ekman slides

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; [email protected] 2


Available guidance in the EU


Overarching Guideline CHMP/473/04 Rev. 1“Guideline on Similar Biological Medicinal Products”

Quality EMA/CHMP/BWP/247713/2012

Adopted 2005, revised 2014


Nonclinical and Clinical EMEA/CHMP/BMWP/42832/2005 Rev. 1


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


• 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• 21 positive (2 withdrawn by the MA holders post-approval), 7

withdrawn during evaluation, 1 negative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


Lääkealan turvallisuus- ja kehittämiskeskus Nov 9, 2015 CMC JPN 2015; [email protected] 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

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of

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69% 65% 63% 55% 76%% mAb/ mAb-like proteins:

2010 2011 2012 2013 2014 H1/2015

~70%


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



• 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


General principles for biosimilar development


• 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)


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; [email protected]

The analytical similarity exercise

Nov 9, 2015

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-90.


• 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


The use of statistics in the analytical

similarity exercise


• 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!


The use of statistics in the analytical

similarity exercise


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



• 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


Glycosylation and effector function analyses


• 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)


Remsima/ Inflectra; Qaulity aspects

Lääkealan turvallisuus- ja kehittämiskeskus Nov 9, 2015 CMC JPN 2015; [email protected] 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)


• 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


Can efficacy and safety data be extrapolated to all

Remsima/Inflectra indications applied for?


• 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


Only for illustration, complete list available in the EPAR


• 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


Clinical impact of the difference in FcγRIIIa

binding?


• 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


Conclusion from the Remsima assessment


• 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


Prerequisites for extrapolation

1) For simple biologics, safety and efficacy studies may not always be necessary


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?


Summary – Value of Physiochemical and

Biological Data in Demonstrating Biosimilarity


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

[email protected]


http://www.ema.europa.eu/ema/

http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000408.jsp&mid=WC0b01ac058002958c

http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002576/human_med_001682.jsp&mid=WC0b01ac058001d124

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