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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
2011-01-11 EFPAC11 Niklas Ekman; [email protected] 3Lääkealan turvallisuus- ja kehittämiskeskus
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
2011-01-11 EFPAC11 Niklas Ekman; [email protected] 4Lääkealan turvallisuus- ja kehittämiskeskus
• 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
2011-01-11 EFPAC11 Niklas Ekman; [email protected] 5Lääkealan turvallisuus- ja kehittämiskeskus
• 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
2011-01-11 EFPAC11 Niklas Ekman; [email protected] 6Lääkealan turvallisuus- ja kehittämiskeskus
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
2011-01-11 EFPAC11 Niklas Ekman; [email protected] 7Lääkealan turvallisuus- ja kehittämiskeskus
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)
2011-01-11 EFPAC11 Niklas Ekman; [email protected] 8Lääkealan turvallisuus- ja kehittämiskeskus
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
2011-01-11 EFPAC11 Niklas Ekman; [email protected] 10Lääkealan turvallisuus- ja kehittämiskeskus
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
2011-01-11 EFPAC11 Niklas Ekman; [email protected] 11Lääkealan turvallisuus- ja kehittämiskeskus
“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
2011-01-11 EFPAC11 Niklas Ekman; [email protected] 12Lääkealan turvallisuus- ja kehittämiskeskus
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)
2011-01-11 EFPAC11 Niklas Ekman; [email protected] 13Lääkealan turvallisuus- ja kehittämiskeskus
– 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
Quality guideline (CHMP/BWP/49348/2005)
2011-01-11 EFPAC11 Niklas Ekman; [email protected] 14Lääkealan turvallisuus- ja kehittämiskeskus
– 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
Quality guideline (CHMP/BWP/49348/2005)
2011-01-11 EFPAC11 Niklas Ekman; [email protected] 15Lääkealan turvallisuus- ja kehittämiskeskus
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
2011-01-11 EFPAC11 Niklas Ekman; [email protected] 16Lääkealan turvallisuus- ja kehittämiskeskus
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
2011-01-11 EFPAC11 Niklas Ekman; [email protected] 17Lääkealan turvallisuus- ja kehittämiskeskus
Source: Dr Falk Ehmann (EMA, UK)
2011-01-11 EFPAC11 Niklas Ekman; [email protected] 18Lääkealan turvallisuus- ja kehittämiskeskus
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
2011-01-11 EFPAC11 Niklas Ekman; [email protected] 19Lääkealan turvallisuus- ja kehittämiskeskus
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
2011-01-11 EFPAC11 Niklas Ekman; [email protected] 20Lääkealan turvallisuus- ja kehittämiskeskus
– 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
2011-01-11 EFPAC11 Niklas Ekman; [email protected] 21Lääkealan turvallisuus- ja kehittämiskeskus
• 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
2011-01-11 EFPAC11 Niklas Ekman; [email protected] 22Lääkealan turvallisuus- ja kehittämiskeskus
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
2011-01-11 EFPAC11 Niklas Ekman; [email protected] 23Lääkealan turvallisuus- ja kehittämiskeskus
Modes of Action of monoclonal antibodies
Source: GB Kress, EMEA workshop on biosimilar MAB, 2009
2011-01-11 EFPAC11 Niklas Ekman; [email protected] 24Lääkealan turvallisuus- ja kehittämiskeskus
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
2011-01-11 EFPAC11 Niklas Ekman; [email protected] 25Lääkealan turvallisuus- ja kehittämiskeskus
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
2011-01-11 EFPAC11 Niklas Ekman; [email protected] 26Lääkealan turvallisuus- ja kehittämiskeskus
Source: http://www.separationsnow.com/coi/cda/detail.cda?chId=4&id=19553&type=Feature&page=1
Ion exchange chromatography
2011-01-11 EFPAC11 Niklas Ekman; [email protected] 27Lääkealan turvallisuus- ja kehittämiskeskus
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/11/WC500099361.pdf
2011-01-11 EFPAC11 Niklas Ekman; [email protected] 28Lääkealan turvallisuus- ja kehittämiskeskus
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
2011-01-11 EFPAC11 Niklas Ekman; [email protected] 29Lääkealan turvallisuus- ja kehittämiskeskus
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
2011-01-11 EFPAC11 Niklas Ekman; [email protected] 30Lääkealan turvallisuus- ja kehittämiskeskus
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?
2011-01-11 EFPAC11 Niklas Ekman; [email protected] 31Lääkealan turvallisuus- ja kehittämiskeskus
T0
Tx
Lifecycle of biosimilar medicinal products
biosimilar (0) referenceproduct (0)
biosimilar (X) referenceproduct (X)
Similar at MAA
Similar throughoutlifecycle?
Marketing authorisation
2011-01-11 EFPAC11 Niklas Ekman; [email protected] 32Lääkealan turvallisuus- ja kehittämiskeskus
T0
Tx
Lifecycle of biosimilar medicinal products
biosimilar (0) referenceproduct (0)
biosimilar (X) referenceproduct (X)
Similar at MAA?
Similar throughoutlifecycle?
Marketing authorisation
ReferenceProduct (1)
2011-01-11 EFPAC11 Niklas Ekman; [email protected] 33Lääkealan turvallisuus- ja kehittämiskeskus
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