Certification of quality and/or non-clinical data for ATMPs

Certification of quality and/or non-clinical data for ATMPs GLP Seminar, Helsinki 16.9.2014 Lääkealan turvallisuus- ja kehittämiskeskus 17.9.2014 Paula Salmikangas 1

Advanced Therapy Medicinal Products Gene Therapy Medicinal Products Somatic Cell Therapy Medicinal Products Tissue Engineering Products Genetically modified cells medical device + ATMP combined ATMP Lääkealan turvallisuus- ja kehittämiskeskus 17.9.2014 Paula Salmikangas 2

The EU legal / regulatory framework Blood 2002/98/EC Clinical Trials 2001/20/EC Paediatrics 1901/2006 Annex I 2003/63/EC 2009/120/EC Tissues/Cells 2004/23/EC Medicinal Products Community Code Dir. 2001/83/EC Advanced Therapy 1394/2007 PhVig legislation Dir. 2010/84/EU Reg. 1235/2010 Medicinal Products Centralised procedure Reg. 726/2004 Falsified Med. Dir. 2011/62/EU Other starting materials Medical Devices 93/42/EC, 90/385/EC GMP 2003/94/EC Orphans 141/2000 Variations 1084(5)/2003 1234/2008 Lääkealan turvallisuus- ja kehittämiskeskus 15.5.2013 Paula Salmikangas 3

Regulation 1394/2007/EC somatic cell therapy products, gene therapy products and tissue engineered products classified as medicinal products (ATMPs) cells either manipulated or intended for non homologous use a centralised marketing authorisation route for all ATMPs establishment of Committee for Advanced Therapies, CAT, for classification certification evaluation of ATMPs scientific advice and guidelines when marketing authorization granted, it is valid in whole EU possible to have post authorization efficacy and safety studies Lääkealan turvallisuus- ja kehittämiskeskus 4

EMA Committees for ATMPs CAT Chair: P.Salmikangas CHMP Chair: Dr. T.Salmonsson 5 double members Lääkealan turvallisuus- ja kehittämiskeskus 5

Marketing authorization applications / CAT 2009 2014 (May) 2009 2010 2011 2012 2013 2014 Total Approved Submitted 3 1 2 3 2 1 12 4 GTMP 2 1 1 3 1 SCTMP 1 1 1 TEP 1 2 2 1 6 2 Variations 0 0 1 1 9 2 13 Approved: ChondroCelect for cartilage repair MACI for cartilage repair Glybera for treatment of LPL deficiency Provenge for treatment of advanced prostate cancer Currently 4 ATMPs under evaluation, 2 new starting Q3 4/2014 Lääkealan turvallisuus- ja kehittämiskeskus 6

Special issues for ATMP assessment ATMPs are complex pharmaceuticals gene therapy: transgene, type of vector, genetically modified cells cell therapy: autologous, allogeneic, complex process, combination products assessment requires expertise from several areas e.g. tissue engineering, gene therapy, cell therapy, biotechnology, surgery, pharmacovigilance, risk management, medical devices and ethics Specific administration of certain ATMPs (catheters, surgery etc.) Specific safety issues (e.g. integrational mutagenesis of GTMPs, biodistribution/ectopic tissue formation of cell based MPs) Mode of action: treatment of disease to repair/regeneration Special challenges concerning manufacturing/quality, safety and efficacy studies Lääkealan turvallisuus- ja kehittämiskeskus

cell based medicinal product DEFINITIONS AND QUALITY PRODUCT DEFINITION qualified cell population (s) in the appropriate vehicle for the intended action PRODUCT CHARACTERISATION - to ensure: Consistency of the active substance / finished product Validation of the manufacturing process Comparability when manufacturing changes are introduced Stability throughout shelf life Release specifications selected from characterisation studies SPECIFIC REQUIREMENTS FOR CBMP : Directive 2009/120/EC + GL CBMP Identity phenotypic profile - cell markers Purity and Viability relevant population / populations in mixture / viable cell % Impurities unwanted cells, reagents, adventitious agents, sterility, endo, mycoplasma Potency quantitative measure of the biological activity related to the intended action karyology, tumourigenicity, genetic stability specially relevant for dividing differentiating cell populations Lääkealan turvallisuus- ja kehittämiskeskus 8

Lääkealan turvallisuus- ja kehittämiskeskus

Lääkealan turvallisuus- ja kehittämiskeskus 17.9.2014 Paula Salmikangas 10

Risks vs. limitations of ATMPs infections (microbial contamination of starting materials or during processing) tumourigenicity (cell transformation, integration to genome) dedifferentation / loss of function of the cells immunogenicity, rejection ectopic engraftment of cells to non-target tissues shedding (genet. modif. CBMPs; germ line, environment) small sample sizes, short shelf-lives, availability of proper animal models, applicability of analytical methods etc. Risk-based approach for all ATMPs http://www.ema.europa.eu/docs/en_gb/document_library/scientific_guideline/2013/03/wc500139748.pdf Lääkealan turvallisuus- ja kehittämiskeskus 17.9.2014 Paula Salmikangas 11

ATMP clinical trials in EU (EudraCT Database) Maciulaitis, R. et al. (2012) Molecular Therapy 20: 479-482 Lääkealan turvallisuus- ja kehittämiskeskus 12

Only for SMEs ATMP certification Scientific evaluation by CAT of - quality data (module 3) - non-clinical data (module 4) 90 day procedure CAT evaluation report and EMA certificate 5 certifications finalised: - Bone marrow derived progenitor cells for cardiac repair (quality: May 2010) - Autologous expanded smooth muscle derived cells for treatment of stress urinary incontinence (quality: Oct 2012 ; non-clinical: Sept 2013) - Autologous oral mucosal cells (quality + non-clinical: April 2014) - Autologous bone marrow derived MSC (quality: April 2014) Lääkealan turvallisuus- ja kehittämiskeskus 17.9.2014 Paula Salmikangas 14

As part of the certification, a site visit can be requested by the assessors and/or CAT GMP-related visit for quality and manufacturing GLP-related visit for non-clinical studies - no standards yet for the site visits - no site visits conducted thus far Lääkealan turvallisuus- ja kehittämiskeskus 17.9.2014 Paula Salmikangas 18

Lääkealan turvallisuus- ja kehittämiskeskus Paula Salmikangas23.4.2010 Thank you for your attention!