Advanced Therapy Medicinal Products: Present and Future Regulation in the EU

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1 Advanced Therapy Medicinal Products: Present and Future Regulation in the EU Definition and development of medicinal products and subclasses Gene transfer/therapy medicinal products Somatic cell therapy and tissue-engineered medicinal products Tissue preparations Klaus Cichutek Paul-, Langen, Germany Frankfurt, 087 March 2007 Advanced Therapy Medicinal Products: Present and Future Regulation in the EU Definition and development of medicinal products and subclasses Gene transfer/therapy medicinal products Somatic cell therapy and tissue-engineered medicinal products Tissue preparations Klaus Cichutek Paul-, Langen, Germany Frankfurt, 08 March 2007

2 Medicinal Product definition according to Article 1 No. 2 of Directive 2001/83/EC Criteria accrdg. to a) substance intended for treatment or prevention of disease in humans Criteria accrdg. to b) restoring, correcting, modifying physiological functions pharmcological, immunological or metabolic action or making a (in vivo) diagnosis Von Chemotherapeutika zu biologischen Arzneimittel Virus-Lebendimpstoffe Gentransfer- Arzneimittel Sera, Immunglobuline, monoklonale Antikörper, Antikörper-Rezeptor Rezeptor- Hybridproteine Blutzubereitungen Chemothera- peutika rekombinante Proteine Somatische Zelltherapeutika Tissue engineered -Arzneimittel

3 Classes of medicinal products (Arzneimittel( Arzneimittel) Drugs contain as the active ingredient a chemical substance Biologicals / Biopharmaceuticals contain as the active ingredient a biological substance Biotechnologicals classical: fermentation products modern: recombinant DNA technology medicinal products Herbal medicines - substances of or extracts of herbs, plants etc. Biological medicinal products (biologicals) Biological medicinal products contain as active substances micro-organisms (incldg. viruses) or their components or (live virus vaccines, split vaccines, gene transfer vectors) plant, human or animal material or (allergens, plasma-derived products, sera, IVIGs, cellular blood components, cells for bone marrow transplantation, cell or gene therapy) or are manufactured by living mammalian or bacterial cells (hormones, cytokines, recombinant proteins, monoclonal antibodies). The quality of biological medicinal products depends on the manufacturing process, in-process-controls, but less so on end-product quality assessment. Biologicals exclude herbal medicines.

4 Classical biologicals Biological medicinal products Vaccines, sera, immunoglobulins, allergens, human plasmaderived products, cellular blood components, immunomodulators, tissue preparations Biotechnology or recombinant DNA technology-derived biologicals monoclonal antibodies, recombinant proteins, hormones, cytokines, enzymes Advanced therapy products gene therapy products cell therapy products tissue engineered products Amtsaufgaben Genehmigung der klinischen Prüfung Zulassung Experimentelle Testung/ staatliche Chargenprüfung und - freigabe Pharmakovigilanz Impfstoffe (human, vet.) Blutzube- reitungen, Plasma- produkte Sera, Immun- globuline, mak Arzneimittel für neuartige Therapien Gentransfer- Arzneimittel Zellthera- peutika (human, xenogen) Gewebe- züchtungs- Arzneimittel GMP-/GCP-/GLP-Inspektionen Gewebe- Zubereitungen (muskulo- Allergene skeletal) Experimentelle Forschung

5 Examples of successful biological medicinal products Recombinant proteins (produced in bacteria or mammalian cells) human recombinant erythropoietin (EPO; Amgen) Monoclonal antibodies (produced in mammalian hybridoma cells) OKT4 (anti-cd4 mab) as an immunosuppressant inhibiting allograft rejection, Herceptin (anti-her2neu mab for mammacarcinoma treatment) Sera and other human plasma-derived products blood clotting factor IX for hemophilia B Vaccines human papilloma virus vaccines (Cervarix (GSK), Gardasil (Sanofi Pasteur MSD)) Blood components human stem cell transplants (BMT) Cell therapy products ACT, human stem cell transplants for heart infarction Gene therapy/transfer products Cerepro (Adv-HSV-tk; Ark Therapeutics Inc.) Allergens grass pollen allergen Pre-clinical and clinical development of medicinal products Die Entwicklung eines neuen Arzneimittels benötigt mehr als 10 Jahre vom Labor bis zum fertigen Produkt... Patentierung AM-Herstellung Klin. Prüfung Zulassungsverfahren In vitro Präklinik In vivo Phase I Phase II Phase III Phase IV Idee Phase II Phase III Phase IV Arzneimittel vector construction, cell transduction, testing in vitro and in an animal model safety safety, dosing efficacy low-frequency Side effects

6 Pre-clinical and clinical development of medicinal products Data required in an application for marketing authorisation. Patentierung AM-Herstellung Klin. Prüfung Zulassungsverfahren In vitro Präklinik In vivo Phase I Phase II Phase III Phase IV Idee Phase II Phase III Phase IV Arzneimittel development genetics, non-clincal data, pharmacologicaltoxicological testing quality, manufacture clinical data

7 Advanced Therapy Medicinal Products: Present and Future Regulation in the EU Definition and development of medicinal products and subclasses Gene transfer/therapy medicinal products Somatic cell therapy and tissue-engineered medicinal products Tissue preparations Klaus Cichutek Paul-, Langen, Germany Frankfurt, 08 March 2007 Beispiel Gentransfer-Arzneimittel 1. Was sind Gentransfer-Arzneimittel? 2. Erfolgreiche und weniger erfolgreiche klinische Prüfungen 3. Fallbeispiele - Krebsbehandlung - Erfolgreiche Behandlung der erworbenen Immunschwächekrankheit X-SCID - Gefäßerkrankungen und Vakzinierungen

8 DNA (ca Gene, identischer Satz in jeder Körperzelle) Genexpression RNA (gewebespezifisch) Proteine (> , gewebespezifisch) Gene addition instead of homologous recombination reality: gene addition future: gene repair

9 Virale Vektoren Nicht-virale Vektoren Therapeutisches Protein Virus und viraler Vektor im Vergleich Virus Vektor Therapeutisches Protein

10 Verpackungszelle zur Produktion von retroviralen Genfähren Virusbausteine Virusgene Therapiegen Genfähren = Vektoren Gentransfer beim Menschen ex vivo 1) Entnahme und Reinigung der Zielzellen/Zellinien 2) Gentransfer 3) Reinfusion modifizierter Zellen (autolog oder allogen) in vivo Direkte Applikation: virale Vektoren nicht-virale Vektoren nackte DNA

11 Entwicklung eines Arzneimittels auf der Basis eines anti-tumoralen tumoralen Gens Transfer des antitumoralen Gens Tumorzelle stirbt ab Präklinische Untersuchungen In vitro Überprüfung des therapeutischen Konzepts in der Zellkultur Auswahl eines optimalen Vektorsystem Wie effizient werden die Tumorzellen abgetötet? In vivo Prüfung des Arzneimittels im Tiermodell Auswahl geeigneter Tiermodelle (Maus-Tumormodell) Wirksamkeit (Schrumpfen Tumoren in der Maus?) Sicherheit (Toxizität) Pharmakologische Parameter (Dosis, Verteilung im Organismus)

12 Phase I kleine Patientengruppe Sicherheit und Verträglichkeit? Dosisfindung? Phase II therapeutisch-exploratorisch Ist eine Wirksamkeit nachweisbar? Nebenwirkungen? Phase III therapeutisch-konfirmatorisch große Patientengruppe (multizentrisch) Doppel-Blindstudien (Placebo!) Statistisch abgesicherte Wirksamkeit Fallbeispiel 1: Behandlung der Ornithin-Transcarbamylase-Defizienz

13 Ornithin Transcarbamylase-Defiziens X-gekoppelt, monogenetisch, rezessiv/dominant (5-10% Frauen weisen Symptome auf) Häufgkeit: 1/25000 Häufig bereits bei der Geburt tödlich auf Grund von erhöhtem NH 4 -Spiegel (Hyperammonemie) Partielle Defizienz: geringe enzymatische Aktivität, Symptome erst in höherem Alter Protein-freie Diät, Lebertransplantation OTC-Gentherapie im Rahmen einer akademischen klinische Prüfung in den USA 18-jähriger männlicher Patient mit geringer Enzymaktivität Behandlung mit adenoviralen Vektoren Dosis 3.8x10 13 Partikel, intrahepatische Arterie Tag 0: Fieber, Übelkeit, Rückenschmerzen Tag 1: Hyperammonämie, Gelbsucht Tag 2-4: disseminierende intravaskuläre Blutgerinnung, Leberversagen, multiples Organversagen, Koma Tod des Patienten nach vier Tagen Ursache: massive Immunreaktion gegen Vektorpartikel, zusätzliche Komplikation durch Hyperammonämie

14 Gentherapie-Todesfall: Krisenmanagement des PEI Gentherapie-Todesfall in den USA im September 1999 (4 Tage nach Verabreichung von Adenovirus-Vektoren) Informationstreffen am PEI ( 62 AMG) Bewertung (PEI und KSG-BÄK) Vorübergehende Unterbrechung von Studien mit ähnlicher Applikationsweise Fallbeispiel 2: Behandlung einer angeborenen Immunschwächekrankheit (X-SCID; severe combined immunodeficiency syndrome

15 Blutzellen bilden sich aus hämatopoetischen Stammzellen Transfer des IL2R-Gens in hämatopoetische Stammzellen

16

17 Retrovirally modified blood stem cells in SCID benefit in 23 of 28 patients 3 leukemias in a SCID-X1 trial (P4, P5 und P10) Cavazzana-Calvo et al., 2000 practical risk/side effect: insertional oncogenesis new measures: monitoring patients for delayed adverse events (longterm follow-up) Adv-VEGF application for neovascularization plasmid DNA - angiogenic genes: FGF, VEGF, andere adenoviral vectors - E1, E2, E4 risks: - acute inflammatory reaction - cancer ( therapeutic gene) - neo-angiogenesis (therapeutic gene)

18 Tumour vaccines theoretical risks: inflammation auto-immune disease Conditionally replicating oncolytic virus: ICH Workshop Chicago (November 2005) Virus engineered to direct their cytotoxicity towards cancer cells normal cell: abortive replication productive replication, cell lysis virus kills tumor cell, spreads to neighbours oncolytic virus tumor cell Theoretical advantages: - viral replication within tumor mass allows infection of additional cells - lack of cross-resistance with standard therapies - ability to cause tumor destruction by different mechanisms Theoretical risks: - introduction of new pathogens into the human population and adaptation

19 DNA and vectored vaccines plasmid DNA AAV MVA Vaccinia adenoviral vectors theoretical risks: cancer auto-immune disease clinical trials in healthy volunteers CHMP and WPs collaborate in support of advanced therapy product development Biologicals Working Party Cell-based Product Working Party Gene Therapy Working Party CHMP Safety Working Party Quality Working Party Pharmacovigilance Working Party Scientific Advice Working Party Efficacy Working Party + Specific ad-hoc working groups or sub-group meetings when needed Blood and Plasma Working Party Vaccine Working Party

20 CHMP Gene Therapy Working Party (GTWP) members harmonize scientific views in gene therapy Core members GTWP chair MS regulators with GT expertise CHMP WP representatives Consultation of gene therapy experts from academia from industry MS contact persons form EU national competent authorities industry experts CHMP WPs academia experts GTWP CHMP MS experts regulatory agencies Concept Papers notify the public about guideline development consultation of stakeholders briefing meetings, protocol assistance, scientific advice, licensing procedure discussion in and among experts in the CHMP WPs and the BCG Concept Paper 3- to 6-months public consultation Note for guidance 3- to 6-months public consultation

21 Gene therapy guidelines (EU) CPMP/BWP/3088/99 Note for Guidance on the Quality, Preclinical and Clinical Aspects of Gene Transfer Medicinal Products Draft Guideline on Genetically Modified Cells product- specific Draft Guideline on Preventive Gene Transfer Vaccines quality CPMP/BWP/2458/03 CPMP Position Statement on Development and Manufacture of Lentiviral Vectors non-clinical EMEA/CHMP/GTWP/203821/05 Guideline on the Non-Clinical Studies Prior to Clinical Use of Gene Therapy Medicinal Products (Released for Consultation November 2005) clinical Draft Clinical monitoring of subjects treated with gene therapy medicinal products EMEA/273974/05 ICH Guideline on Non-Clinical testing for Considerations Inadvertent Germline Transmission of General Principles to Gene Transfer Vectors (Adopted by CHMP Address the Risk of November 2006) Inadvertant Germline Integration of Gene EMEA/CHMP/203831/05 Therapy Vectors Guideline on the Scientific Requirements (Oct. 2006) for the Environmental Risk Assessment of Gene Therapy Medicinal Products (Released for Consultation Nov. Federal 2005) Agency for Sera and Vaccines Principle regulatory issues in gene therapy Replication-competent virus generated in helper cell RCR initially detected, batches not released RCA accepted to a certain extent in cancer RCL discussion on-going safer packaging cell lines in use Direct effects of vector particles acute DIC induced by adv following systemic use of high titers liver toxicity of AAV particles in seropositives due to immune effects Non-target effects of vector or gene product biodistribution of vector after in vivo delivery inadvertant germline transmission retinal neoplasm by circulating FGF retinal neovascularization by circulating VEGF leukemia induced by vector insertions Complexity of the technology various vectors (>6) various genes (30.000) various gene applications (3) (protein, antisense, ribozyme) various disease applications (common and rare) various treatment strategies preventive, therapeutic, in vivo diagnostic

22 Non-clinical pharmacology/ biodistribution studies in animals (2 different species (rodent and non-rodent), both sexes) Draft decision tree: non-clinical germline transmission studies prior to first use of vector/dna in non-sterile patients/subjects Is vector DNA found associated with the gonads? yes Is vector DNA detected within cells in the gonadal compartment? no no no Does the vector DNA signal persist with time? yes Germline transmission studies not necessary. no Is vector transmitted from F0 to F1 (breeding study)? Studies resulting in a negative answer to the respective question listed in one of the squares should be followed by considering further testing as indicated. However, additional studies are not mandatory, but should be considered taking into account the parameters described in the text. yes yes sperm Is vector DNA detected within oocytes/sperm cells? yes cells oocytes Directive 2001/20/EC No gene therapy trials may be carried out which result in modifications to the subject s germline genetic identity.

23

24 High visibility in the field of regulatory responses to leukemia-cases in

25 + 2 gene transfer medicinal products on the Chinese market: - Since 2003: adv-p53 - Since 2005: Onyx-like oncolytic replicating adv (Oncorine)

26 Advanced Therapy Medicinal Products: Present and Future Regulation in the EU Definition and development of medicinal products and subclasses Gene transfer/therapy medicinal products Somatic cell therapy and tissue-engineered medicinal products Tissue preparations Klaus Cichutek Paul-, Langen, Germany Frankfurt, 08 March 2007 Are cells used in humans medicinal products? Definition of the term medicinal product according to Article 1 No. 2 of Directive 2001/83/EC Criteria: 1) Cells are substances. 2) According to a) the cells are intended for treatment or prevention of disease in human beings. 3) According to b) they may be administered to human beings with a view to making a medical diagnosis or to restore, correct or modify physiological functions. 4) They exert pharmacological, immunological or metabolic action.

27 Cell-containing medicinal products blood products containing cells gene therapy MPs somatic cell therapy MPs other cell-containing containing MPs cells for haematopoietic reconstitution or transfusion medicine cells intendedly modified by preventive, diagnostic or therapeutic gene(s) cells manipulated non-manipulated to achieve cells substantial alteration of their biological characteristics Advanced therapy products at present: gene therapy and somatic cell therapy products Legal EU definition according to Directive 2001/83/EC Somatic Cell Therapy Medicinal Products (SCT-MPs) Criteria living cells from humans or animals substantially altered as a result of their manipulation to obtain a diagnostic, preventive or therapeutic effect

28 Somatic Cell Therapy (CT) Medicinal Products contain substantially altered living cells cell line allogeneic cells autologous cells manipulations likely to result in substantially altered biological characteristics for intended use - culture - growth factor treatment - differentiation/ dedifferentiation - stimulation/activation Somatic Cell Therapy MPs manipulations unlikely to result in substantially altered biological characteristics for intended use - cell isolation - cell selection - purification - protease treatment Other cell-containing MPs Reasons for regulatory classification are the resulting regulatory and procedural consequences For a somatic cell therapy medicinal product (MP) a manufacturing authorisation is required (GMP) unless the cells are not industrially produced, the hospital exemption applies (in some EU member states) or the MP is manufactured and administered by one physician (Germany). Medicinal product is administered by a physician, as a licensed MP (standard therapy), in off-label use, In a clinical trial, under compassionate use (one patient, one physician), Medicinal products regulations apply to marketing and ensure free distribution and safety and efficacy of MPs, but do not apply to compassionate use on a single doctor-patient exemption basis and do not apply to distribution of MPs by a single doctor in a single department/hospital (directional use).

29 Reasons for regulatory classification are the resulting regulatory and procedural consequences Human somatic cell therapy products (hsct-mps) contain or consist of intendedly manipulated cells resulting in substantial alteration of their biological characteristics. As a consequence of being classified as SCT-MPs, it is necessary to obtain marketing authorisation for use in standard therapy, to obtain marketing authorisation for all EU member states via a single application to the European Medicines Agency (EMEA), to undertake clinical trials under GCP intended to collect data for marketing authorisation have to be done (authorisation within 90 days), to obtain manufacturing authorisation including GMP, to undertake some non-clinical pharmacological-toxicological studies under GLP. Reasons for regulatory classification are the resulting regulatory and procedural consequences Human somatic cell therapy products (hsct-mps) contain or consist of intendedly manipulated cells resulting in substantial alteration of their biological characteristics. As a consequence of being classified as SCT-MPs, it is necessary to obtain marketing authorisation for use in standard therapy, to obtain marketing authorisation for all EU member states via a single application to the European Medicines Agency (EMEA), to undertake clinical trials under GCP intended to collect data for marketing authorisation have to be done (authorisation within 90 days), to obtain manufacturing authorisation including GMP, to undertake some non-clinical pharmacological-toxicological studies under GLP.

30 Examples of somatic cell therapy medicinal products - peptide loaded dendritic cells (DCs) - DC/tumor hybrid cells - other professional APCs - antigen-specific T-cells - killer cells (CTLs, NK cells) - other effector cells stem or progenitor cells - CD34+ cells for heart muscle regeneration - chondrocytes for cartilage repair (may include scaffolds) - pancreatic islet cells to restore function - liver cells to restore liver function during sepsis - neuronal cells for treatment of Parkinson s disease Examples of somatic cell therapy medicinal products - peptide loaded dendritic cells (DCs) - DC/tumor hybrid cells - other professional APCs cell-based tumour vaccines, not genetically modified - antigen-specific T-cells - killer cells (CTLs, NK cells) - other effector cells adoptive immunotherapy, e.g., for HIV or CMV regenerative medicine - CD34+ cells for heart muscle regeneration - chondrocytes for cartilage repair (may include scaffolds) - pancreatic islet cells to restore function - liver cells to restore liver function during sepsis - neuronal cells for treatment of Parkinson s disease

31 -> > New Annex I, Part IV, to Directive 2001/83/EC Products containing cells which had contact with animal cells are xenogeneic cell therapy products SPECIFIC STATEMENT ON XENO-TRANSPLANTATION MEDICINAL PRODUCTS (Directive 2001/83/EC) For the purposes of this Annex, xeno-transplantation shall mean any procedure that involves the transplantation, implantation, or infusion into a human recipient of either live tissues or organs retrieved from animals, or, human body fluids, cells, tissues or organs that have undergone ex vivo contact with live non-human animal cells, tissues or organs. Somatic Cell Therapy Medicinal Products include products containing xenogeneic cells. Transfer of xenogeneic material is not generally prohibited, but has its restrictions use of bovine sera discouraged due to TSE risk Risk of transmitting animal retroviruses (e.g., PERV or MuMLV) is a major issue which led to prohibition/discouragement of xenogeneic cell transfer into humans Use of xenogeneic material to culture human cells, e.g. murine feeder layer cells, would put the SCT-MP under high scrutiny.

32 CPMP Guideline on cell-based products including TEPs

33 In vivo administration : preparation in the clinic, viability, relevant biological characteristics Challenges es for clinical trial approval: preclinical testing program of SCT-MPs Source: donor screening, microbiology of cell explantation, banking of cell lines, history of cell line, identity, homogeneity Cells in medicinal products Transport to manufacturing facility: cold chain, cell viability, chemicals for cryopreservation Non-clinical studies : proof-of-concept, secretion of biologically active molecules, cell function, biodistribution, pre-neoplastic changes Manufacturing : virus/microbiological safety, changes in intended and safety-related biological characteristic EU Directives regulating donation, testing and processing of tissues and cells Directive 2004/23/EC Effective 7 April 2006 quality and safety for the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells Directive 2006/17/EC Effective Nov 2006 donation, procurement and testing of tissues and cells Directive 2006/86/EC Effective Sept 2007 traceability requirements serious adverse reactions and events coding, processing, preservation, storage and distribution of human tissues and cells Directives in progress Import/export: established in 2008 A single European coding system: Effective Sept 1, 2008

34 EU Directive 2004/23/EC Setting standards of quality and safety for the donation, procurement, testing, processing, preservation, storage and distribution of humanh tissues and cells This Directive applies to tissues and cells including hematopoietic peripheral blood and blood cells, donor lymphocyte infusion following hhsct), umbilical-cord (blood) and bone marrow stem cells, reproductive cells (eggs, sperm), foetal tissues and cells, and adult and embryonic stem cells It was published in the Official Journal of the European Union on April 7, 2004 and entered into force

35 Viral safety of blood transfusions after introduction of NAT The selection of healthy donors and highly developed testing methods have reduced the risk drastically. The residual risk of contracting a virus infection through a blood transfusion is extremely low and can only be assessed very roughly: For HIV and HCV it is markedly below 1 : 3,000,000 For HBV, NAT is difficult to perform and is not obligatory; in spite of this, only isolated transmissions HBV occur; Testing for anti-hbc is introduced. Experience will show whether new developments in the pathogen inactivation (of blood components) will bring about further progress in the field of blood products. Aims of non-clinical studies prior to first clinical use: somatic cell therapy products Studies should be designed and carried out aiming at establishing the following: functionality and proof-of-concept in non-clinical model(s) release of biologically active molecules maintenance of the intended phenotype and absence of pre-neoplastic changes biodistribution and half-life in the living organism recommendation on initial dose and dose escalation scheme to be used in the proposed clinical trial (max. feasible dose) identification of potential mechanisms and target organs of toxicity identification of parameters to be monitored in the proposed clinical trial identification of patient eligibility criteria

36 About 113 Tissue Engineering Companies in Europe European Commission Joint Research Center Institute for Prospective Technology Studies, 2003

37 Avanced Therapy Clinical Trial Applications in the EU since August 2004 ( , EudraCT) clinical use number Somatic cell therapy MPs 73 trials / 59 original products cancer immunotherapy 23 cardio-vascular 17 skin/liver/lung/diabetes/intestine/bone TE 12 neurological 4 lymphohistiocytosis (HLH) 1 AIDS 1 infertility 1 Advanced therapy products will also include tissue-engineering engineering products

38 European Commission proposed to differentiate between TEPs and CTPs Types of Somatic Cell Therapy Products (hsct( hsct-mps) cell-based vaccines (induce an immune response) -> not genetically modified tumour vaccines -> other cell-based vaccines containing APCs cell-based products for adoptive immunotherapy -> CTLs for treatment of acute virus infections (e.g., CMV) -> NK cells used to treat immunogenic tumours -> effector cells of auto-immune disease -> DLI in the context of haematopoietic reconstitution cell-based products used in regenerative medicine -> repair or replacement of tissues, e.g., heart muscle, cartilage Tissue-engineered engineered Products (TEPs( TEPs; ; in the future) Potency assay for batch release: based on genomics

39 Hyalo-cartilage formation in immuno- suppressed nude mice as a potency assay for chondrocyte progenitor cells Potency prior to first clinical use: first evidence for potential clinical mechanism of action and efficacy Potency assay for batch release: based on genomics Cell therapy products the regulatory levels Regulation addressing all Advanced Therapy Medicinal Products Proposal: Regulation on Advanced Therapy Medicinal Products (ATPs) Definition of ATPs including TE products Central licensing requirement 1 Regulation 726/2004 (Mar 2004) Centralized procedure via EMEA Existing Legislation on Tissues & Cells, (Medical Devices) and Medicines Directive 2001/83/EC (Nov 2001) amendend by 2003/63/EC (Jun 2003) Community code relating to all medicinal products for human use Technical requirements with a view to licensing Directive 2004/23/EC (Mar 2004) setting standards of quality and safety for donation, procurement, testing, processing, preservation, storage and distribution of human tissues/cells 2 Technical Requirements Directive 2006/17/EC technical requirements for donation, procurement and testing Directive 2006/86/EC technical requirements for coding, processing, preservation, storage, distribution 3 Guidelines Guideline on cell-based products including TEPs (Fall 2007/2008) Note for guidance on gene transfer medicinal products and related guidance (2003 Federal until Agency present) for Sera and Vaccines

40 MP development phases and scientific advice EMEA scientific advvice (SAWP, CHMP) briefing meeting (GTWP, CPWP) national scientific advice CHMP phase III phase II/III large-scale GMP manufacture phase I/II orientational phase I or I/II non-clinical studies small-scale GMP manufacture first proof-ofconcept in animal development genetics Advanced Therapy Medicinal Products: Present and Future Regulation in the EU Definition and development of medicinal products and subclasses Gene transfer/therapy medicinal products Somatic cell therapy and tissue-engineered medicinal products Tissue preparations Klaus Cichutek Paul-, Langen, Germany Frankfurt, 08 March 2007

41 Organismus Organ (Ausnahme Haut) Gewebe und Haut Zelle Knochentransplantate (Spongiosa/Corticalis)

42 Entnahmelogistik Entnahmetechniken (Lig. patellae, Achillessehne, T. tib. ant.) Peressigsäure/Ethanol-Sterilisation (PES) Exsikkator auf Schüttler Unterdruckeinheit

43 Tissues and cells as products for human use: the current regulatory patchwork in the EU 1. Step mode of action e.g. principal mode of action achieved by pharmacological, immunological or metabolic means Medicinal Products Health Products other products such as blood (2002/98/EC), human tissues and cells (2004/23/EC) e.g. principal mode of action not achieved by pharmacological, immunological or metabolic means Medical Devices

44 Advanced Therapy Medicinal Products: Present and Future Regulation in the EU Definition and development of medicinal products and subclasses Gene transfer/therapy medicinal products Somatic cell therapy and tissue-engineered medicinal products Tissue preparations Klaus Cichutek Paul-, Langen, Germany Frankfurt, 08 March 2007 Licensing, scientific advice Dev. of NfGs (EMEA) CHMP Gene Therapy WP (EMEA/CHMP) WHO Clinical Gene Therapy Monitoring Group Innovative biotechnology medicinal products Gene Transfer Medicinal Products (vectors, DNA, gen. mod. cells, micro-org.) Somatic/Xenogeneic Cell Therapy MPs (human cells; immunotherapy) Tissue Engineering MPs Tissue Preparations Ehrlich- Institut Medical Biotechnology Basic scientific research (human cells incldg. stem cells) (human sinews, valves, bones, ) Retrovirology ( HIV / SIV and HERV / PERV ) Clinical trial, manufacture Commission of Somatic Gene Therapy Clinical trial approval Inspections Gene therapy ( AIDS and tumor gene therapy ) Cell therapy/te ( Signal transduction, stem cell diff. )

45 Medicinal product expert Technical requirements Public relations expert International Fora, aquisition of applications/clients, advertisement of PEI s health politics Public health and legal expert Advice on legal and political issues, public health Scientist Basic and applied research

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