Industry Day Symposium SESSION 2: “The Regulatory Imperative: International Perspective”

1. World CongressTissue Engineering and Regenerative Medicine International Society Vienna, Austria September 5-8, 2012 Industry Day Symposium SESSION 2: “The Regulatory Imperative: International Perspective” Organized by TERMIS-AM and TERMIS-EU Industry Committees

2. Concept/Discovery Researchto Successful Product Public/Private Funding DiscoveryResearch Successful Product Market Clinical Trials ? Intellectual Property& Patent Protection Regulatory Evaluation & Product Approval Public(s) Perception& Market Acceptance SCIENCETalent/People

3. TERMIS-EU Industry Committee • Established 2011 • Mission • Motivate translation of academic research into commercial products, in Tissue Engineering/Regenerative Medicine (TE/RM) • Connect the scientific & clinical communities with TE/RM industries • Goals • Give answers to critical questions, paving the road of TE/RM commercial translation, by key stakeholders, from past experiences • Promoteacademia–industry meetings & partnerships for more effective commercial translation in TE/RM • Members • Yves Bayon, PhD; Covidien – Sofradim Production; Chair • Simon Ellison, MBA; NHS Blood & Transplant • John Barry, PhD; Baxter Innovations • Paul Stroemer, PhD, Reneuron • Chris Mason, PhD; University College of London • Alain Vertes, PhD; London Business School Sloan Fellow 3

4. TERMIS-AM Industry Committee • Established 2009 • Mission • Support commercialization in Tissue Engineering/Regenerative Medicine (TE/RM) • Goals • Define and address obstacles/hurdles to product commercialization • Promote collaborations to build a viable TE/RM industry • Members • Kiki B. Hellman, PhD; The Hellman Group. LLC; Chair • Timothy A. Bertram, DVM, PhD; Tengion • Peter C. Johnson, MD; Avery Dennison • Mark Van Dyke, PhD; Wake Forest University Health Sciences • Bill Tawil, PhD; Baxter Biosurgery

5. TERMIS-AM Industry Committee‘Commercialization Hurdles’ 2010 – First Annual Industry Committee Symposium* • Survey of TERMIS-AM membership on perceived hurdles to commercialization of TE/RM products • Most common hurdles identified by academe, and start-up, development stage, established companies • Funding • Regulatory pathway • IP and technology transfer ----- *Publications: • “Hurdles in Tissue Engineering/Regenerative Medicine Commercialization: A Survey of North American Academe and Industry,” Tissue Engineering, January 2011. • “Challenges in Tissue Engineering and Regenerative Medicine Product Commercialization: Building an Industry,” Tissue Engineering, January 2011.

6. TERMIS-AM Industry Committee‘Funding’ 2011 – Second Annual Symposium* • Survey of financial community (public, private, government) • Key Findings • Investment interest >60% • Perceived challenges for investment • Regulatory pathway clarity • Clinical translation --- Publication: “Hurdles in Tissue Engineering/Regenerative Medicine Commercialization: A Survey of the Financial Industry,” Tissue Engineering, November 2012 (in press).

7. The Regulatory Imperative: International Perspective TERMIS-NA Industry Committee Surveys Regulatory pathway a major hurdle Regulatory clarity and predictability – key for commercialization and industrial development

8. The Regulatory Imperative: International Perspective Regulatory Framework Principles and requirements governing assessment of regenerative products, i.e., review and marketing approval Globalization Challenges for regulatory authorities due to the global R&D effort in TE/RM outside their purview, i.e., outside US and EU Regulatory Harmonization Development of a common dialogue and approach among regulatory authorities leading to congruence of national practices and consensus on regulatory requirements, i.e., a unified regulatory strategy

9. Symposium Participants Presentations Lucia D’Apote, PhD; European Medicines Agency (EMEA), United Kingdom Celia Witten, MD, PhD; Center for Biologics Evaluation and Research (CBER), Food and Drug Administration (FDA), United States Panel Tim Bertram, DVM, PhD; Tengion, Inc., USA Maria Pascual-Martinez, PhD; TiGenix Alison Wilson; Cell Data Services Leslie Wolfe, PhD; Genzyme Chair Kiki B. Hellman, PhD; The Hellman Group, LLC, USA Summary Tim Bertram, DVM, PhD; Tengion, Inc., USA

10. European Regulatory environment of regenerative medicine TERMIS Industry Symposium 7 September 2012, Vienna (Austria) Presented by: Lucia D’Apote, PhD European Medicines Agency

11. Overview • The EMA CAT and the RegMed pipeline in Europe • Regulatory path and regulatory requirements • Specificities and Challenges • International Cooperation (EMA-FDA) 11 Lucia D’Apote - EMA

12. The EMA CAT and the RegMed pipeline in Europe 12 Lucia D’Apote - EMA

13. Established in 1993, operational since 1995 • 7 Westferry Circus Canary Wharf London E14 4HB United Kingdom • Tel: +44 (0) 20 7418 8400 • Fax: +44 (0) 20 7418 8416 • www.ema.europa.eu Lucia D'Apote - EMA 13

14. The ATMP Regulation Committee for Advanced Therapy Committee for Advanced Therapy • New Scientific Arena • Expertise • Beyond Traditional • Research Lucia D'Apote - EMA 14

15. ATMP Pipeline – what we see Lucia D'Apote - EMA 15

16. Objective : Facilitate development of ATMPs and access to MA procedure • understand trends in research and development,with a view to planning CAT workload and resources accordingly http://www.ema.europa.eu/docs/en_GB/document_library/Work_programme/2010/11/WC500099029.pdf 16

17. ATMP Pipeline – what we will see • 318 clinical trials from EudraCT (1 May 2004 - 31 December 2010) • 244 national = more than 70% • 74 multinational = less than 30% Lucia D'Apote - EMA 17

18. Products • Based on self-classification: • GTMPs + sCTMPs + TEPs: 250 • GTMPs =54 = 22% • sCTMP/TEPs= 196 = 78% • phase I and II or I/II: 81% • phase III/IV:19% • phase IV, as assigned in the database: 7 CT 18

19. Sponsors: who • Who is conducting the CT with ATMPs in Europe? 173 sponsors • 104=60% Academia/hospitals, • 69=40% Industry (including SMEs) • 4% big pharma • 24% SMEs • 72% other (non registered SMEs) 19

20. Sponsors: from where • 19 countries in total • 15 EU/EFTA Countries (SP, DE, UK, NL, FR, BE) • 4 non-EU/ EFTA region (US, Israel, Switzerland, Canada) • almost all academia/charity sponsors situated in Europe • some commercial sponsors (24/69 or 34%) situated outside Europe 20

21. Therapeutic areas majority of CT in solid tumours (67 products), followed by the cardiovascular area (48 products), and haematology including haematological malignancies (33 products) Lucia D'Apote - EMA 21

22. Orphan ATMPs 26 CT with Orphan ATMPs Mainly commercial sponsors Majority with cell-based products 75 ODD so far are ATMPs !!! Lucia D'Apote - EMA 22

23. Regulatory path and regulatory requirements 23 Lucia D’Apote - EMA

24. EU Marketing Authorisation (MA) for ATMPs • A medicinal product may only be placed on the marketin the EU, • when a marketing authorisation has been issued by the European Commission (via the Centralised Procedure – EMA) • or • it is regulated by the competent authority of a EU Member State • (hospital exemption) EMA - Lucia D'APOTE 24 24 24

25. Lucia D'Apote - EMA 25

26. Risk based approach Lucia D'Apote - EMA 26

27. Risk-management plan and follow-up safety/efficacy Lucia D'Apote - EMA 27

28. Same evaluation, different MA? • Conditionalapproval vs Exceptionalcircumstances • - to meet unmet medical needs of patients and in the interest of public health Lucia D'Apote - EMA 28

29. Accellerated assessment 150 days • in order to meet, in particular the legitimate expectations of patients and to take account of the increasingly rapid progress of science and therapies, for medicinal products of major interest from the point of view of public health and in particular from the view point of therapeutic innovation. • There is no single definition of what constitutes major public health interest. This should be justified by the applicant on a case-by-case basis. • Accelleratedassessment Lucia D'Apote - EMA 29

30. Specificities and Challenges 30 Lucia D’Apote - EMA

31. ATMP Translation: perceived challenges • Gene and Cell based products are complex • Market (specific and small) • Lack of funds and costly investments • Regulatory barriers 31 Lucia D’Apote - EMA

32. Challenges with ATMPs: examples Scientific challenges Manufacturing constraints & quality issues Non-clinical challenges Clinical challenges Disclaimer: ATMPs are a very diverse group of products, so the challenges listed in the next slides are only examples! 32

33. Quality/manufacturing issues Control of all starting and raw materials Human cells/tissues + any human/animal reagents (e.g serum) Recombinant growth factors History of cell-lines / vector constructs Appropriate characterisation and product testing (including potency assay*) Poor definition and control of a product may directly effect safety & efficacy Good control of the product is essential for manufacturing changes (e.g. product upscale) Manufacture in GMP environment * Potency assay: product specific, at least semi-quantitative, linking product testing with clinical effect /biological activity 33

34. Non-clinical challenges What animal models to be used to test a human cell-based therapy or gene therapy product? Use of a homologous model? / Disease models?/ Other relevant animal models? Proof of concept studies / toxicity studies Dose finding studies? Bio-distribution studies? Germ line transmission for GTMP Environmental risk / Shedding studies for GTMP 34

35. Clinical challenges Dose finding studies How to find the most effective dose, e.g. for a TEP? Design of clinical trial What is a suitable compatitor? Blinding might be very difficult Endpoints for TEP (how to measure structure repair?) Effect of concomitment treatment / surgery on Efficacy & Safety? Long term efficacy and safety follow-up studies 35

36. Challenges with ATMPs Scientific challenges Yes! But not all challenges are scientific! Regulatory issues Lack of regulatory expertise Resources Reimbursement issues Competition with ‘hospital exempted ATMPs’ 36

37. Prospective product development Courtesy of dr. Paula Salmikangas, 2012 Lucia D'Apote - EMA 37

38. Retrospective product development Courtesy of dr. Paula Salmikangas, 2012 38 Lucia D'Apote - EMA

39. The way forward • Raise awareness – strengthen dialogue • Learn from experience 39 Lucia D’Apote - EMA

40. Nature Reviews Drug Discovery, vol 9, March 2010, 185-201 Regulatory Rapporteur, vol 8, July-August 2011, 4-7 40

41. Advice during development Lucia D'Apote - EMA 41

42. Regulatory strategy: save time Scientific advice: Complying with SA/PA is significantly associated with positive outcome Regnstrom J, Koenig F, Aronsson B, et al. (2010) Factors associated with success of market authorisation applications for pharmaceutical drugs submitted to the European Medicines Agency; EJCP 66:39-48 Lucia D'Apote - EMA 42

43. 43 Lucia D’Apote - EMA

44. 44 Lucia D’Apote - EMA

45. International Cooperation (EMA-FDA) • FDA-EMA-HC ATMP Cluster • ICH Regulators Forum Cell Therapy Group • Parallel Scientific advice http://www.ema.europa.eu/docs/en_GB/document_library/Other/2009/11/WC500014868.pdf 45 Lucia D’Apote - EMA

46. Parallel Advice FDA Confidentiality Agreement FDA Applicant to address request to both Agencies Agreement principles since 2004 pilot Applicant initiative- exceptionally Agency initiative 46

47. Procedure Parallel Advice Initial discussion both Agencies Prime candidates-breakthrough products – no GL exist or GLs differ between Agencies Submit request in usual manner Timetable agreed between Agencies Tele-video-conference about D60 47

48. Outcome No applicant involvement in draft reports Parallel separate advice given not ‘joint’ advice Confidentiality maintained Standard fee applies 48

49. Thank you for your attention! Lucia D’APOTE European Medicines Agency (EMA) lucia.dapote@ema.europa.eu Lucia D'Apote - EMA 49

50. Regulatory and Scientific Experience in Regenerative Medicine in OCTGT Celia M. Witten, PhD, MD Office Director Office of Cellular, Tissue, and Gene Therapies Center for Biologics Evaluation and Research United States Food and Drug Administration Termis Industry Symposium Vienna, Austria September 7, 2012