnology-derived proteins."
"As an example of the evolution of
EMA's guidance on biosimilars, new
regulatory documents were released
in 2015, including the 'Guideline on
similar biologica l medicina l prod-
ucts containing biotechnolog y-de-
rived proteins as active substance:
non-clinical and clinical issues'," adds
Francesco Lanucara, senior consul-
tant, PharmaLex. "The new guidance
allows for clinical trials to be con-
ducted with reference products autho-
rized outside the EU, thus removing
the requirement to repeat these trials
within the EU, with an EU-approved
reference produc t , re su lt i ng i n a
st rea m l ined pat h to approva l and
reduced costs for the applicant."
Another development in EU bio-
s i m i l a r r e g u l a t i o n i n v o l v e s t h e
replacement of non-clinical in-vivo
testing with in-vitro assays, ref lect-
ing the changes in animal protection
legislation (8), Manley emphasizes.
"Fur thermore, ana ly tica l advances
have led to developments in analyt-
ica l cha racter izat ion, compa rat ive
pha r macok inet ic mon itor ing, a nd
post-marketing review," she explains.
"Past challenges to biosimilar devel-
opment have occurred at the stage of
establishing product comparabilit y,
which has hindered a number of man-
ufacturers due to the identification of
quantitative or qualitative differences."
Add it iona l ly, t here ha s been a
re-evaluation of the use of biomark-
ers in clinical studies and the amount
of immunogenicit y data requ ired,
particularly for products with com-
plex mechanisms of action, Lanucara
continues. " The EM A 'Ref lection
paper on statistical methodology for
the comparative assessment of quality
attributes in drug development' was
drafted in 2017 and published in 2021
(9), offering to both applicants and
regulatory experts a tool to carefully
examine the biosimilarity data at the
quality level, and have an appropriate
control on the risk of false positive
similarity," he says.
UK VERSUS EU:
POST-BREXIT APPROACHES
Since the United Kingdom's depar-
t u r e f rom t he Eu rop e a n Un ion ,
which was finalized in January 2021,
the Medicines and Healthcare prod-
ucts Regulatory Agency (MHRA)—
the UK's reg ulator y body—has set
out its ow n g uidance for biosimi-
lar licensing (10). " In the MHR A
Guidance, the requirements for cer-
tain clinical tests, previously required
by EMA, have been relaxed slightly,"
e x pl a i n s L a nc a s te r. " I n p a r t ic u-
lar, MHR A in most cases no lon-
Regulatory Sourcebook Biosimilars
