From bench to bedside in regenerative medicine development of stem cell therapies Dr. Gudrun Tiedemann

Transcription

1 From bench to bedside in regenerative medicine development of stem cell therapies Dr. Gudrun Tiedemann Gründungsveranstaltung der Deutschen Plattform NanoBioMedizin Frankfurt, 4. März 2015

2 Regenerative Medicine repair of malfunctioning cells, tissues and organs by stimulation of the body's own regenerative and repairing processes biological replacement new therapeutic approaches with conventional medicinal products (Growth factors, Cytokines, ) new products based on living cells cell and gene therapeutics engineered tissues combinations of cells/tissues and materials 2

3 Products based on living cells special features mainly defined by manufacturing process patient specific, often autologous concepts small batches specific application, often within surgery procedures very complex products, may contain additional substances (bio-molecules, biomaterials, chemical substances, scaffolds or matrices) may include medical devices as integral part rules necessary (as for all medical treatment) governing development, production, distribution and use with the essential aim: to safeguard public and patient health and without hindering research and innovation 3

4 From bench to bedside in regenerative medicine Medicines new scientific and technological developments often one step ahead existing rules necessitate often new/adapted rules, regulations and acts Agenda European Regulatory Environment Definition/Classification ATMPs Legal basics/regulatory requirements Translation from bench to bedside RTC - Development of (stem)cell based therapies Integration of Nanotechnology in RegMed 4

5 European Regulatory Environment two main regulatory regimes* the Medicines Directive (Germany: AMG) Medicinal Products (MP) European Directives (Germany: MPG) Medical Devices (MD) active substance with pharmacological, metabolic or immunological mechanism devices/materials with another mechanism (e.g. physical) when more than one mechanism involved (e.g. MP/MD, MP/Blood products) MP-/MDroute or both principal intended mechanism? Viable cells? Combination products *specific routes for: Transplantation (TPG): Organs, Transfusion (TFG): Blood products, Tissue: Quality and safety of human tissues and cells and others: cosmetics, food, care (spa treatments, massages,...) 5

6 European Regulatory Environment between the regimes? close the gap 2008 REGULATION (EC) NO 1394/2007 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL ON ADVANCED THERAPY MEDICINAL PRODUCTS (ATMP) 2009 implemented in German Arzneimittelgesetz (AMG, 15. Novelle) Arzneimittel für neuartige Therapien 6

7 REGULATION (EC) 1394/2007 lex specialis MP: additional provisions to Directive 2001/83/EC ADVANCED THERAPY MEDICINAL PRODUCTS ATMP GT gene therapy medicinal products to treat genetic diseases SCT somatic cell therapy medicinal products to cure, diagnose or prevent a disease TEP tissue engineered products to repair, regenerate or replace damaged or diseased human tissues Combination products cells/tissues (MP) incorporating medical device(s) (MD) as integral part Justification for combination products devices directive specifically excludes human cells or tissues being devices (European Council 1993a) where viable cells are present, their metabolic action is always considered to be the principal mode of action (European Parliament and Council 2007) where a product contains viable cells or tissues, the pharmacological, immunological or metabolic action of those cells or tissues shall be considered as the principal mode of action of the product (Reg. (EC) 1394/2007/EC Art.2.2) 7

8 Definitions/Classification Dir. 2009/120/EC amending Dir. 2001/83/EC as regards ATMPs Somatic cell therapy medicinal product (SCT) contains or consists of cells or tissues substantial manipulation* not intended to be used for the same essential function(s) treating, preventing or diagnosing a disease through the pharmacological, immunological or metabolic action of its cells or tissues Gene therapy medicinal product (GT) contains an active substance which contains or consists of a recombinant nucleic acid with a view to regulating, repairing, replacing, adding or deleting a genetic sequence its therapeutic, prophylactic or diagnostic effect relates directly to the recombinant nucleic acid sequence it contains, or to the product of genetic expression of this sequence *manipulations listed in Annex I to Regulation (EC) No 1394/2007 8

9 Definitions/Classification Reg. (EC) 1394/2007/EC Art.2.1 (b) Tissue engineered product (TEP) contains or consists of engineered cells or tissues to repair, regenerate or replace damaged or diseased human tissues may contain cells or tissues of human or animal origin, or both (viable or non-viable) may contain additional substances, such as cellular products, bio-molecules, biomaterials, chemical substances, scaffolds or matrices engineered cells or tissues Reg. (EC) 1394/2007/EC Art.2.1 (c) that have been subject to substantial manipulation* so that biological characteristics, physiological functions or structural properties relevant for the intended clinical use have been altered, or that are not intended to be used for the same essential function(s) in the recipient and the donor *manipulations listed in Annex I, in particular, shall not be considered as substantial manipulations The finished medicinal products may be combined with a medical device or active implantable medical device 9

10 Definitions/Classification Reg. (EC) 1394/2007/EC Art.2.1 (d) Combined advanced therapy medicinal product must incorporate, as an integral part of the product, one or more (active implantable) medical devices and its cellular or tissue part must contain viable cells or tissues, or its cellular or tissue part containing non-viable cells or tissues must be liable to act upon the human body with action that can be considered as primary to that of the devices referred to Issues and requirements for MA of combined ATMPs MD part shall meet the essential requirements of the MD-legislation (MD-route) whole product subject to final evaluation by the CAT (MP-route EMA) application for MA shall include (according to MD-Directives) a description of the physical characteristics of the MD-part the results of the assessment by a notified body 10

11 Legal basics/regulatory requirements REGULATION (EC) NO 1394/2007 (Article 1).lays down specific rules concerning the authorisation, supervision and pharmacovigilance of ATMPs Scope EXEMTION ATMPs which are intended to be placed on the market in MS and either prepared industrially or manufactured by a method involving an industrial process (in accordance with Directive 2001/83/EC) Main elements centralized MA procedure benefits outweigh the risks quality, efficacy and safety profile specific technical requirements guidelines and provisions for quality and preclinical/clinical data specific provisions for products that combine biological materials and chemical structures REG 1394/ Hospital Exemtion ATMPs prepared on a non-routine basis according to specific quality standards, and used within the same Member State in a hospital under the exclusive professional responsibility of a medical practitioner, in order to comply with an individual medical prescription for a custom-made product for an individual patient National requirements of MS Germany 4,3 + 21a,2-8 AMG 11

12 Germany AMG: ATMP centralized v. Hospital Exemtion CTD ATMP within the Scope of REG 1394/2007 EXEMTION 28 Preclinical development Clinical trials (GCP) ATMP EU-Marketing authorization : Centralized procedure (EMA/Commission) ATMP German Hospital Exemtion 4b ( 4b,3 given to others) mini CTD ATMP German- Marketing permission 21a AMG (PEI) manufactured in Germany according to specific quality standards on a non-routine basis medical prescribed in Germany as custom-made product for an individual patient used in Germany in a specialized patient care institution under responsibility of a medical practitioner ATMP: Manufacturer = User (decision by regional+federal CA) ATMP German Manufacturing Authorization 13 AMG (GMP) + 20b AMG withdrawal-permission 12

13 ATMPs from bench to bedside classical route according to MPs regimes Product development/manufacturing validation/application/authorization IMP-/product- manufacturing basic research pre-/nonclinical development clinical trials Phase I,II,III MA centralized/ (national) therapy/ market REGISTRY programs research/ ideas/ developmentstrategies in vitro/in vivo quality/safety characterisation validation animal models biodistribution differentiation... RCTs: safety efficacy CTD: quality safety efficacy added value/ reimbursement careresearch/ therapyvigilance? MP Industry: years, 1 Bio EUR 50 % for clin. trials, half for Phase III 13

14 ATMPs from bench to bedside through the jungle of regulations and quality requirements (EU/Germany) MD: development, application added value/ reimbursement CE- Mark EMA Product development/manufacturing validation/application/authorization IMP-/product- manufacturing GMP basic research research/ ideas/ developmentstrategies GLP pre-/nonclinical development in vitro/in vivo quality/safety characterisation validation animal models biodistribution differentiation... GCP clinical trials Phase I,II,III RCTs: safety efficacy MA centralized/ national CTD: quality safety efficacy nat. MA Hospital exemtion 4b,3+21a to others mini CTD EU MA therapy/ market? REGISTRY programs GVP careresearch/ therapyvigilance? Hospital exemtion 4b: manufacturer = user 14

15 ATMPs from bench to bedside through the jungle of Authorities and bodies (Germany/M-V) MD: development; notified body; product/manufacturing/application development basic research Animal protection research/ ideas/ developmentstrategies + GLP pre-/nonclinical (States) development (GLP) + in vitro/in vivo quality/safety characterisation validation animal models Ethic Commissions biodistribution differentiation... Notified Bodies (federally authorized sites) GLP-Supervisory Authorities + GCP clinical trials Phase I,II,III (GCP) RCTs: safety efficacy added value/ reimbursement CE- Mark EMA German State Authorities GMP (regional) i.e. AMÜSt in MV IMP-/product- manufacturing (GMP) MA EU (European/ MA national) CTD: quality safety efficacy therapy/ (market) REGISTRY programs careresearch/ therapyvigilance GVP mini CTD nat/ Hospital exemtion 4b,3+21a to others 4b/ 21a Hospital exemtion 4b: manufacturer = user? 15

16 Advice from Competent Authorities PEI Innovation office (ATMP) coordination of scientific advices regulatoriy issues incl. clinical trials preliminary tests of SME-status at EMA Referat for clinical trials questions to procedures of clinical studies application/approval of clinical trials (90+90 days!) National authorization of ATMP according to 4b/21a AMG German State Authorities for MPs (regional) manufacturing authorization withdrawal permission classification/advices application/approval of clinical trials for MD EMA - Committee for Advanced Therapies (CAT) Scientific Recommendation on Classification Certification of ATMPs Scientific Advice Briefing Meetings ATMP Evaluation of ATMS for MA draft opinion to CHMP CHMP opinion EC decision (total 277 days!) 16

17 ATMP Progress?? CAT monthly report ( ) Initial Evaluation of MAA for ATMP EU Total Submitted MAAs Positive draft opinion 1 TEP 0 1 GT** 1 GT** 1 SCT 1 TEP 1 0 6* Withdrawals Ongoing MAAs 4 *corresponding to 5 ATMPs ** same product Glybera PEI ( ) National MA for ATMP Germany Total Positive Opinion (TEP) 4 (TEP) 1 (SCT) 0 7 CAT monthly report ( ) Scientific recommendation on ATMP-classification EU Total Submitted o adopted Combined thereof 10* *7 TEP 2 SCT 1 GT 17

18 Translation Centers for Regenerative Medicine in Germany RTC founded in 2008 by Prof. Gustav Steinhoff, Director Heart Surgery, Rostock University financed by BMBF and State M-V located in the BMFZ of Rostock University Focus Regenerative Medicine stem cell research/ development/therapy Cardiovascular diseases 18

19 RTC Rostock Therapies (KHC: 800 OPs p.a.) Coronary surgery (350) Heart valves (300) Aorten surgery,. Stem cell therapies R&D Basic research SC-technologie SC-differentiation SC-modulation Cell programming forward pr. direct repr. Pre-/non clinical development in vitro assays animal models Clinical trial-program PoC-Manufacturing Translation Regulatory Affairs QA (GMP, GLP, GCP) Innovation management PR Training 19

20 RTC Bench to Bedside Quality assured GLP Pre-/non clinical development in vitro assays animal models Autologous BM GMP in-the box Manufacturing of cell products (contract/ Point of Care ) CliniMACS Prodigy Phase I (15) MI/Bypass/ CD /01-03/03 04/03-07/05 Promizing results! Phase II (20/20) MI/Bypass/ CD 133+ Phase III PERFECT (71/71) MI/Bypass/CD /09 ongoing Therapy/ REGISTRY Rostock MI/Bypass/CD ongoing GCP Clinical Trial program CD133+ primary BM-cells GVP SC-Registry 20

21 RTC Translation from bench to bedside GOAL Reimbursement QA Therapy GVP Register Basic Research new Research Approaches QA THE REGROWING HEART Cinical Development GCP Translation Manufacturing GMP Non-clinical Development GLP 21

22 RTC R&D programs including Nanotechnology Transfection of mirna in SC via magnetic nanoparticles Transfection of marker genes in cell lines with magnetic polyplexes CD133 + HSCs Modulation of CD133+ cells Cy3* mir/pei/mnp 18h DIC EGFP Transfected CD133 + HSCs hmscs 24 h after transfection with mirna/pei/mnp complexes, scale bar = 5 µm Efficient knockdown of target genes Functionality of delivered mirna Schade et al., Int. J. Mol. Sci.,2013 Flow cytometry Microscopy Uptake efficiency & cytotoxicity N. Voronina, P. Müller, F. Hausburg Stem cell marker expression (CD34; CD45; CD133; 7AAD) hmscs 24 h after transfection with pdna/pei/mnp complexes, scale bar = 10 µm Delyagina et al., Nanomedicine (Lond.).,2013

23 Nanotechnology in Regenerative Medicine - Options Medicinal product Material/Nano-part Intended for examples Tissue Cells/Tissue (bio) functional surfaces (bio) functional surfaces Tissue replacement cell growth in vitro/in situ Cells/Tissue Combination products application, distribution, retention (Stem)Cells detection of biomarker non/viral vectors for transfection drug targeting, diagnostic forward programming, SC-differentiation, SC-modulation, Gene therapy skin heart valves implants artificial organs (heart) capsulation, release targeted application, detection of malfunctioning cells, tissues and organs, therapy monitoring transfection of marker genes and microrna, mrna for improvement of intracellular mechnisms, Biological Pacemakers 23

24 Summary Regenerative Medicine new therapeutic/diagnostic approaches for regeneration, repair, replacement; based on living cells; may contain substances or materials (MD) Products of high Complexity interdisciplinary work along the value chain essential EU-Regulation since 2008 ATMPs (GT, SCT, TEP, combined products ) under the roof of MP-legislation regulatory requirements adapted to the specific features of ATMP classical MP-route centralized MA-procedure, quality requirements Hospital exemtion in very specific cases Translation Authorizations mandatory different Authorities, Commissions & Bodies including ethics and commercial calculations ( Added Value for reimbursement) Integration of Nanotechnology promotes Regenerative Medicine (Tissue Engineering, Cell programming, drug targeting, diagnostics..) A platform for NanoBioMedicine may enhance Innovation 24

25 Thank you!