Expectations for Analytical Characterisation in the Evaluation of Biosimilarity: A Regulator`s Perspective Christian Mayer AGES - Austrian Agency for Health and Food Safety Analytical Technologies Europe 2016 Vienna, Austria, March 15-18, 2016 www.ages.at Austrian Agency for Health and Food Safety
Disclosure and Disclaimer The views and opinions expressed in the following PowerPoint slides are those of the individual presenter and do not necessarily reflect the view of the AGES and/or the EMA. www.ages.at Austrian Agency for Health and Food Safety 2
Organization AGES Austrian Agency for Health and Food Safety: - Expert organization for risk minimization in all matters related to health, food safety, and consumer protection. AGES MEA - Austrian Medicines and Medical Devices Agency: - One of five divisions of the AGES - National competent authority for regulation of medicinal products and medical devices - A partner to competent authorities and agencies throughout Europe and pharmaceutical industry www.ages.at Austrian Agency for Health and Food Safety 3
Organization www.ages.at Austrian Agency for Health and Food Safety 4
Assessment & Analytics A S S E S S M E N T Clinical Assessment of Safety & Efficacy - CASE Biologicals, Preclinical & Statistical Assessment, Veterinary Medicinal Products - BPSV Assessment Pharmacovigilance - APHV Analytics of Biological Medicinal Products - BAMA Analytics of Chemicalpharmaceutical Medicinal Products - CPAA O M L C 1200 Traisengasse Vienna 1160 Possingergasse & 1090 Zimmermanngasse Vienna www.ages.at Austrian Agency for Health and Food Safety 5
Organization Activities of AGES MEA according to the lifecycle of a medicine www.ages.at Austrian Agency for Health and Food Safety 6
What is a Biosimilar A copy version of an already authorised biological medicinal product (the Reference Medicinal Product - RMP) produced or extracted from a biological source, such as bacteria, yeast, or mammalian cells in culture with demonstrated similarity in physicochemical and biological characteristics, efficacy and safety based on a comprehensive comparability exercise www.ages.at Austrian Agency for Health and Food Safety 7
What is a Biosimilar Biosimilars are complex biological molecules Manufactured by a complex, multi-step manufacturing process - Small manufacturing changes can have a high impact Large size and complex 3-D structure Instable and sensitive to ph and temperature extremes, ionic strength, shear forces, oxidation, light Batch-to-batch variability/micro-heterogeneity in structure www.ages.at Austrian Agency for Health and Food Safety 8
Spectrum of Complexity www.ages.at Austrian Agency for Health and Food Safety 9
Biosimilar Pathway Standard generic approach of comparing bioavailability with reference products is normally applied to chemically derived medicinal products Due to the complexity of biological products the generic approach is scientifically not appropriate for these products The biosimilar pathway based on a comparability exercise has to be followed www.ages.at Austrian Agency for Health and Food Safety 10
Biosimilar Pathway Principles of establishing biosimilarity Establish similarity between the biosimilar and the RMP by the best possible means, ensuring that the previously proven safety and efficacy of the RMP also applies to the biosimilar Stepwise approach recommended throughout the development programme, starting with a comprehensive physicochemical and biological characterisation /comparability programme Extent and nature of the non-clinical/clinical studies depend on the level of evidence obtained from physicochemical and biological characterisation www.ages.at Austrian Agency for Health and Food Safety 11
Biosimilar Pathway Biosimilarity is based primarily on quality Demonstration of a comparable quality profile is a prerequisite Significant differences in quality cannot be overruled by showing equivalence in clinical trials - Clinical trials should confirm biosimilarity already demonstrated at the quality level - Are least sensitive to detect differences should any exist www.ages.at Austrian Agency for Health and Food Safety 12
Biosimilar Development www.ages.at Austrian Agency for Health and Food Safety 13
Biosimilar Development Defining the target Quality Target Product Profile QTPP prospective summary of quality characteristics of a drug product that ideally will be achieved (ICH Q8) Based on data obtained from an extensive characterisation of a sufficient number of RMP batches publicly available information on the RMP Development tool some target ranges may evolve during development, as further information on the RMP becomes available www.ages.at Austrian Agency for Health and Food Safety 14
Biosimilar Development Identify Critical Quality Attributes A CQA is a physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality (ICH Q11) For biologicals it may be challenging to identify the CQAs Use risk-assessment tools to rank or prioritize quality attributes (and include a sufficiently detailed description of the used risk-assessment tools into the dossier) www.ages.at Austrian Agency for Health and Food Safety 15
Biosimilar Development Ranking of quality attributes Scoring system or risk ranking can be performed in order to justify the relative importance of individual quality attributes www.ages.at Austrian Agency for Health and Food Safety 16
Biosimilar Development Ranking of quality attributes Structure-function relationships, can contribute to the assessment of risk for some product attributes Prior knowledge can be used at the beginning of development and assessments can be iteratively updated with development data It is important to identify CQAs that may impact safety and/or efficacy www.ages.at Austrian Agency for Health and Food Safety 17
Biosimilar Development Setting ranges Quantitative ranges should be established for the biosimilar comparability exercise, where possible Should not be wider than the range of variability of representative RMP batches A descriptive statistical approach to establish ranges for quality attributes could be used, if appropriately justified but raw data should always be provided, not just the ranges or intervals www.ages.at Austrian Agency for Health and Food Safety 18
Biosimilar Development Setting ranges statistical approaches www.ages.at Austrian Agency for Health and Food Safety 19
Biosimilar Development Reflection paper Should provide an overview of statistical principles with a potential of useful application in the context of the comparison of quality attributes Should also discuss options and limitations of alternative approaches for comparability evaluation where repeated (correlated) samples within batches are considered as unit of observation www.ages.at Austrian Agency for Health and Food Safety 20
Biosimilar Development Reflection paper Will also try to comment on deficiencies/limitations of particular methods which have been discussed in regulatory dossiers in the past (e.g. tolerance interval, confidence interval for difference in / ratio of means, six sigma, etc.) Primarily applicable for comparison of quality aspects - within biosimilar developments (biosimilar versus RMP) - after manufacturing changes (pre- versus post-change material) www.ages.at Austrian Agency for Health and Food Safety 21
Biosimilar Development Shifts in the quality profile of the RMP RMP may evolve through its life cycle May lead to shifts in the quality profile of RMP Could occur during development phase of a biosimilar and may result in a development according to a QTPP which is no longer fully representative of the RMP on the market www.ages.at Austrian Agency for Health and Food Safety 22
Biosimilar Development Analysis of commercial Enbrel batches sourced in the EU and the US: Schiestl et al, April 2011 www.ages.at Austrian Agency for Health and Food Safety 23
Biosimilar Development Shifts in the quality profile of the RMP The ranges identified before and after the observed shift in quality profile could normally be used to support the biosimilar comparability exercise at the quality level Either range is representative of the RMP Data from pre- and post-shift batches should be clearly highlighted and separated in the dossier Values outside or between the range(s) determined for the RMP should be appropriately justified www.ages.at Austrian Agency for Health and Food Safety 24
Demonstrating Biosimilarity Side-by-side analysis Extensive state-of-the-art characterisation studies should be applied to the biosimilar and RMP in parallel To demonstrate that the proposed biosimilar is similar to the RMP Not expected that all quality attributes of the biosimilar will be identical to the RMP but: Any differences detected in the quality attributes will have to be appropriately justified with regard to their potential impact on safety and efficacy www.ages.at Austrian Agency for Health and Food Safety 25
Demonstrating Biosimilarity Benepali example (Biosimilar to Enbrel) Case Study Hydrophilic interaction ultra-performance liquid chromatography (HILIC-UPLC) has been used to determine the relative quantity of N-glycan species N-glycan profiles of Benepali batches are different from those of EU Enbrel In particular afucosylated glycan content in Benepali is higher than observed for EU Enbrel FcγRIIIa (both allotypes) binding assay showed as well slight differences FcγRIIIa binding activity associated with ADCC EPAR Public AR www.ages.at Austrian Agency for Health and Food Safety 26
Demonstrating Biosimilarity Benepali example (Biosimilar to Enbrel) Case Study However, ADCC is not considered to be a Mode of Action (MoA) of etanercept These differences are not clinically meaningful Results from ADCC analysis demonstrate similar low ADCC activity between Benepali and Enbrel Justification that observed differences in the biosimilarity assessment have no impact on the efficacy and safety when comparing Benepali with its RMP is acceptable EPAR Public AR www.ages.at Austrian Agency for Health and Food Safety 27
Side-by-Side Analysis Physicochemical properties and quantity - Primary and higher order structures - N- and C-terminal amino acid sequences - Free SH groups and disulfide bridges - If appropriate, presence and extent of post-translational modifications o Glycosylation o Oxidation o Deamidation o www.ages.at Austrian Agency for Health and Food Safety 28
Side-by-Side Analysis N-glycosylation analysis for monoclonal antibodies (mabs) - Oligosaccharide structure, attachment sites and distribution - Glycan profile and micro-heterogeneity: o Content of the different biantennary glcyan forms (G0F, G1F, G2F) o Afucosylated glycan variants o High-mannose variants - Monosaccharide analysis - Content of sialic acid (NANA, NGNA) www.ages.at Austrian Agency for Health and Food Safety 29
Side-by-Side Analysis Purity and impurities - Product related variants and impurities - Comparative stability testing under stress conditions (e.g. ph and temperature extremes, oxidative, light, mechanical stress) o For comparison of degradation pathways and kinetics (e.g. oxidation, deamidation, aggregation) o Data showing comparable degradation support biosimilarity claim - Generally not required for a biosimilarity exercise: o Comparison of process-related impurities (host cell DNA, host cell proteins, Protein A, ) o Comparison of adventitious agents o But an appropriate control system for these impurities has to be in place www.ages.at Austrian Agency for Health and Food Safety 30
Side-by-Side Analysis Immunological functions (of mabs and fusion proteins based on IgG Fc) - Binding of the Fab to its target - Fc-domain: Binding to representative isoforms of the relevant three Fc gamma receptors (FcγRI, FcγRII and FcγRIII), to the neonatal receptor (FcRn), and to the complement (C1q) - Binding characteristics to FcγR s may be requested for comparability purposes even when Fc effector function does not play a role in the MoA - Detected differences here may trigger the request for additional cell-based assays - Sometimes these studies are presented in the Nonclinical section (Module 4) of the dossier >>> reference to the respective sections in Module 4 should then be given in the quality part www.ages.at Austrian Agency for Health and Food Safety 31
Side-by-Side Analysis Biological activity - Biological assays using different and complementary approaches o In many cases a set of binding and cell-based assays used for characterisation and comparison of the biological activity - For mabs: Fab-associated functions (e.g. neutralization of a soluble ligand, receptor activation or blockade) - For mabs with Fc effector function: Fc-associated functions (e.g. ADCC, CDC, complement activation) - ADCC: Consider using more than one effector cell type (e.g. Peripheral Blood Mononuclear Cells (PBMCs) and Natural Killer (NK) cells) - An evaluation of ADCC and CDC is generally not needed for mabs directed against non-membrane bound targets www.ages.at Austrian Agency for Health and Food Safety 32
Demonstrating Biosimilarity Remsima example (Biosimilar to Remicade) Case Study Remsima exhibits a lower level of afucosylated glycans, hence a lower binding affinity to FcγRIIIa and a lower activity in the most sensitive ADCC assay using NK cells as effector cells and tmtnfα Jurkat target cells Differences in ADCC using NK cells but not PBMC is likely to be attributed to the mixed cell population present in PBMC, with multiple Fc receptors available for binding to Remsima and Remicade EPAR Public AR www.ages.at Austrian Agency for Health and Food Safety 33
Demonstrating Biosimilarity Remsima example (Biosimilar to Remicade) Case Study A comprehensive battery of additional in vitro assays applied to characterise biological activity No difference detected in several experiments that are more representative of pathophysiological conditions, and therefore more relevant clinically (e.g. in blood, PBMC) Observed differences suitably justified during the assessment of this MAA. EPAR Public AR www.ages.at Austrian Agency for Health and Food Safety 34
Dossier The biosimilarity data should be presented in CTD section 3.R Regional Information of Module 3 An introductory summary/overview of the conducted biosimilarity exercise is highly welcomed Comparability after manufacturing changes (according to ICH Q5E) should be presented separately from the biosimilarity exercise www.ages.at Austrian Agency for Health and Food Safety 35
Thank you for your Attention The floor is yours www.ages.at Austrian Agency for Health and Food Safety 36