Three basic types of EU legislation

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1 Cord Blood & ATMP Christian CHABANNON November 7th, 2010 World Cord Blood Congress Marseille, France

2 Disclaimer I am not a member of the European Medicine Agency (EMA) The current presentation only expresses my own understanding of current regulations, and my interpretation of their consequences in our professional activities

3 Three basic types of EU legislation A regulation is similar to a national law with the difference that it is applicable in all EU countries Directives set out general rules to be transferred into national law by each country as they deem appropriate, within a defined delay A decision only deals with a particular issue and specifically mentioned persons or organisations

4 New Regulations on Advanced Therapy Medicinal Products The main elements of the Regulation were: The establishment of a centralized marketing authorization procedure A new, multidisciplinary committee (Committee for Advanced Therapies or CAT) A number of special incentives for small and medium sized enterprises

5 Definition of ATMP (1) Stems from REGULATION (EC) No 1394/2007 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 13 November 2007 on advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004 Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use. The Directive dealt with the disparities between certain national provisions, in particular between provisions relating to medicinal products, which directly affected the functioning of the internal market of the European Union.

6 Definition of ATMP (2) Advanced Therapy Medicinal Products Gene therapy medicinal products Somatic cell therapy medicinal products Tissue engineering products Combined ATMPs + medical devices Gene therapy medicinal products and somatic cell therapy products defined in Annex I to Directive 2001/83/EC Tissue engineering products: Tissue engineering is the regeneration of biological tissue through the use of cells, with the aid of supporting structures and/or biomolecules Defined in regulation EU n 1394/2007.

7 Definition of ATMP (3) In case ATMP containing both autologous and allogenic cells or tissues it shall be considered to be for allogenic use In case product falls in definition of TEP and sct it shall be considered as TEP In case products falls in definition of GT and TEP or sct, then GT>TEP>sCT

8 Definition of ATMP (4) Somatic cell therapy medicinal product means a biological medicinal product which has the following characteristics: contains or consists of cells or tissues 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 of cells or tissues that are not intended to be used for the same essential function(s) in the recipient and the donor; is presented as having properties for, or is used in or administered to human beings with a view to treating, preventing or diagnosing a disease through the pharmacological, immunological or metabolic action of its cells or tissues. For the purposes of 1 st point, the manipulations listed in Annex I to Regulation (EC) No 1394/2007, in particular, shall not be considered as substantial manipulations.

9 Definition of ATMP (5): the following shall not be defined as substantial manipulations (Annex 1) cutting grinding shaping centrifugation soaking in antibiotic or antimicrobial solutions sterilization irradiation cell separation, concentration or purification filtering lyophilization, freezing cryopreservation vitrification

10 Implementation of ATMP regulation Principles existing legislation on medicines apply to advanced therapies: marketing authorization demonstration of Quality, Safety & Efficacy post-authorization vigilance (pharmacovigilance) EMA guideline on risk management systems for medicinal products for human use (EMEA/CHMP/96268/2005) EMA Guideline on Cell-Based Medicinal Products (EMEA/CHMP/410869/2006) GMP guidelines currently available for public consultation 30 December Policy to provide SME with guidance and advices in the process of obtaining MA Committee for Advanced Therapies (CAT)

11 Committee for Advanced Therapies (1) The Committee for Advanced Therapies is composed of: five members or co-opted members of the Committee for Medicinal Products for Human Use (CHMP), with their alternates, appointed by the CHMP itself; one member and one alternate appointed by each EU Member State whose national competent authority is not represented among the members and alternates appointed by the CHMP; two members and two alternates appointed by the European Commission to represent clinicians; European Society of Gene and Cell Therapy European Group for Blood and Marrow Transplantations two members and two alternates appointed by the European Commission to represent patients associations. European Genetic Alliances' Network (EGAN) European Organisation for Rare Diseases Members of the CAT are appointed for a renewable period of three years. The Chair and Vice-chair of the CAT will be elected from its members for a term of three years, which may be renewed once.

12 Committee for Advanced Therapies (2) Tasks of CAT Initial evaluation, re-examination, post-marketing activities for ATMPs Draft opinion to CHMP Classification procedure: is a product an ATMP? scientific recommendation from CAT Certification procedure: Q/N-C review, for ATMP only CAT opinion EMA certification Scientific Advice for ATMP CAT actively involved in all SA for ATMP Other task, eg consultation by CHMP on non- ATMPs, advice to Commission

13 Committee for Advanced Therapies (3) Members of the Cellbased Products Working Party (CPWP): Lisbeth Barkholt Louise Bisset Egbert Flory (Vice-Chair) Carla Herberts Romaldas Mačiulaitis Margarida Menezes-Ferreira Giovanni Migliaccio Tiina Palomäki Paula Salmikangas (Chair) Torsten Tonn (European Society of Gene and Cell Therapy) Members of the Gene Therapy Working Party (GTWP): Alessandro Aiuti Nathalie Cartier Pablo de Felipe Maria Cristina Galli (Chair) Harm Hermsen Vincent Irwin Rune Kjeken Sharon Longhurst Dominique Masset Matthias Renner

14 Regulation Pre-authorisation requirements For products incorporating medical devices: compliance with Essential Requirements Specific guidelines on GMP (Good Manufacturing Practice) and GCP (Good Clinical Practice) Specific rules for labelling/packaging Post-authorisation requirements Follow-up of efficacy and adverse reactions, and risk management: obligation for EMEA to inform relevant device/tissue national authorities Traceability

15 Highlights from risk factors assessment (Quality, Safety, Efficacy) Identity parameters should be established for all components of the product Demonstration of potency/ functionality of the cells is one of the key issues A production process standardized and defined to produce a consistent product as GMP requires Batches vs single products As part of the safety testing, the possibility of tumorigenic transformation of the cells during the manufacturing process shall be analyzed

16 Hospital exemption (art 28(2) of regulation) Additional exclusion under very specific conditions e.g.: Non-routine basis of production Specific quality standards Used in same member state in hospital (manufacturing authorized by Comp. Authority of MS) Custom-made product for individual patient Under the exclusive professional responsibility of a practitioner National rules on the use of cells on ethical grounds will consider production based on GMP principles or by a licensed manufacturer, scale of production, commercial evaluation Clinical trials

17 Conclusion: three different situations ATMP, European Marketing Authorization ATMP, Hospital Exemption, National Marketing Authorization Cell therapy products that are not considered nor regulated as drugs No marketing authorization Regulated at a national level (in France, authorization for cell therapy facilities as well as tissues banks + authorization for distinct cell or tissue engineering processes), however must comply with the 2004/23/CE Directive (setting standards of quality and safety for the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells)

18 Consequences (1) Under existing European regulations, most current medical uses for cord blood, do not fall under the definition of ATMP Allogenic related or unrelated cord blood transplantation, for the purpose or correcting inherited or acquired disorders that affect the function of part or all of the hematopoietic tissue, or to treat hematological malignancies through allogenic recognition of host tumor cells by donor-derived immune effectors ( Hematopoietic Stem Cell Transplantation ) Cell procurement. Cell engineering limited to volume reduction, cryopreservation, thawing, and even immuno-selection of phenotypically defined cells (CD34 + ): no substantial manipulation

19 Consequences (2) The situation is already changing for some procedures: CD34 + cell expansion Production of mesenchymal stem cells from Wharton jelly Production of dendritic cells from cord blood

20 Consequences (3) The situation will further change for upcoming uses, such as some of those discussed during this meeting (when or if they come to the clinic!) Autologous cord blood cells for the treatment of cerebral palsy and other acquired brain injuries ( nonhomologous use) Isolation of endothelial progenitors from cord blood for clinical uses Derivation of Unrestricted Somatic Stem Cells...

21 Consequences (4) Non-substantially manipulated Substantially manipulated HPC(M) TC-MSC TC-DC HPC(A) TC(A) HPC(CB)

22 Press release: May 25, 2010 Other products already on the market: Carticell (Genzyme) ChondroCelect (Tigenix, Belgium) Hyalograft C (Fidia Advanced Biopolymers, Italy) t2cure GmbH is a biopharmaceutical company developing and marketing stem cell-based regenerative therapies t2c001 is the first product ever to obtain a certificate under the EMA regulations for Advanced Therapy Medicinal Products (ATMPs). It is a somatic cell therapy product derived from autologous bone marrow, that is currently developed for the treatment of cardiovascular diseases.

23 Wish to know more? EMA webpage st ATMP workshop nd Regional Meeting of ISCT Europe, ATMP workshop (ISCT website)

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25 Other European regulations to deal with Directive EC 2001/20/EC relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use Directive EC 2003/94/EC laying down the principles and guidelines of good manufacturing practice in respect of medicinal products for human use and investigational medicinal

26 Acknowledgements Centre de Thérapie Cellulaire. Institut Paoli-Calmettes & Inserm CBT-510. Marseilles Claude Lemarié Boris Calmels Lise-Marie Billard-Daufresne Carine Malenfant Martine Bouyssié Patricia Parc François Féraud AFSSaPS Stephane Paliès Sophie Lucas-Samuel Karine Martinière Jacques-Olivier Galdbart Pierrette Zorzi JACIE Office, Executive Committee & Board Eoin McGrath Jane Apperley Derwood Pamphilon Allessandro Rambaldi Mark Lowdell Legal & Regulatory Affairs Committee (LRA). ISCT Europe Ineke Slaper-Cortenbach Martino Introna Doris Hermann Mike Scott Megha Deviprasad Christopher A Bravery