Advanced Therapy Medicinal Products: Role and Funtion of the CAT. Martina Schuessler-Lenz,M.D. Paul-Ehrlich Institut, Germany

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1 Advanced Therapy Medicinal Products: Role and Funtion of the CAT Martina Schuessler-Lenz,M.D. Paul-Ehrlich Institut, Germany

2 Paul-Ehrlich Institut, Langen, Germany -German Federal Agency for Sera and Vaccines -Division of Medical Biotechnology (Klaus Cichutek, Chairman of GTWP of EMEA) -Chairman of the Committee for Advanced Therapies: Christian Schneider:

3 Advanced Therapy Regulation Challenges with Advanced Therapies The Committee for Advanced Therapies (CAT) June 25, 2009 Martina Schuessler-Lenz 3

4 The new Regulation (EC)1394/2007 on Advanced Therapy Medicinal Products Applies for - ATMPs intended to be placed on the community market and either prepared industrially or manufactured by a method involving an industriell process - Products derived from autologous or allogenic cell origin For further reading: June 25, 2009 Martina Schuessler-Lenz 4

5 Bridging the Gap Legislation Medical Devices Science 93/42/EEC Regulation on Advanced Therapies Advanced Therapies Medicinal Products 2001/83/EC Medical Devices Tissue Engineering Cell Therapy Gene Therapy Biotech (e.g. insulin) Pharmaceuticals (e.g. aspirin) NEW Committee for Advanced Therapies (CAT) Specific expertise CHMP expertise June 25, 2009 Martina Schuessler-Lenz By P. Celis, EMEA 5

6 What are Advanced Therapy Medicinal Products? Advanced Therapy medicinal products (ATMP) - Gene therapy products - Somatic Cell therapy products - Tissue engineered products TEP Defined in new legislation (Regulation 1394/2007) Gene therapy and somatic Cell therapy MP Annex I to Dir 2001/83 (under revision) June 25, 2009 Martina Schuessler-Lenz By P. Celis, EMEA 6

7 Key Elements from Regulation (1) Definition of Advanced Therapy MP Definition of Tissue engineered product - TEP now considered MP Principles of existing legislation on medicines apply to advanced therapies: - marketing authorisation - demonstration of Quality, Safety & Efficacy - post-authorisation vigilance Centralised procedure mandatory: - pooling of Community expertise - harmonised requirements & evaluation - ensure uniform and direct access to market June 25, 2009 Martina Schuessler-Lenz By P. Celis, EMEA 7

8 Key Elements from Regulation (2) New Committee for Advanced Therapies (CAT) - Multidisciplinary committee - Gather some of the best available experts in Europe - To assess the quality, safety and efficacy of ATMPs June 25, 2009 Martina Schuessler-Lenz By P. Celis, EMEA 8

9 EudraCT clinical trial applications in the EU Somatic cell therapy MPs 3Q Q Q Q Q 2009 (trials / original products) ( 25 / 13 ) ( 73 / 59 ) (132/112) (213/171) (249/186) cancer immunotherapy cardio-vascular skin/liver/lung/eye/diabetes/ intestine/bone TE neurological lymphohistiocytosis (HLH) AIDS infertility June 25, 2009 Martina Schuessler-Lenz 9

10 Somatic cell therapies/ TE products: a variety of products/indications Cartilage repair Autologous chondrocyte transplantation (ACT) 1st & 2nd & 3 rd generation products Skin regeneration Different skin cells (keratinocytes, fibroblasts) in combination with a sheet-like matrices/scaffolds Acute wounds, diabetic foot skin ulcers Bone regeneration Osteoblasts or bone-marrow-derived stem cells combined with ceramic-based scaffolds or biomaterials Cardiovascular regeneration Hematopoetic or Mesenchymal Stem/Stromal Cells for heart regeneration Engineered autologous/allogeneic blood vessels or heart valves June 25, 2009 Martina Schuessler-Lenz 10

11 Challenges of Advanced Therapies Aims: Quality aspects -Tumorigenicity -Identity -Purity -Sterility -Potency -Cell viability Well defined investigational product Non-clinical aspects -Suitable animal model -Biodistribution -Tumorigenicity -Immunogenicity Information on target organs, Selection of safe dose, Information on route of administration/schedule Predict response in humans Clinical aspects Safety Efficacy Benefit/Risk June 25, 2009 Martina Schuessler-Lenz 11

12 Challenge: Potency ICH Q6B: Potency is the quantitative measure of biological activity based on the attribute of the product, which is linked to the relevant biological properties should be based on the intended biological effect which should ideally be related to the clinical response can be in vitro or in vivo test can be surrogate marker can also be measured on mode of action (e.g. ectopic model) ideally in place when first IMD is produced combination of assays may be needed during development markers for potency and purity should not be mixed reference to preclinical and clinical data may be needed June 25, 2009 Martina Schuessler-Lenz By R. Sanzenbacher, PEI 12

13 Challenge: Potency Example autologous chondrocyte implanation: The relevant biological properties of chondrocytes to be implanted: capacity to generate hyaline cartilage. In vivo potency assay: takes too much time, consumes too much cells - no cells left for implantation. Solution: surrogate in vitro assay: e.g. collagen type II expression, aggrecan release, proteoglycans. But: how relate to clinical response when many factors influence clinical outcome? -quality of harvest cells -patient microinvironment in knee -genetic factors -quality of surgery -post-op rehabilitation June 25, 2009 Martina Schuessler-Lenz 13

14 Challenge: Non-clinical Toxicology Toxicity of genetically modified salmonella - Cancer vaccine: attenuated salmonella carrying tumor antigen - Human vaccine strain does not induce an immune response in mice - Salmonella typhimurium strain in homologous mouse model: different biodistribution, toxicity not predictive for humans Challenge: No sufficiently informative non-clinical model at all! June 25, 2009 Martina Schuessler-Lenz 14

15 Challenge: Clinical development General aspects (GL on human cell-based medicinal products) When a CBMP enters the clinical development phase the same principles as for other medicinal products apply... a deviation from Phase I to Phase III clinical trials progression is acceptable but needs to be justified by the specificity of CBMP. The clinical development plan should include - pharmacodynamic studies, - pharmacokinetic studies, - mechanism of action studies, - dose finding studies, - randomized controlled trials June 25, 2009 Martina Schuessler-Lenz 15

16 Challenge: Clinical development Example Autologous chondrocyte implantation (ACI) - Since 1994 more than ACIs performed - Several companies in EU provide expanded autologous chondrocyte products for implantation - Efficacy and safety for most products not proven no mechanism of action studies, no dose finding studies, in general no randomized controlled trials Challenge: sufficient information on efficacy and safety for Market Authorisation? June 25, 2009 Martina Schuessler-Lenz 16

17 Quality Non-Clinical - Impurities - Cells: Culture conditions and their impact on differentiation - ( ) - tissue cross-reactivity? - unwanted biodistribution? - toxicity? B R I D G I N G Clinical - additional clinical data required? By Ch. Schneider June 25, 2009 Martina Schuessler-Lenz 17

18 Science - (see above) - How to find the correct regulatory routes for guidance documents (e.g. cell-based tumour vaccines) -How to deal with products that have already been used without evidence? - Regulation of long-term follow-up of efficacy Regulation B R I D G I N G Ethics - How to perform first-in-human trials? - How to deal e.g. with the risk of inserational mutagenesis? June 25, 2009 Martina Schuessler-Lenz By Ch. Schneider 18

19 Why the CAT Evaluation of ATMPs requires very specific expertise -Beyond traditional pharmaceutical field -Covers areas bordering biotechnology -Medical device Composition shall ensure coverage of all relevant scientific areas -Gene therapy -Cell therapy -Medical device -Pharmacovigilance -Tissue engineering -Ethics (Recital 10, 11 of Regulation EC 1394/2007) June 25, 2009 Martina Schuessler-Lenz 19

20 The CAT Composition - 1 member per member state (+ 1 alternate) - 5 joint CHMP-CAT members* - 2 members representing patient organisations (+2 alternates) - 2 members representing doctors (+ 2 alternates) * Spain, Denmark, Lithuania, Portugal, Luxemburg June 25, 2009 Martina Schuessler-Lenz 20

21 Composition of the CAT CAT June 25, 2009 Martina Schuessler-Lenz 21 By M-P Pinheiro

22 CAT Expertise June 25, 2009 Martina Schuessler-Lenz L. D Apote 22

23 The CAT Tasks of CAT - Draft opinion to CHMP on marketing authorisation of ATMPs - Classification procedure: is a product an ATMP? Scientific recommendation from CAT - Certification procedure: Q/N-C review, for ATMP only CAT opinion EMEA certificatio - Develop guidelines on ATMPs - Scientific Advice for ATMP CAT actively involved in all SA for ATMP (via SAWP) - Other task, eg consultation by CHMP on non-atmps, advice to Commission (Article 23 of Regulation EC 1394/2007) June 25, 2009 Martina Schuessler-Lenz 23

24 Assessment teams for standard products Assessment Team 1 Assessment Team 2 CHMP Rapporteur CHMP Rapporteur Q / S / E Experts Q / S / E Experts For any scientific evaluation in respect of a procedure a rapporteur shall be appointed from amongst the members of the Committee or alternates. The appointment of the rapporteur shall be made on the basis of objective criteria, which will allow the use of the best available expertise in the EU on the relevant scientific area. Reference document: CHMP RAPPORTEUR/CO-RAPPORTEUR APPOINTMENT: PRINCIPLES, OBJECTIVE CRITERIA and METHODOLOGY (EMEA/124066/2005 ) June 25, 2009 Martina Schuessler-Lenz 24 By M-P Pinheiro

25 CAT-CHMP assessment teams for ATMPs(1) Two extended assessment teams responsible for review of ATMP MAA Assessment Team 1 Assessment Team 2 CAT Rapporteur CAT Co-Rapporteur CHMP Co-ordinator CHMP Co-ordinator Q/S/E/Phvg/ERA (ATMPs) experts Q/S/E/Phvg/ERA (ATMPs) experts June 25, 2009 Martina Schuessler-Lenz 25 By M-P Pinheiro

26 CAT-CHMP assessment teams for ATMPs (2) ASSESMENT TEAM 1 CAT Rapporteur CHMP Co-ordinator ASSESMENT TEAM 2 CAT Co-Rapporteur CHMP Co-ordinator Q/S/E/Phvg/ERA (ATMPs) experts CHMP Q/S/E/Phvg/ERA (ATMPs) experts CAT (Co)Rapp coordinate procedure & discussions at CAT + prepare draft opinions and assessment reports Peer review by 1 CHMP member + 1 (or more) CAT member(s) CHMP Co-ordinator ordinator(s) responsible for flow of information between CAT & CHMP + discussion/adoption of opinion at CHMP June 25, 2009 Martina Schuessler-Lenz 26 By M-P Pinheiro CAT

27 CAT * Scientific Assessment (incl. Day 80/150 AR, Adoption LoQ, LoOI) * Adopt draft opinion (Day 182) CHMP * Appoint Rapporteur [Art. 62(1) Reg. 726/2004] * Adopt FINAL CHMP opinion (by 210 Days) APPOINT ASS. TEAMS CAT SCIENTIFIC ASSESSMENT CAT SCIENTIFIC ASSESSMENT Appointment Assessment teams Evaluation Start Day 0 Day 80 AR CHMP Comments Day 120 LoQ Day 121 response Day 120 LoQ to CHMP - highlights M.O./divergence Day 150 AR CHMP Comments Day 170 LoOI Day 171 CAT OE Day 171 Grounds for approval/ refusal transmission to CHMP* Day 200 CAT adopts draft opinion Day 210 CHMP adopts final opinion CHMP INTERACTION with CAT * Day 180 CHMP discussion on grounds for approval/refusal By M-P Pinheiro June 25, 2009 Martina Schuessler-Lenz ** Day 210 CHMP discussion and decision on 27 need for adoption of a LoOI and/or an oral explanation

28 The CAT within EMEA Combined ATMP/MD EU NB PDCO BPWP VWP CTWP Diabetes & Endocrinology QWP Cardiovascular Oncology SWP CNS CAT SAWP CHMP ATMP (Gene) BWP GTWP HIV/ Viral Diseases Phgenomics WP Diagnostics PhWP EWP COMP WPs SAGs GMO June Competent 25, 2009 Martina Schuessler-Lenz 28 Authorities By M-P Pinheiro

29 CAT MONTHLY REPORT INITIAL EVALUATION ATMP MAAs CONTRIBUTION TO SCIENTIFIC ADVICE April meeting -Lecture on trachea transplants, Spain -Guidelines discussed -Scientific discussion on xenogeneic cells -LoQ for marketing authorisation adopted -Statistics SCIENTIFIC RECOMMENDATION CERTIFICATION June 25, 2009 Martina Schuessler-Lenz 29 Draft opinion prepared by the CAT will be reflected in the CHMP press release

30 Thank you for your attention Special thanks to Patrick Celis and collegues from CAT Secretariat June 25, 2009 Martina Schuessler-Lenz 30