EU Regulatory Perspectives on Biosimilars IFPAC Annual Meeting January 19, 2011 Baltimore, MD, USA Niklas Ekman, Ph.D Senior Researcher Finnish Medicines Agency Helsinki, Finland niklas.ekman@fimea.fi To be or not to be similar
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; niklas.ekman@fimea.fi 2
Cloning the gene of interest into an expression vector pexpression Changes in the production process during development or post marketing Transfer into host cell ICH Topic Q5E Comparability of Biotechnological/Biological Products Formulation and filling Purification Fermentation 2011-01-11 EFPAC11 Niklas Ekman; niklas.ekman@fimea.fi 3
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; niklas.ekman@fimea.fi 4
Comparability on the quality level must always be demonstrated If differences between quality attributes of the pre- and postchange product are observed, and especially if the relationship between specific quality attributes and safety and efficacy has not been established, additional nonclinical and/or clinical studies might be required in the comparability exercise 2011-01-11 EFPAC11 Niklas Ekman; niklas.ekman@fimea.fi 5
Usually identical pexpression Usually different Similar or different cells Usually similar or same formulation Cloning the gene of interest into an expression vector Transfer into host cell Different cell growth and fermentation conditions Formulation and filling Different purification process Purification Fermentation 2011-01-11 EFPAC11 Niklas Ekman; niklas.ekman@fimea.fi 6
Spectrum of complexity Aspirin MW: 0.2 kda Chemicals IFN alfa 165AA, MW: 19 kda IgG ~1300AA, MW: ~150 kda Recombinant DNA technology FVIII ~2330AA, MW: ~330 kda Virus like particle MW: ~20 000 kda BloodImmunologicals 2011-01-11 EFPAC11 Niklas Ekman; niklas.ekman@fimea.fi derived Advanced 7 therapy Source: Dr Kowid Ho (Afssaps, France)
Legal environment for biosimilars in EU Dir 2001/83 Dir 2003/63 Dir 2004/27 Overarching GL Quality and Nonclinical/Clinical GL Product-specific GLs Draft GL on mabs 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 Omnitrope EC negative opinion First filgrastim biosimilar authorised Omnitrop CHMP positive opinion Omnitrop submission First eopoetin biosimilars authorised First somatropin (Omnitrope + Valtropin) biosimilar authorised 2011-01-11 EFPAC11 Niklas Ekman; niklas.ekman@fimea.fi 8
GLs 2011-01-11 EFPAC11 Niklas Ekman; niklas.ekman@fimea.fi 9
Overview of biosimilar guidelines User guide Draft 2004 / Adopted 2005 Overarching Guideline (CHMP/473/04) Guideline on Similar Biological Medicinal Products General guidelines Quality and (Non)clinial Draft 2005 / Adopted 2006 Nonclinical and Clinical (CHMP/49348/05) Quality (CHMP/49348/05) Revision will start in 2011 Class specific guidance ADOPTED Insulin (2006) Somatropin (2006) Epoetin (2006, revised 2010) G-CSF (2006) IFNα (2009) LMWH (2009) UPCOMING rfsh IFNβ Monoclonal Abs 2011-01-11 EFPAC11 Niklas Ekman; niklas.ekman@fimea.fi 10
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; niklas.ekman@fimea.fi 11
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; niklas.ekman@fimea.fi 12
Quality guideline (CHMP/BWP/49348/2005) 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 2011-01-11 EFPAC11 Niklas Ekman; niklas.ekman@fimea.fi 13
Quality guideline (CHMP/BWP/49348/2005) 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 2011-01-11 EFPAC11 Niklas Ekman; niklas.ekman@fimea.fi 14
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; niklas.ekman@fimea.fi 15
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 prelicensing for long term treatment Risk management program / pharmacovigilance plan to be provided 2011-01-11 EFPAC11 Niklas Ekman; niklas.ekman@fimea.fi 16
Source: Dr Falk Ehmann (EMA, UK) 2011-01-11 EFPAC11 Niklas Ekman; niklas.ekman@fimea.fi 17
Biosimilar MAA Procedures (Dec 2010) 1 Omnitrope (somatropin) Sandoz Authorised 2 Valtropin (somatropin) Biopartners Authorised 3 Alpheon (interferon alfa) Biopartners Negative 4 Binocrit (epoetin alfa) Sandoz Authorised 5 Epoetin alfa Hexal (epoetin alfa) Hexal Authorised 6 Abseamed (epoetin alfa) Medice Authorised 7 Silapo (epoetin zeta) Stada Authorised 8 Retacrit (epoetin zeta) Hospira Authorised 9 Insulin Marvel Short (human insulin) Marvel Life Sci Withdrawn 10 Insulin Marvel Interm (human insulin) Marvel Life Sci Withdrawn 11 Insulin Marvel Long (human insulin) Marvel Life Sci Withdrawn 12 Filgrastim Ratiopharm (filgrastim) Ratiopharm Authorised 13 Ratiograstim (filgrastim) Ratiopharm Authorised 14 Biograstim (filgrastim) CT Arzneimittel Authorised 15 Tevagrastim (filgrastim) Teva Authorised 16 Filgrastim Hexal (filgrastim) Hexal Authorised 17 Zarzio (filgrastim) Sandoz Authorised 18 Nivestim (filgrastim) Hospira Authorised 2011-01-11 EFPAC11 Niklas Ekman; niklas.ekman@fimea.fi 18 Modified from Xavier Luria s presentation at Biosimilar mab workshop, EMEA 2 July 2009
Example of analytical comparability exercise 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 Source: PDB 2011-01-11 EFPAC11 Niklas Ekman; niklas.ekman@fimea.fi 19
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 2011-01-11 EFPAC11 Niklas Ekman; niklas.ekman@fimea.fi 20
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; niklas.ekman@fimea.fi 21
Trends in EMA Scientific advices for biosimilars 12 11 10 8 6 6 4 2 3 2 1 1 1 1 0 Filgrastim IFN insulin mab 2003-2008; Average per year 2009 2010 2011-01-11 EFPAC11 Niklas Ekman; niklas.ekman@fimea.fi 22
Modes of Action of monoclonal antibodies Source: GB Kress, EMEA workshop on biosimilar MAB, 2009 2011-01-11 EFPAC11 Niklas Ekman; niklas.ekman@fimea.fi 23
Quality considerations for biosimilar monoclonal antibodies CPMP/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; niklas.ekman@fimea.fi 24
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; niklas.ekman@fimea.fi 25
Ion exchange chromatography Source: http://www.separationsnow.com/coi/cda/detail.cda?chid=4&id=19553&type=feature&page=1 2011-01-11 EFPAC11 Niklas Ekman; niklas.ekman@fimea.fi 26
http://www.ema.europa.eu/docs/en_gb/document_library/scientific_guideline/2010/11/wc500099361.pdf 2011-01-11 EFPAC11 Niklas Ekman; niklas.ekman@fimea.fi 27
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; niklas.ekman@fimea.fi 28
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; niklas.ekman@fimea.fi 29
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; niklas.ekman@fimea.fi 30
Lifecycle of biosimilar medicinal products T 0 biosimilar (0) reference product (0) Similar at MAA Marketing authorisation T x biosimilar (X) reference product (X) Similar throughout lifecycle? 2011-01-11 EFPAC11 Niklas Ekman; niklas.ekman@fimea.fi 31
Lifecycle of biosimilar medicinal products T 0 biosimilar (0) reference product (0) Reference Product (1) Similar at MAA? Marketing authorisation T x biosimilar (X) reference product (X) Similar throughout lifecycle? 2011-01-11 EFPAC11 Niklas Ekman; niklas.ekman@fimea.fi 32
The concept of biosimilarity is evolving with science 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 2011-01-11 EFPAC11 Niklas Ekman; niklas.ekman@fimea.fi 33