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Biosimilars in the EU –
Regulatory update with focus on CMC
Niklas Ekman, Ph.D., Senior ResearcherFinnish Medicine Agency (FIMEA), Helsinki, Finland
CMC Strategy Forum Japan 2015
Tokyo Marriott Hotel, Tokyo, Japan
November 9-10, 2015
Disclaimer: The views expressed are my personal views and should not be
understood or quoted as being made on behalf of or reflecting the position of the
Finnish Medicines Agency, the European Medicines Agency or one of its
committees or working parties.
Lääkealan turvallisuus- ja kehittämiskeskus
What is a biosimilar?
Current EU regulatory definition of biosimilars
A biosimilar is a biological medicinal product that contains a
version of the active substance of an already authorised
original biological medicinal product (reference medicinal
product).
A biosimilar demonstrates similarity to the reference medicinal
product in terms of quality characteristics, biological activity,
safety and efficacy based on a comprehensive comparability
exercise
The scientific principles of a biosimilar comparability exercise are
based on those applied for evaluation of the impact on changes in
the manufacturing process of a biological medicinal product (as
outlined in ICH Q5E)
Nov 9, 2015 CMC JPN 2015; niklas.ekman@fimea.fi 2
Lääkealan turvallisuus- ja kehittämiskeskus
Available guidance in the EU
Nov 9, 2015 CMC JPN 2015; niklas.ekman@fimea.fi 3
Overarching Guideline CHMP/473/04 Rev. 1“Guideline on Similar Biological Medicinal Products”
Quality EMA/CHMP/BWP/247713/2012
Adopted 2005, revised 2014
Adopted 2006, revised 2014
Nonclinical and Clinical EMEA/CHMP/BMWP/42832/2005 Rev. 1
Adopted 2006, revised 2015
UNDER REVISION
G-CSF (2006, CP 2015)
LMWH (2009, dGL 2013)
Immunogenicity
assessment of biotech
proteins (2008, CP 2014)
ADOPTED
Somatropin (2006)
Epoetin (2006, revised 2010)
IFNα (2009)
Monoclonal Abs (2012)
rFSH (2013)
IFNβ (2013)
Insulin (2006, revised 2015)
Definitions and main principles
Generalguidelines
Class/ product specificguidance
Lääkealan turvallisuus- ja kehittämiskeskus
• 29 Marketing Authorisation (MA) applications for biosimilars
reviewed by the CHMP
• 21 positive (2 withdrawn by the MA holders post-approval), 7
withdrawn during evaluation, 1 negative
• 19 biosimilar medicinal products currently holding a valid
marketing authoriation
• 1 somatropin (authorised in 2006), 5 epoetin (first authorised in
2007), 8 filgrastim (2008), 2 infliximab (2013), 2 follitropin alfa
(2013), 1 insulin glargine (2014)
• 4 biosimilar MA applications currently under review (Sep 2015)
• Enoxaparin sodium, etanercept, infliximab, insulin human
Biosimilar product experience in EU
Nov 9, 2015 CMC JPN 2015; niklas.ekman@fimea.fi 4
Lääkealan turvallisuus- ja kehittämiskeskus Nov 9, 2015 CMC JPN 2015; niklas.ekman@fimea.fi 5
EMA biosimilar scientific advices 2004-2014
0
5
10
15
20
25
30
35
40
2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014
First advice Follow-up advice
Nu
mb
er
of
advi
ces
69% 65% 63% 55% 76%% mAb/ mAb-like proteins:
2010 2011 2012 2013 2014 H1/2015
~70%
Lääkealan turvallisuus- ja kehittämiskeskus
General principles for biosimilar development
• In principle, the concept of a biosimilar is applicable to any
biological medicinal product
• The success of developing a biosimilar depends on;
• The ability to manufacture a close copy of the reference
medicinal product in a consistent manner
• The ability to perform thorough physicochemical and
biological characterization and to understand the clinical
relevance of any differences detected
• The ability to demonstrate bioequivalence
• The availability of suitable clinical models; sensitive endpoints,
possibility to identify relevant comparability margins
Nov 9, 2015 CMC JPN 2015; niklas.ekman@fimea.fi 6
Lääkealan turvallisuus- ja kehittämiskeskus
• Similar physicochemical and biological properties is the basis
for successful biosimilar development
• Composition, physical properties, primary and higher order
structures, purity, product-related isoforms and impurities, and
biological activity
• Note, no ”scaling” of similarity in EU legislation and
guidelines → “similar”, ”highly similar” and ”highly similar with
finger-print like similarity” = ”similar”
• It may be challenging to claim biosimilarity if relevant quality
differences are confirmed for which absence of an impact on
safety or efficacy will be difficult to justify
• Clinical data cannot be used to justify substantial
differences in quality attributes
Nov 9, 2015 CMC JPN 2015; niklas.ekman@fimea.fi 7
General principles for biosimilar development
Lääkealan turvallisuus- ja kehittämiskeskus
• The development and documentation for biosimilars should
cover two distinct aspects
• Performance and consistency of the manufacturing process of the
biosimilar on its own
• Quality attributes of the target product profile should be comparable
to the reference
• Quality Target Product Profile (QTPP)
• Based on data collected on the chosen reference medicinal product,
including publicly available information and data obtained from
extensive characterisation of the reference medicinal product
• Form the basis for the development of the biosimilar product and its
manufacturing process
• The manufacturing system needs to be properly designed to
achieve the QTPP (e.g. with regard to the expression system)
Nov 9, 2015 CMC JPN 2015; niklas.ekman@fimea.fi 8
Manufacturing process development
Lääkealan turvallisuus- ja kehittämiskeskus 9
• An extensive, side-by-side comparability
exercise is required.
• Analytical methods should be appropriately qualified and applied with sufficient sensitivity to detect relevant differences
• Orthogonal methods should be used whenever possible
• Quantitative comparability ranges should be established
• Ranges should be based primarily on the measured quality attribute ranges of reference product and should not be wider than the range of variability of the representative reference product batches
CMC JPN 2015; niklas.ekman@fimea.fi
The analytical similarity exercise
Nov 9, 2015
Pic
ture
modifie
d fro
m N
at B
iote
chnol. 2
008 S
ep;2
6(9
):985
-90.
Lääkealan turvallisuus- ja kehittämiskeskus
• Currently, the CHMP does not recommend any specific
statistical method for assessment of biosimilarity• EMA/CHMP/BWP/247713/201 “A descriptive statistical approach to
establish ranges for quality attributes could be used”
• Proposals for statistical analysis are welcomed but should be
justified in the dossier • QA criticality ranking (link to the overall statistical approach), assay
considerations, level of the QA in the product etc.
• Appropriateness and limitations of the statistical analysis
• Various factors can influence the outcome of statistical tests• Sample size (unit of observation), origin (sampling strategy, sources
of variability) and distribution (normality)• Risk of false positive conclusion• Acceptance/ equivalence ranges chosen
Nov 9, 2015 CMC JPN 2015; niklas.ekman@fimea.fi 10
The use of statistics in the analytical
similarity exercise
Lääkealan turvallisuus- ja kehittämiskeskus
• Similarity ranges established based on statistical intervals can
lead to wide ranges with little (or no) clinical relevance
• Depending on the chosen statistical tool (e.g. TI, PI, SD) and the
data set available, the use of statistical intervals may result in an
inability to detect relevant difference
• If inferential statistics is used, testing for equivalence (two-sided)
should generally be applied
• One-sided test could be acceptable for certain QAs (e.g. impurities)
• The final conclusion on analytical biosimilarity can not be drawn
only based on statistical analyses
• Raw data should always be provided in a suitable format
• A statistically insignificant difference could in principle be clinically
significant!
Nov 9, 2015 CMC JPN 2015; niklas.ekman@fimea.fi 11
The use of statistics in the analytical
similarity exercise
Lääkealan turvallisuus- ja kehittämiskeskus
Experience from addressing the impact of
glycosylation differences observed for a
biosimilar monoclonal antibody
Marketing Authorisation Application for
Remsima/ Inflectra1
1 European public assessment report (EPAR) available at www.ema.europa.eu
Nov 9, 2015 CMC JPN 2015; niklas.ekman@fimea.fi 12
Lääkealan turvallisuus- ja kehittämiskeskus
• Recombinant mAbs contain a large amount of different glycan
types
• As some of the glycan structures may affect activity, clearance
and/or immunogenicity, detailed comparison of glycan
structures is usually necessary
• N-linked glycan analysis; site, structure and occupancy
• Carbohydrate content; neutral and amino sugars
• Sialic acid content (NANA and NGNA)
• Antennary profile, high-mannose variants
• Binding to Fc receptors (FcRn, FcγRI, FcγRII, FcγRIII)
and complement (C1q)
• Fc associated functional studies; ADCC and CDC
• Especially if the MoA is known to involve Fc functions
Nov 9, 2015 CMC JPN 2015; niklas.ekman@fimea.fi 13
Glycosylation and effector function analyses
Lääkealan turvallisuus- ja kehittämiskeskus
• High similarity between the biosimilar and the reference
demonstrated for
• Primary, secondary and tertiary structures
• In vitro TNFa neutralisation, binding affinity (soluble and transmembrane TNFa, TNFb, FcγRIa, FcγRIIa, FcRn, C1q), in vitro functional tests (apoptosis, CDC, ADCC using PBMNC effector cells from healthy volunteers)
• Minor differences reported for• C-terminal lysine content, aggregates, intact IgG level, charged
molecular variants, glycosylation pattern
• Binding to FcγRIIIa
• Ex vivo binding to NK cells of healthy donors or CD patients (genotype dependent, only seen for V/V and V/F genotypes). No difference in the presence of diluted CD patient serum (to mimic the in vivo environment)
Nov 9, 2015 CMC JPN 2015; niklas.ekman@fimea.fi 14
Remsima/ Inflectra; Qaulity aspects
Lääkealan turvallisuus- ja kehittämiskeskus Nov 9, 2015 CMC JPN 2015; niklas.ekman@fimea.fi 15
Potential mechanisms of action for anti-TNFs
Modified from Thalayasingam N. et al., Best Pract Res Clin Rheumatol. 2011 Aug;25(4):549-67
Neutralisation
of soluble
TNFa
Primary MoA Additional potential MoAs, especially in
inflammatory bowel diseases (IBD)
Lääkealan turvallisuus- ja kehittämiskeskus
• Remsima was shown to contain a lower level of afucosylated
glycans than Remicade, resulting in a lower binding affinity to
FcγRIIIa and FcγRIIIb
• Directive 2001/83, part II, Annex 1
In case the originally authorised medicinal product has more than
one indication, the efficacy and safety of the medicinal product
claimed to be similar has to be justified or, if necessary,
demonstrated separately for each of the claimed indications
As Fc-mediated functions could potentially be involved in the mode of action of infliximab, the Company was asked to provide further experimental data, in combination with an overall discussion, confirming that the differences detected do not affect efficacy or safety in any of the applied indications
Nov 9, 2015 CMC JPN 2015; niklas.ekman@fimea.fi 16
Can efficacy and safety data be extrapolated to all
Remsima/Inflectra indications applied for?
Lääkealan turvallisuus- ja kehittämiskeskus
• No difference in reverse
signaling through tmhTNFa
• Inhibition of apoptosis
• Blockade of pro-inflammatory
cytokine production
• No difference in blocking
soluble hTNFa in an in vitro
IBD model
• Suppression of pro-
inflammatory cytokine (IL-6
and IL-8) secretion from co-
stimulated epithelial cell line
• Suppression of epithelial cell
line apoptosis
• No difference in Complement-
dependent cytotoxicity (CDC)
activation
Nov 9, 2015 CMC JPN 2015; niklas.ekman@fimea.fi 17
Only for illustration, complete list available in the EPAR
Lääkealan turvallisuus- ja kehittämiskeskus
• No difference in Regulatory Macrophage function (regMø)
• Quantity of induced regulatory macrophages, suppression of T cell
proliferation, in vitro wound healing
• No difference in Antibody-dependent cell-mediated cytotoxicity
(ADCC) using
• tmhTNFα-Jurkat cells as target cells and PBMCs (from healthy
donors or CD patients), NK cells (from healthy donors) whole blood
(from healthy donors) as effector cells
• LPS-stimulated monocytes (from healthy donors or CD patients) as
target cells and PBMC as effector cells
Difference in ADCC functional assay detected only with
• tmhTNFα-Jurkat cells as target cells and NK cells from CD patient
donors (158V/V or 158V/F genotypes, but not 158F/F) as effector
cells
Nov 9, 2015 CMC JPN 2015; niklas.ekman@fimea.fi 18
Clinical impact of the difference in FcγRIIIa
binding?
Lääkealan turvallisuus- ja kehittämiskeskus
• Functional difference was seen only in an ADCC assay
employing artificially high tmTNFα expressing Jurkat target cells
in combination with highly purified NK effector cells
• No differences in experimental models regarded as more
relevant to the pathophysiological conditions in CD patients
• No published reports describing the induction of ADCC by TNF
antagonists in CD patients
• No firm evidence that the FcγRIIIa polymorphism has an impact
on the clinical course of CD
The CHMP concluded that the differences detected were not
clinically meaningful, a positive opinion issued was issued
Nov 9, 2015 CMC JPN 2015; niklas.ekman@fimea.fi 19
Conclusion from the Remsima assessment
Lääkealan turvallisuus- ja kehittämiskeskus
• Similar physicochemical and structural characteristics, similar
biological function in in vitro models
• Similar human pharmacokinetics (exposure), pharmacodynamics,
efficacy, safety, and immunogenicity at least in one therapeutic
indication1
• Sound scientific justification
• Clinical experience and available literature data from the reference
product
• Mechanism of action of the active substance in each indications
• Evidence that the lead indication is representative for the other
therapeutic indications, both with regard to safety and efficacy
Extrapolation of indication(s) is always a case-by-case
decision and will depend on the totality of evidence presented
Nov 9, 2015 CMC JPN 2015; niklas.ekman@fimea.fi 20
Prerequisites for extrapolation
1) For simple biologics, safety and efficacy studies may not always be necessary
Lääkealan turvallisuus- ja kehittämiskeskus
Analytical and biological comparability is the cornerstone for successful biosimilar development and forms the basis for the non-clinical and clinical comparability programs
As demonstrated by the Remsima case, thorough physicochemical and biological characterisation is also foremost important for successful extrapolation of indications
For more simple biologics, certain (non-) clinical studies could be waived by the CHMP based on comprehensive physicochemical and biological comparability data
• Only appropriate if biosimilarity can be convincingly concluded
based on physicochemical and functional characterisation (in
combination with PK and PD profiles)
• Could at some point be possible for more complex biologics as well?
Nov 9, 2015 CMC JPN 2015; niklas.ekman@fimea.fi 21
Summary – Value of Physiochemical and
Biological Data in Demonstrating Biosimilarity
Lääkealan turvallisuus- ja kehittämiskeskus
Thank you for your attention!
EMA Websitehttp://www.ema.europa.eu/ema/
Biosimilar guidelineshttp://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_cont
ent_000408.jsp&mid=WC0b01ac058002958c
Remsima EPAR (European public assessment report)http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/00
2576/human_med_001682.jsp&mid=WC0b01ac058001d124
Niklas Ekman, Ph.D.
Senior Researcher, Quality/CMC Assessor
Finnish Medicine Agency (FIMEA), Helsinki, Finland
niklas.ekman@fimea.fi
Nov 9, 2015 CMC JPN 2015; niklas.ekman@fimea.fi 22
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