1. Current trend of regulation, approval and development of advanced therapy medicinal products in Europe Balázs Sarkadi, Hungarian Academy of Sciences, Budapest, Hungary

2. Advanced Therapy Medicinal Products (ATMP) Regulation – the role of EMA-CAT Regulatory Pathways to Medicinal Product Authorisation within EU EMA - London Formerly EMEA, from 2010: European Medicines Agency

3. The EMA (formerly EMEA) Created 1993, operational 1995 Budget 2008: 183 M euros which includes 40 M EU budget Staff 630, + around 4000 experts One system with 2 marketing authorisation procedures –Centralised for biotech and innovative Based on the single market Coordination of national expertise Commission decision Management Board Management Board Executive Director Executive Director CHMP Veterinary Medicines and Inspections Veterinary Medicines and Inspections Pre-authorisation Evaluation of Human Medicines Pre-authorisation Evaluation of Human Medicines Communications and Networking Communications and Networking Administration EMEA Secretariat Post-authorisation Evaluation of Human Medicines Post-authorisation Evaluation of Human Medicines National competent authorities European experts National competent authorities European experts EU institutions: Commission and Parliament CVMP HMPC COMP PDCO Executive Support CAT Committe for Advanced Therapies

4. Regulation (EC) 1394/2007 for Advanced Therapy Medicinal Products (ATMP) Development of new avenues for medical treatment demanding specific rules within the general pharmaceutical framework Ensuring patients access to such treatments and an equal level of public health protection through a single set of rules across EU Creating a framework which promotes innovation and competitiveness in a key biotechnology area Discussions in the Council and the European Parliament throughout 2006-2007 Regulation adopted on 13 November 2007 Applies from 30 December 2008

5. Advanced Therapies Regulation from 2009 New medicinal products based on genes - cells - tissues Drivers – need for harmonised rules  Uniform patients access  Support development emerging biotechnology industry Main elements  Centralised MA  New Multidisciplinary Committee (CAT)  Tailored technical requirements  Risk management and traceability  Support for SMEs

6. Regulation (EC) 1394/2007  ATMP scope : gene therapy, somatic cell therapy, tissue engineering  Technical requirements adapted to the particular characteristics of these products  Centralized marketing authorization procedure  New Committee for Advanced Therapies (CAT)  Special incentives for small and medium-sized enterprises  Gene therapy and somatic cell therapy: covered by Annex I to the Community Code on medicinal products for human use  New definition of tissue engineered product  Combined products containing cells or tissues and medical devices: which regulatory framework should apply? Key questions: EMEA-CAT scientific recommendations on classification

7. Marketing authorisation procedure: Role of CAT and CHMP (Committee for Human Medical Products)  The Agency’s draft opinion is prepared by CAT and delivered to CHMP  CHMP adopts the Agency’s final opinion but it consults the CAT on any scientific assessment of ATMPs (initial or re-examination)  If the final opinion departs from the CAT’s draft opinion, the CHMP must motivate any divergences  Based on EMEA-CHMP opinion authorization is issued by the European Commission (Enterprise and Industry) The CAT:  delivers opinions on all ATMPs authorised in the Community  participates in the shaping of the technical and scientific requirements applicable to the authorisation through scientific guidance  is involved in the practical implementation of the scope of the Regulation and the solution of borderline issues  promotes the development of new products through certification and scientific advice

8. Optional (upon company request) Procedure 40 to 70 days Face to face meetings for 50% of advice Fee-related activity (fee waiver/reduction for SMEs) Not only product specific, but qualification of biomarkers and other novel methodologies Scientific Advice and Protocol Assistance Special incentives for small and medium-sized enterprises (SMEs) Reduction of fees for scientific advice (SMEs and other applicants) SMEs developing advanced therapy products may submit to the EMEA quality and, where available, non-clinical data, for scientific evaluation and certification Reduction to MA and post-authorisation fees to hospitals or SMEs that can prove a Community public health interest in the ATMP concerned

9. Exclusions from scope  What is really an ATMP – a marketed medicinal product  The “hospital exemption”: ATMP prepared on a non-routine basis according to specific quality standards, 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 Still: Manufacturing of these products shall be authorised by the competent authority of the Member State. Member States shall ensure that national traceability and pharmacovigilance requirements as well as the specific quality standards referred to in this paragraph are equivalent to those provided for at Community level in respect of advanced therapy medicinal products for which authorisation is required pursuant to Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004  National rules on the use of cells on ethical grounds (exclusion of certain products from national markets)

10. The Committee for Advanced Therapies (CAT) Committee for Human Medicinal Products (CHMP) BWP PhVWP BPWP QWP SWP SAWP EWP CPWPGTWP PgWP VWP BMWP 5 co-opted members Committee for Advanced Therapies (CAT) 5 „double members“ v Biologics Working Party (BWP) Blood Products Working Party (BPWP) Cell-based Products Working Party (CPWP) Efficacy Working Party (EWP) Gene Therapy Working Party (GTWP) Joint CHMP/CVMP Quality Working Party (QWP) Patients' and Consumers' Working Party (PCWP) Phamacogenomics Working Party (PgWP) Pharmacovigilance Working Party (PhVWP) Safety Working Party (SWP) Scientific Advice Working Party (SAWP) Vaccine Working Party (VWP)

11. Day 150 Joint Rapp./ Co-rapp. AR Hearing Day 181 CHMP List of Questions Day 120 (Co)Rapporteurs’ Assessment Report Day 80 Day 1 Max. 6 months Applicant Hearing? Day 180 Day 121 Response to LoQ Day 210 Adoption of Opinion Start Clock Stop Clock Start Clock Stop Clock Primary Evaluation PhaseSecondary Evaluation Phase Evaluation Phase

12. Definition of Gene Therapy Medicinal Product Gene therapy medicinal product means a biological medicinal product, with the exception of vaccines against infectious diseases: –the active substance of which contains or consists of a recombinant nucleic acid where the recombinant nucleic acid is used in or administered to human beings with a view to regulating, repairing, replacing, adding or deleting a genetic sequence; and –whose 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. Relevance: Only Biological Medicinal products (synthetic oligonucleotides are not GTMP) Exclusion of vaccines against infectious diseases

13. Definition of somatic Cell Therapy MP Somatic cell therapy medicinal product means a biological medicinal product which: –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, And –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.

14. Exclusions from the definition of somatic Cell Therapy MP For the purposes of the first indent of this definition, the manipulations listed in Annex I to Regulation (EC) No 1394/2007, in particular, shall not be considered as substantial manipulations –Non-substantial manipulations: Cutting, grinding, shaping Centrifugation Soaking in antibiotic/antimicrobial solutions Sterilisation / Irradiation Cell separation, concentration or purification Filtering Lyophilisation, freezing, cryopreservation Vitrification

15. Tissue Engineered Medicinal Product A tissue engineered product means a product that: –Contains or consist of engineered cells or tissues and –Is presented as having properties for, or is used in or administered to humans with a view of regenerating, repair or replacing a human tissue Engineered tissues or cells: –Subject to substantial manipulation so that biological characteristics, physical function or structural properties relevant for intented regeneration, repair or replacement are archieved List of non-substantial manipulation in Annex I to Reg 1394/2007 –Cells/tissues not intended to be used for the same essential function(s) in recipient & donor

16. Hierarchy of the AT procedures and Medicinal Products Transplantation protocols >> Transplantation MPs >> Medicinal Products with Hospital Exemption >>> ---------------------------------------------- somatic Cell Therapy Medicinal Products >> Gene Therapy Medicinal Products >> Tissue Engineering Medicinal Products Evaluated and licensed by the Member State Competent Authorities: Evaluated and licensed by the European Commission (Reg. EC 1394/2007):

17. Advanced therapies and their challenges – Regulatory issues Gene therapy medicinal products Somatic cell therapy medicinal products Genetically modified cells Tissue engineering products Nat Biotechnol 2005, 23(7) www.heartandmetabolism.org www.biomed.brown.edu Based on the presentation of Dr. Christian K Schneider, Paul-Ehrlich-Institut, Germany, Chairman of CAT