IFPAC11 Ekman EU Regulatory Perspectives on Biosimilars · EU Regulatory Perspectives on...

EU Regulatory EU Regulatory Perspectives on Perspectives on

BiosimilarsBiosimilars

Niklas Ekman, Ph.DSenior Researcher

Finnish Medicines AgencyHelsinki, Finland

[email protected] To be or not to be similar…

IFPAC Annual MeetingJanuary 19, 2011

Baltimore, MD, USA

2011-01-11 EFPAC11 Niklas Ekman; [email protected] 2Lääkealan turvallisuus- ja kehittämiskeskus

Biosimilar medicinal products in the EU

• Data protection/patents for the first original biotherapeutics has recently expired or will expiry in the near future

• This has initiated the development and of copy versions, called biosimilars by the industry

• Biosimilars are similar but not identical to the originator• Generally, the biosimilar uses the same dose to treat the same

disease as the originator • In Europe, the scientific evaluation of marketing authorisation

applications for biosimilars is conducted centralised by the Committee for Medicinal Products for Human Use (CHMP)

• The multidisciplinary CHMP biosimilar working party (BMWP) is chaired by Dr Christian Schneider (PEI, Germany)

• For time being, the CHMP has no opinion on interchangeability• Substitution is a national decision of each Member State


FermentationPurification

Formulation and filling

Cloning the gene of interest into an

expression vector

pExpression

Transfer into host cell

Changes in the production process during development

or post marketing ICH Topic Q5E

Comparability of Biotechnological/Biological

Products


• The extent of the studies to demonstrate comparability will depend on– The production step where the changes are introduced– The potential impact of the changes on the purity as well as on

the physicochemical and biological properties of the product, particularly considering the complexity and degree of knowledge of the product

– The availability of suitable analytical techniques to detect potential product modifications and the results of these studies

– The relationship between quality attributes and safety and efficacy


• Comparability on the quality level must always be demonstrated

• If differences between quality attributes of the pre- and post-change product are observed, and especially if the relationship between specific quality attributes and safety and efficacy has not been established, additional nonclinicaland/or clinical studies might be required in the comparability exercise


FermentationPurification

Formulation and filling

Cloning the gene of interest into an

expression vector

pExpression

Transfer into host cell

Usually identical

Usually different

Similar ordifferent

cells

Different cell growth and

fermentation conditions

Different purification

process

Usually similar or

same formulation


Spectrum of complexity

Chemicals Recombinant DNAtechnology

AspirinMW: 0.2 kDa

IFN alfa165AA, MW: 19 kDa

IgG~1300AA,

MW: ~150 kDa

Blood-derived

FVIII~2330AA,

MW: ~330 kDa

Advanced therapy

Immunologicals

Virus like particleMW: ~20 000 kDa

…

Source: Dr Kowid Ho (Afssaps, France)


Legal environment for Legal environment for biosimilarsbiosimilars in EUin EU

2001 2002 2003 2004 2005 2006 2007 2008 2009 2010

Dir 2004/27

Dir 2001/83 Draft GL on mABs

Product-specific GLs

Quality and Non-clinical/Clinical GL

Overarching GL

Dir 2003/63

First filgrastim biosimilar authorised

First eopoetin biosimilarsauthorised

First somatropin (Omnitrope + Valtropin) biosimilar authorised

Omnitrope ECnegative opinion

Omnitrop CHMP positiveopinion

Omnitrop submission


GLs


Overview of biosimilar guidelines

User guideDraft 2004 / Adopted 2005

General guidelinesQuality and (Non)clinial

Draft 2005 / Adopted 2006

Class specificguidance

Overarching Guideline (CHMP/473/04)

“Guideline on Similar Biological Medicinal Products”

Nonclinical and Clinical (CHMP/49348/05)

ADOPTED

Insulin (2006)Somatropin (2006)

Epoetin (2006, revised 2010)G-CSF (2006)IFNα (2009)

LMWH (2009)

UPCOMING

rFSHIFNβ

Monoclonal Abs

Quality (CHMP/49348/05) Revision will start in 2011


“Overarching guideline”

• Guideline on similar biological medicinal products (CHMP/437/04)– Scope: Any biological medicinal product, but more likely to be

applied to highly purified products which can be thoroughly characterised

– Biosimilarity should be established at all levels (Q/S/E) using a reference medicinal product authorised in the Community on the basis of a complete dossier

– The pharmaceutical form, strength and route of administration should be the same as for the reference. Any differences must be supported by non-clinical/clinical data

– The specific medicinal product given to the patient should be identified in order to support pharmacovigilance monitoring


Quality guideline (CHMP/BWP/49348/2005)

– Scope:• Recombinant DNA-derived proteins and peptides, their

derivatives and products of which they are components (e.g. conjugates)

– Manufacturing process• Own drug development for the biosimilar• Complete CTD module 3 should be submitted for the biosimilar• The suitability of the formulation should be demonstrated, even if

identical to the reference product• The clinical comparability study should be conducted with the

biosimilar product manufactured using the final manufacturing process (i.e. representing the quality profile of the batches to be commercialised)


– Comparability exercise versus the reference product (Quality)• Comparison against official data (e.g. pharmacopoeial monographs

or against published scientific data) is not sufficient• Comparability for medicinal product and active substance

• Care should be taken if isolation of the active substance from the RP is required

• Suitability of the analytical methods• Methods should be appropriately qualified for the purpose of

comparability• Before entering clinical comparability studies, release test methods

should be validated according to ICH Q2(R1)• Shelf life of the RP to be considered



– Comparability exercise versus the reference product (Quality)• Comparative characterisation studies should include assessment of

composition, physical properties, primary and higher order structures, purity, product-related isoforms and impurities, and biological activity

• Stressed and accelerated stability studies are included to determine degradation profiles

• Process-related impurities are expected to differ• Quality attributes are not expected to be identical between

biosimilar and reference• With more sensitive analytical methods being developed, more

differences will be detected• Any differences must be justified in relation to safety and efficacy



Non-clinical / Clinical guideline (CHMP/BMWP/42832/2005)– Indication(s)

• Each claimed indication should be justified or demonstrated separately

• Extrapolation is possible, but depends on clinical experience, available literature data, same mechanisms of action or receptor(s) involved in all indications

– Non-clinical studies• Comparative in nature; designed to detect differences• In vivo studies should be conducted in relevant species

• Pharmacodynamic study, plus at least one repeat dose toxicity study• Safety pharmacology, reproduction, mutagenicity and carcinogenicity

studies are usually not required


Non-clinical / Clinical guideline (CHMP/BMWP/42832/2005)– Clinical studies

• Comparative pharmacokinetics (PK) and pharmacodynamics(PD) studies are requested

• In certain cases, comparative PK/PD studies might be sufficient to demonstrate clinical comparability, but usually comparative efficacy trials are required

– Clinical safety and pharmacovigilance• Pre-licensing safety data should be obtained• One year follow-up data on immunogenicity usually required pre-

licensing for long term treatment• Risk management program / pharmacovigilance plan to be

provided


Source: Dr Falk Ehmann (EMA, UK)


Biosimilar MAA Procedures (Dec 2010)1 Omnitrope (somatropin) Sandoz Authorised2 Valtropin (somatropin) Biopartners Authorised3 Alpheon (interferon alfa) Biopartners Negative4 Binocrit (epoetin alfa) Sandoz Authorised5 Epoetin alfa Hexal (epoetin alfa) Hexal Authorised6 Abseamed (epoetin alfa) Medice Authorised7 Silapo (epoetin zeta) Stada Authorised8 Retacrit (epoetin zeta) Hospira Authorised9 Insulin Marvel Short (human insulin) Marvel Life Sci’ Withdrawn10 Insulin Marvel Interm (human insulin) Marvel Life Sci’ Withdrawn11 Insulin Marvel Long (human insulin) Marvel Life Sci’ Withdrawn12 Filgrastim Ratiopharm (filgrastim) Ratiopharm Authorised13 Ratiograstim (filgrastim) Ratiopharm Authorised 14 Biograstim (filgrastim) CT Arzneimittel Authorised15 Tevagrastim (filgrastim) Teva Authorised16 Filgrastim Hexal (filgrastim) Hexal Authorised17 Zarzio (filgrastim) Sandoz Authorised18 Nivestim (filgrastim) Hospira Authorised

Modified from Xavier Luria’s presentation at Biosimilar mAB workshop, EMEA 2 July 2009


Source: PDB

– Background• Biosimilar; Nivestim (Hospira UK Limited)• Reference product; Neupogen (Amgen)

sourced from the Community• Filgrastim is a non-glycosylated G-CSF

produced in E. coli• The same indications were claimed for the

biosimilar as for the originator

– References• European Public Assessment Report for

Nivestim; www.ema.europa.eu• Skrlin et al., Biologicals 38 (2010) 557-566

Example of analytical comparability exercise


– Analytical similarity between Nivestim and Neupogen was demonstrated for• Physical and chemical parameters

• Appearance, pH, IEF, SDS-PAGE (reducing and non-reducing), protein concentration (UV/VIS and RP-HPLC), intact molecule mass determination

• Purity• SEC-HPLC, RP-HPLC, IC

• Potency• In vitro receptor binding assay and a cell-based assay based on the

stimulatory effect of filgrastim on the proliferation of NFS-60 cells• Additional assays

• Fluorescence spectroscopy, circular dichroism, peptide mapping with C- and N-terminal sequencing, disulphide bridges and AA sequencing by peptide mapping

• Degradation impurity profiling under stress conditions• 12 weeks at 40°C

Example of analytical comparability exercise


• Quality comparability studies did not reveal any significant differences between Nivestim and Neupogen with regard to identity, physical properties, primary and higher order structures, biological activity, content, as well as purity/impurity profiles

• Non-clinical PD and toxicological studies confirmed the similarity• The two phase I studies designed to compare the PK, PD and safety

characteristics as well as the one phase III study to demonstrate therapeutic equivalence, established the clinical similarity between Nivestim and Neupogen

• Nivestim was authorised throughout the European Union on June 8, 2010


Trends in EMA Scientific advices for biosimilars

3

1 1

6

21 1

11

0

2

4

6

8

10

12

Filgrastim IFN insulin mAb

2003-2008; Average per year 2009 2010


Modes of Action of monoclonal antibodies

Source: GB Kress, EMEA workshop on biosimilar MAB, 2009


Quality considerations for biosimilar monoclonal antibodiesCPMP/BWP/437/04“The active substance of a similar biological medicinal product must be

similar, in molecular and biological terms, to the active substance of the reference medicinal product.“

“For example, a medicinal product containing interferon alfa-2a manufactured by Company X claiming to be similar to another biological medicinal product should refer to a reference medicinal product containing as its active substance interferon alfa-2a. Therefore, a medicinal product containing interferon alfa-2b could not be considered as the reference medicinal product.“

The current understanding is that a biosimilar must be identical on the amino acid level with the originator


What and how much characterisation data is needed?– Detailed physicochemical characterisation is possible but can

be technically challenging– Several alternative methods and assays for comparing

quality attributes should be used– Extensive heterogeneity within the products

• Deamidation, oxidation, acetylation, N-terminal pyro-Glu, C-term Lys removal, disulphide bond shuffling/cleavage, fragmentation/clipping, glycosylation…

• Effect on biological activity/safety not always clear – Bioactivity data are complementary to characterisation data

• Less precise, more holistic• Mode of action must be considered • Link to 3D structure (usually) and clinical outcome (desirable)• Cell-based assays and binding assays


Source: http://www.separationsnow.com/coi/cda/detail.cda?chId=4&id=19553&type=Feature&page=1

Ion exchange chromatography


http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/11/WC500099361.pdf


Draft guideline on biosimilar mABs(EMA/CHMP/BMWP/403543/2010)– Scope

• Defines the non-clinical and clinical requirements for biosimilar mABs• Second- or next generation biologicals are beyond the scope of the

guideline

– Non-clinical studies• A risk-based approach to decide on the choice and extent of in vitro

and especially in vivo studies is recommended

– Clinical studies• Pharmacokinetics and pharmacodynamics

• Comparative PK study in a sufficiently sensitive and homogeneous study population

• Multiple PK studies may be recommendable to support extrapolation between indications of different therapeutic areas

• The possibility to study dose-concentration-response relationship should be explored


Draft guideline on biosimilar mABs(EMA/CHMP/BMWP/403543/2010)– Clinical studies

• Clinical Efficacy and Safety• Usually, efficacy need to be demonstrated in adequately powered

equivalence trials• Safety is normally studied as part of the clinical efficacy study• Focus should be given on adverse reactions described for the reference

product• Extrapolation of Indications

• Possible, based on the overall evidence of biosimilarity provided• For antibodies licensed both as immunomodulators and as anticancer

antibodies, extrapolation is more challenging

• Pharmacovigilance and post-authorisation follow-up• Risk management program should be in place at time of MA• Post-authorisation safety studies might be required; for indications based

on extrapolation, occurrence of rare but serious adverse events described for the reference (e.g. PML), detection of novel safety signals


Conclusions and future perspectives

• Legal framework introduced in Directive 2001/83 as amended• The same EU authorised reference medicinal product must be used

for all parts of the comparability exercise• General, as well as class-specific guidelines are available• So far, the CHMP has reviewed marketing authorisation applications

for 18 biosimilar medicinal products, including five product classes i.e. Somatropin, Interferon alfa, Epoetin, Insulin and Filgrastim – 14 applications have been approved– 3 withdrawn by the Company– 1 negative opinion

• Future perspectives and challenges– The first biosimilar monoclonal antibodies– Global development of biosimilars– Lifecycle of biosimilars; are or should the biosimilars and the

originators be similar throughout the lifecycle?


T0

Tx

Lifecycle of biosimilar medicinal products

biosimilar (0) referenceproduct (0)

biosimilar (X) referenceproduct (X)

Similar at MAA

Similar throughoutlifecycle?

Marketing authorisation


T0

Tx

Lifecycle of biosimilar medicinal products

biosimilar (0) referenceproduct (0)

biosimilar (X) referenceproduct (X)

Similar at MAA?

Similar throughoutlifecycle?

Marketing authorisation

ReferenceProduct (1)


The concept of The concept of biosimilaritybiosimilarity is evolving with is evolving with science and experiencescience and experience……

Thank you for your attention!Acknowledgements;

Dr Kowid Ho (Afssaps, France), Dr Martijn van der Plas (Rivm, NL), Dr Falk Ehmann (EMA, BMWP, UK), Colleagues at EMA, BMWP and BWP

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