Requirements for demonstrating biosimilarity of monoclonal antibodies

Transcription

1 Requirements for demonstrating biosimilarity of monoclonal antibodies Dr. Steffen Gross Section Mono-/Polyclonal Antibodies Paul-Ehrlich-Institut Germany Outline Biosimilars Regulatory frame work Why biosimilar and not biogeneric Biological characterisation of biosimilar mabs Comparability of Biosimilars (Quality) Regulatory frame work Revision of the quality guideline Recision of the Guideline on Similar Biological Medicinal Products Containing Monoclonal Antibodies Non-clinical and clinical issues Guideline on similar biological medicinal products (CHMP/437/04) Scope: Any biological medicinal product Biotechnology derived protein Immunogicals (e.g. vaccines and allergens): Blood products or recombinant alternatives: Others (e.g. gene, cell therapy) "Generic approach": not appropriate to biologics due to complexity of molecular structure and/or production Biosimilarity to be established at all levels: Q / S / E Importance to clearly identify the product to support pharmacovigilance monitoring When pharmaceutical form or strength or route of administration are not the same:must be supported by non-clinical/clinical trials Reference medicinal product: must be authorised in the Community on the basis of a complete dossier 1

2 Why biosimilar (and not biogeneric )? Aspirin 180 Da Insulin 5700 Da monoclonal antibody 150 kda Development of biosimilars Defines principles Overarching Guideline (CHMP/437/04). Guideline on Similar Biological Medicinal Products Biotechnology- derived proteins Quality General guidelines Quality / Safety Efficacy Insulin Somatropin GCSF Epoetin IFN- LMWH mabs follitropin-a IFN-b Product class specific data requirements Economic impact of biosimilars Slide by Paul Cornes, MD presented at EGA Annual Conference on Biosimilars 14 April 2011 London 2

3 Humanisation of therapeutic proteins Evolution of monoclonal antibodies ( -mab ): = murine = human Murine mab Chimaeric mab Humanized mab Fully Human mab New constructs - bispecific antibodies - diabodies - single chain fragments - engineered Fc mabs - conjugated mabs omab -iximab -zumab -umab Arcitumomab (CEA-Scan ) (1996) Infliximab (Remicade ) (1999) Trastuzumab (Herceptin ) (2000) Adalimumab (Humira ) (2003)? Immunogenicity Immunogenicity Quality guideline (CHMP/BWP/49348/2005) Comparability exercise versus reference product Comparison against official data is not sufficient Quality attributes: -not expected to be identical. -Limits: not wider than the range of variability of the reference product -Differences: to be justified in relation to safety and efficacy. Reference product: -Comparability for medicinal product + active substance -Same reference for all three parts of the dossier (Q/S/E) -To be clearly identified (brand name, pharmaceutical form,formulation and strength ) -Shelf life of the reference product to be consider? Exampel 1 In order to provide assurance that the molecular structure of the active substance present in the similar biological medicinal product can be considered comparable to that in the reference medicinal product, it is generally necessary to conduct appropriate comparative tests at the level of the active substance. (Guideline text) Any approach to isolate representative active substance derived from the reference medicinal product in order to perform the comparative analysis at the active substance level may lead to a difference in the active substance rather due to the extraction method than due to real differences between the similar and the reference product. 3

4 How far does similarity need to go? 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. current understanding is that a biosimilar must be identical on the amino acid level To what extent should glycosylation be "similar", given the functional (modulatory) activity of some sugar moieties? The reference medicinal product is a mixture of different "variants" of the antibody: Does a biosimilar antibody also have to contain the same variants in comparable amounts or is one variant acceptable? To what extent could certain differences be acceptable, given the broad experience that exists with mabs? Exampel 2 Heterogeneity: AA-sequence C-terminal: ±Lys, truncation to Pro-amide N-terminal variants: -Reduce or eliminate the amidated form, variants are not present at comparable levels in marketed products or found naturally in human IgG. -Discuss the observed qualitative change (truncated, amidated variant) with regard to the following aspects: - functional consequences based on theoretical considerations - functional consequences based on other antibodies, where the same modification has been observed Biotechnological products are highly complex molecules - high molecular weight - complexity (primary / secondary / tertiary / quartery structure; post-translational modifications) - heterogeneity - process- and product-related impurities - species specificity - immunogenicity 4

5 The process is the product. -fluctuations in the manufacturing process (e.g., ph, temperature, culture media): - changes in the manufacturing process (e.g., expression system): Batch inconsistency (glycosylation spectra, aggregates) New product (cell bank) One process one product paradigm Global manufacturing process harmonization, adaption of the manufacturing process Global development Companies developing biosimilars set up global developments, at least for the major ICH regions. Reference products are often the same or highly similar in different countries, even though licensed under different jurisdictions, but are legally different products - Often, documentation is available in the public domain, confirming that the products are the same (e.g., produced in a single location and shipped worldwide) - Sometimes, however, different specifications in various regions. - Scientifically, comparability of reference products of one original manufacturer could be established by analytical methods and clinical PK/PD. Sourced vs. licensed in Europe (legal debate ongoing) Christian Schneider 5

6 Comprehensive set of analytical methods increasing sensitivity Physicochemical characterisation, e.g. - Mass spectrometry techniques (e.g., MALDI-TOF) - Nuclear magnetic resonance - Capillary electrophoresis with laser-induced fluorescence detection (CE-LIF) Primary structure - peptide map Secondary structure detection, e.g. - Circular dichroism in near- and far-uv spectra Product related variants and impurities - SEC, CE-SDS, CZE, CEX, etc. Antigen-antibody interaction, e.g. - Surface plasmon resonance - FACS Combination of methodologies, e.g. - liquid chromatography combined with mass spectrometry Increased complexity by posttranslational modifications Setting specifications All features of the molecule, relevant for safety/efficiacy Possibility to define different specifications for biological activity depending on the mode of acvtion (and indication) Binding might not be sufficient For biosimilars within the originators range but tight (justified) for process related impurities, state of the art limits 6

7 Increased complexity by posttranslational modifications Exampel 3 Complete quality range for justification of limits and claiming biosimilarity basic variants ADCC Differences seen in the amount of basic or acidic variants or fucosylated structures 7

8 Expression system- Example 5 The product is produced in glyco-engineered Pichia pastoris. It has an identical amino acid sequence, but has a different N- glycan composition (i.e. lack of fucose and terminal α-1,3 galactose) The chosen approach, i.e. generating a drug substance which is a priori known to be qualitatively different from the reference product, is not in accordance with the biosimilar concept to minimise differences to the reference product as much as possible. Comparability vs. Biosimilarity Prior to submission of the MAA, the manufacturing process will be transferred to a commercial facility. The drug product material manufactured at the commercial facility will be compared to batches manufactured earlier in development for the clinical trials, according to the principles of ICH Q5E. These commercial batches will also be compared back to data obtained from reference medicinal product batches accumulated. Comparison of commercial scale batches with the reference product to ensure no cumulative drift occurred during the commercialization scale-up. GUIDELINE ON SIMILAR BIOLOGICAL MEDICINAL PRODUCTS CONTAINING BIOTECHNOLOGY-DERIVED PROTEINS AS ACTIVE SUBSTANCE: QUALITY ISSUES states that although it is acknowledged that the manufacturing process will be optimized during development, it is advisable to generate the required clinical data for the comparability study with product manufactured with the final manufacturing process and therefore representing the quality profile of the batches to be commercialised Design Space Concept for biosimilars ICH Q8, Q9 and Q10 are applicable for biosimilars manufacturers for their own developments in the same way as for the originators. A design space depends on a particular manufacturing process 8

9 Quality by design The Regulatory Quality System Quality Risk Management Quality Risk Management (Q9) Quality Systems Quality by Design (Pharmaceutical Development) Quality by Design (Q8) Existing GMP s Quality Systems (Q10) Requirement for close interaction assessors-inspectors Assessment: stronger focus on IPC Conclusion Quality Current methodology sensitive to detect differences in primary structure, identity and amount of related variants including aggregates, glycosylation profile etc. Major question is not the ability to detect differences but the determination of their clinical relevance to be answered by combining physicochemical results with functional assays and the qualification in preclinical and clinical studies Revision Biosimilar Quality Guidance 9

10 Key Items The formulation of the biosimilar does not need to be identical to that of the reference medicinal product. The stability of the biosimilar product should be determined according to ICH Q5C. The similar biological medicinal product will have its own lifecycle and that manufacturing process changes may be introduced during development in line with ICH Q5E Reference medicinal product and biosimilar product are highly similar at the level of the finished product Scientific necessity to compare reference active substance with biosimilar active substance. The target amino acid sequence of the biosimilar should be confirmed experimentally to be the same as for the reference medicinal product. The N- and C-terminal amino acid sequences should be compared and modifications/truncations quantified. In the case of monoclonal antibodies or related substances (e.g. fusion proteins based on IgG Fc), the immunological properties should be fully compared Biologics are threesome Quality - impurities - batch inconsistency - contaminants - microheterogeneity - fragments - tissue cross-reactivity? - toxicity? - immunotoxicity? Non- B R I D G I N G - additional safety measures required? - immunogenicity Guideline on Similar Biological Medicinal Products Containing Monoclonal Antibodies. Non-clinical and clinical issues In vitro studies = step 1 - Binding to target antigen(s) - Binding to Fcγ receptors (FcγRI, FcγRIIA, FcγRIIB, FcγRIIIA and FcγRIIIB ), FcRn and complement (C1q) - Fab-associated functions (e.g. neutralization of a soluble ligand, receptor activation or blockade) - Fc-associated functions (e.g. ADCC and CDC assays, complement activation ), check the necessary Fgc R variants and isoforms 10

11 step 2 Determination of the need for in vivo studies = step 2 Factors to be considered, when the need for additional in vivo non-clinical studies is evaluated, include but are not restricted to: The use of a different cell expression system compared with the reference medicinal product (e.g. yeast, insect, plant, vs. mammalian expression system). Significant differences in formulation e.g use of excipients not widely used for mabs. step 3 In vivo studies = step 3 Animal studies should be designed to maximise the information obtained. The principles of the 3Rs (replacement, refinement, reduction) should be considered when designing any in vivo study. The conduct of toxicological studies in non-human primates is not recommended. Also the conduct of toxicity studies in non-relevant species (e.g. to assess unspecific toxicity only, based on impurities) is not recommended. Discussion on non-clinical issues Reduced non-clinical programme is possible (and ethically may be better acceptable); should focus on the specific needs and mechanism of action (e.g. as regards the requirement to show comparable impact on signalling events). Toxicity mostly related to target-related toxicity. Use of nonrelevant species not appropriate For unknown impurities: Alternative approaches preferred, e.g. tissue cross-reactivity, reduce impurities, tox studies have not to be comparative. 11

12 Example local tolerance studies The use of a different excipient is acceptable in the formulation of the biosimilar drug product, as long as quality as well as pre-clinical and clinical data show comparability with the reference product; however data on function/effectors mechanism and toxicological data should be provided. Provided that excipients are used in medicinal products for parenteral use in humans, the substance is not considered as a novel excipient. Given that it is a "novel" excipient in monoclonal antibodies preparations, information should be provided on its function/effector mechanism and toxicology. Dossier requirements CTD Module Originator Biosimilar Quality comparability data Non clinical cross reference clinical cross reference (extrapolation?) Scientific Advices National EMA All Source: X. Luria, Products EMEA workshop on biosimilar Companies MAB, 2009 Advices 12

13 published data Others Others data decision National approvals Oth Mutual Recognition er Oth Procedure.. er Decentralized Procedure.. Oth Oth er er.... Centralised approvals Oth er.. data decision 13