The European Landscape for Regenerative Medicine

Transcription

1 Tokyo, December 8-9, 2014 The European Landscape for Regenerative Medicine Margarida Menezes Ferreira Senior Assessor at INFARMED PT expert at BWP/CHMP - EMA member of the CAT - EMA (margarida.menezes@infarmed.pt) I attend this conference as an individual expert and do not represent the CAT. The views expressed here are my personal views, and may not be understood or quoted as being made on behalf of the CAT or reflecting the position of the CAT

2 ARIGATO - OBRIGADO Thank you for your hospitality since we first met in 1543! Nanbam screens. Museu Nacional d Arte Antiga, Lisboa

3 Businessweek July

4 "The Long and Winding Road" ADVANCED THERAPY MEDICINAL PRODUCTS - ATMP Somatic cell therapy Gene therapy National authorisations DE, IT, FR TEP not defined Tissue engineered Centralised marketing authorisations (MA) from 1/2009 = CAT TEP / regenerative medicine Combined products Non-substantial manipulation Long term efficacy follow up Hospital exemption... NEW DEFINITIONS for GeneTherapy and Somatic Cell Therapy ATMP specific Dossier requirements for MA Directive 2001/83/EC revised 4 4

5 Advanced Therapy Medicinal Products ATMP definitions Gene therapy medicinal product (Directive 2009/120/EC revised Annex I of Directive 2001/83/CE ) recombinant nucleic acid for regulating, repairing, replacing, adding or deleting a genetic sequence; its effect relates directly to the recombinant nucleic acid sequence it contains, or to the product of genetic expression of this sequence. NOT vaccines against infectious diseases. Somatic cell therapy medicinal product cells or tissues subject to substantial manipulation cells or tissues not for the same essential function(s) in the recipient and the donor for treating, preventing or diagnosing a disease through the pharmacological, immunological or metabolic action of its cells or tissues. Tissue engineered product engineered cells or tissues = subject to substantial manipulation cells or tissues not for the same essential function(s) in the recipient and the donor used to regenerating, repairing or replacing a human tissue, / primary function combined with devices Margarida Menezes Ferreira

6 "The Long and Winding Road" ADVANCED THERAPY MEDICINAL PRODUCTS - ATMP Definitions suporting regenerative medicine TEP / Combined - medical devices Clarfying fronteers - Non-substantial manipulation to separate from transplantation Centralised MA from Jan 2009 / new Committee CAT national system for hospital exemption for named patient and non routine within one MS Traceability flow between cell donation vigilance - pharmacoviglance Specific GMP requirements Long term safety and efficacy follow up hesc - national prohibitions apply Incentives for SME Revise Annex 1 of Directive 2001/83/EC to establish new dossier requirements Directive 2009/120/EC specific requirements for ATMP 6 6

7 Directive 2001/83/EC revised by 2009/120/EC - requirements for ATMP Directive 2009/120/EC specific requirements for ATMP Human cells collected and donor tested according to Directives 2004/23/CE, 2006/17/CE and 2006/86/CE Traceability of all raw, starting materials and active substance TSE minimization and viral safety of active substance considering all raw and starting materials Scaffolds, cells, vectors, bank to produce vector = starting materials bioactive molecules and cell medium not part of AS = raw materials Characterisation include identity, purity, viability, potency, kariology, tumourigenicity, genetic stability Genetically modified cells = gene therapy + cell therapy requirements Biocompatibility of matrix, scafold, cells, excipients, substances in final product Risk based approach to construct the dossier Risk management plan include long term follow-up of safety and efficacy 7

8 Use favourable legal tools specific for ATMP Article 14º RISK BASED APPROACH Long term safety and efficacy follow up 8

9 RISK BASED APPROACH FOR ATMP S Due to the specific nature of advanced therapy medicinal products, a risk-based approach may be applied to determine the extent of quality, non-clinical and clinical data to be included in the marketing authorisation application,. The risk analysis, when applied, shall be included and described in Module 2. 9

10 RISK BASED APPROACH GUIDELINE published feb 2013 Guideline is intended to support the Applicant to identify the risks and associated risk factors and to establish a risk profile for their ATMP under development With the use of the identified risk profile the Applicant will be able to justify the extent of data to be included in the MAA dossier Risk: an unfavorable effect that can be attributed to the ATMP and is of concern to the patient and/or to third parties. Risk factor: a qualitative or quantitative characteristic that contributes to a specific risk following administration of an ATMP. Risk profiling: a methodological approach to systematically integrate all available information on risks and risk factors in order to obtain a profile of each individual risk associated with a specific ATMP. Risk profiling: Plot Map 10

11 RISK BASED APPROACH Consequences for the dossier Risk based approach not mandatory Strategy for each risk and discussion on conclusions and justifications supporting the extent of data to be included in the MAA CTD Mod 2.2. Result of the risk-based approach can be used as one starting point for the safety specifications as part of the Risk Management Plan. 11 The Risk-based approach for ATMP

12 RISK BASED APPROACH Examples of Risks regarding ATMPs Transmission of disease (viral, bacterial, fungal) Unwanted immune reaction Unwanted ectotopic engraftment/biodistribution Tumor formation Unintented alteration of cell homeostasis Toxicity of compounds and/or final product Shedding and transmission... 12

13 RISK BASED APPROACH Examples of potential risk factors for CBMP Origin of cells (autologous vs allogeneic) Ability to proliferate and differentiate Ability to initiate an immune response (as target or effector) Level of cell manipulation ( in vitro / ex vivo expansion/activation, genetic manipulation) manufacturing process including biologically active reagents Mode of administration (ex vivo perfusion, local, systemic) Duration of exposure (short to permanent) The Risk-based approach for ATMP

14 Cell Based Medicinal Products (Directive 2009/120/EC + Regulation 1394/2007) Somatic cell therapy medicinal product Tissue engineered Products - TEP Include cells or tissues subject to substantial manipulation cells or tissues subject to substantial manipulation so that biological characteristics, physiological functions or structural properties relevant for the intended clinical use have been altered Or just indicated for heterologous use not intended to be used for the same essential function(s) used to treating, preventing or diagnosing a disease through the pharmacological, immunological or metabolic action of its cells or tissues. = somatic cell therapy used with a view to, regenerating, repairing or replacing a human tissue = TEP 14

15 NOT substantial = NOT medicinal product : cutting; grinding; shaping; centrifugation; Regulation 1394/2007/EC soaking in antibiotic or antimicrobial solutions; sterilization; irradiation; cell separation, concentration or purification; filtering; lyophilization; freezing; cryopreservation; vitrification; heterologous use = medicinal product 15

16 TO BE A MEDICINAL PRODUCT not a TRANSPLANT CERTIFIED GMP UNDER MUTUAL RECOGNITION WITHIN EU AND WITH OTHER AGREED NON EU MEMBERS SUPPLIER QUALIFICATION FOR ALL RAW MATERIALS AND TRACEABILITY VALIDATION OF ASSEPTIC MANUFACTURING PROCESS GMP ANN1 EQUIPMENT QUALIFICATION GMP ANN15 BATCH RELEASE BASED ON PRODUCT TESTING BY QP PRE-ASSESSMENT FOR PRODUCT QUALITY, SAFETY EFFICACY AND FOLLOW-UP MODE OF ADMINISTRATION UNDER MANUFACTURER SUVERVISION PHARMACOVIGILANCE FOR LIFE LIABILITY ON ALL PARTS OF THE PROCUREMENT / PROCESS / PRODUCT / USE

17 Cell product definition - diversity Autologous or allogeneic Toti pluri adult starting material Separated enriched - clonal Single population multifactorial complex combination Cultured cell divisions genetic stability Cell bank or cell stock - Differentiation to be concluded prior or post administration Cell suspension matrix - combined CAT CLASSIFICATION PROCEDURE Margarida Menezes Ferreira

18 CLASIFICATION NON BINDING lack of harmonisation within EU and elsewhere DEFINITIONS REQUIRED cell, tissue, organism, vaccine, industrialprocess, heterologous use AUTOLOGOUS NO SUBSTANTIAL MANIPULATION Adipose stromal fraction cells separated by Collagenase Cells obtained and administered in the same surgical procedure DIFFERENT ESSENTIAL FUNCTION (NON-HOMOLOGOUS USE) bone marrow mesenchymal stromal cells in bone 163 pages of comments from 60 stakeholders many from organisations

19 CELL BASED MP IN EUROPEAN MEMBER STATES UNDER HOSPITAL EXEMPTION OR SPECIAL AUTHORISATION PROVISIONS Autologous / obtained in hospital or academic setting - MSC s for cardiac repair / bone reconstruction - Adypocytes for reconstruction - Chondrocyte - Dendritic cells for cancer - EU CENTRALISED AUTHORISATION - 2 Chondrocyte CHONDROCELECT MACI Li MD et al Regen. Med. (2014) 9(1), Dendritic cells - PROVENGE

20 Sources of variability in cell therapy MATERIALS Donor Collection Dynamic starting cell material Biological raw materials CONTROL Bioanalytical methods No standardised reference materials MANUFACTURE Same process different dynamics Length of process different differentiation stages Complex process multiple stages ADMINISTRATION Complex system often surgical procedures Patient response Margarida Menezes Ferreira

21 hierarchy of guidelines! 21

22 TARGET PROFILE Directive 2009/120/EC SPECIFICATIONS required for CB-ATMP identity, purity, viability, potency, kariology, tumourigenicity, genetic stability Genetically modified cells = gene therapy + cell therapy requirements EXTENSIVE CHARACTERISATION Based on previous knowledge + development relevant for CONSISTENCY - PROCESS VALIDATION - CQA COMPARABILITY 22 Margarida Menezes Ferreira

23 CHARACTERISATION physico-chemical PURITY = phenotypic and genotypic profile = Phenotype + Quantify / viable total (flow cytometry) - Relevant cells - Inert cells - Deleterious cells - Apoptotic cells - Viable cells - Cell debris - Exosomes = Genotype (sequencing PCR STR) - separated / purified populations - clonal cells - differentiation stage - genetically modified vs non GM Margarida Menezes Ferreira

24 potency assay considerations Potency has to be quantitative and related to relevant biological properties = drawn from characterisation (and preclinical studies) Potency may evolve during development define reference preparations Potency assay required for consistency, comparability, stability validated for MA Potency of active substance if final product not possible Functional assay might not be quantitative but can serve to cross validate potency measurement of surrogate markers mixed approaches possible and often necessary Quantification of mrna should be complemented with the expressed protein cells and induced differentiation / engraftment / ex vivo use might need kinetic studies to validate relevant biological activity(ies) 24

25 Confounding aspects to potency testing of CBMP insufficent knowledge on the active component(s) limited sample size / shelf life (autologous, primary cells) unknown mode of action / lack of appropriate biological atribute Structural complexity / Multifactorial actions - poor specificity Interfering substances / poor parallelism - poor accuracy inappropriate tools acceptance criteria / specifications too wide non linearity characterisation under dynamic conditions 25

26 MANUFACTURING PROCESS CELL SOURCING Standardise collection acceptance criteria SEPARATION Commercial devices Not substantial manipulation Generally not CPP Microbiol safety RSpecs? EXPANSION Developpment studies to define critical raw materials critical steps and cqa Upscale - comparability CPP - AS CQA or RSpecs Microbiol safety MODIFICATION Developpment studies to define critical raw materials critical steps and cqa CPP - AS CQA Microbiol safety FORMULATION Combination - biocompatibility CPP for TEP Microbiol safety FINAL PRODUCT Criopreservation Bedside preparation administration RSpecs Process validation Microbiol safety Standardise practice Margarida Menezes Ferreira

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28 Human cells = starting materials authorisation of tissues and cells procurement + donor testing by transplantation authority authorisation of collection and testing and tissue establishments (TE) for banking Export / Import activities in the EU by authorised TE TE ensures that imported cells from 3rd countries allows traceability to donor and collection and testing under equivalent standards as Directive Cells exported from EU comply with this Directive 28

29 Raw materials : reagents general text in the Eur Phar in preparation for serum/medium cytokines / growth factors enzymes (such as trypsin) antibodies individual proteins buffers plasmids/ viral vectors Identity Purity Biological Activity / Functionality Specific Activity Total Protein content Impurities, Product-related Impurities, Process-related Viral Safety / TSE compliance Microbial Contamination Stability / Storage conditions -GUIDELINE the use of bovine serum in the manufacture of human biological medicinal products (EMA/CHMP/BWP/457920/2012 rev.1) UNDER NEW REVISION - GUIDELINE the use of porcine trypsin used in the manufacture of human biological medicinal products (EMA/CHMP/BWP/814397/2011) DRAFT

30 ALL MEDICINAL PRODUCTS USING STEM CELLS AS STARTING MATERIAL Adult stem cells - Hematopoietic stem cells (HSC); Mesenchymal/stromal stem cells (MSCs); Tissue specific stem cells Embryonic stem cells (hescs) maintained in in vitro culture conditions as cell lines pluripotent - can differentiate to every cell type. in vitro differentiation generates cell populations with heterogeneity of cell surface markers as well as marker genes for pluripotency transplanted form teratoma (benign tumours) can be differentiated in vitro using either external factors in the culture medium, or by genetic modification Induced pluripotent stem cells (ips) artificially generated stem cells reprogrammed from somatic adult cells self-renewing capacity pluripotent form teratoma differentiation capacity seems to be dependent on the cell type and age of the cells from which the ips cells were reprogrammed.

31 QUALITY GENERAL identifying potential risks related to pluripotency, differentiation and lineage commitment Embryonic stem cells and ips cells should be lineage-committed before administration to patients Raw materials used in manufacturing require proper qualification (ie clinical grade) according to their use and persistance in the final product cells / viral vectors / factors / cytokines / antibodies / hormones / conditioned media always viral safety and TSE s - traceability ips if genetically modified = gene + cell therapy guidelines + GL on cell bank ICH Q5D

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33 Li MD et al Regen. Med. (2014) 9(1), 27 39

34 analysis of the impact on EU approvals Hospital exemption Classification status (EU vs national) EU requirements (eg GMP) Marketing authorisation procedure Certification Scientific advice Incentives (fee reductions for pre and post MA other than SME s) REVISION OF ATMP REGULATION 1394/2007 TO START SOON

35 THANK YOU FOR YOUR ATTENTION!