1. AT I MPs GOOD CLINICAL PRACTICE Lola Briones, PhD, MBA BIO ROI Consulting SL Lbriones@bioroi.com M. 639 83 31 61

2. Madrid, 28- Marzo-2012 L.Briones, PhD, MBA. BIO ROI Consulting SL. 2 Detailed EU guidelines on GCP specific to ATMPs ENTR/F/2/SF/dn D(2009) 35810, 2009 02/12/2015 Perfil de compañía 2

3. Madrid, 28- Marzo-2012 L.Briones, PhD, MBA. BIO ROI Consulting SL. 3 ATIMPs GCP 2009 Introduction Specific ATMPs GCPs required Regulation(EC) 1394/2007 on ATMPs Supplements E6-ICH GCP on IMP (1996) WMA Helsinki Declaration 1964 (Seul 2008) Pending final adoption ATMPs vs AT I MPs Advanced Therapies Investigational Medicinal Product

4. Madrid, 28- Marzo-2012 L.Briones, PhD, MBA. BIO ROI Consulting SL. 4 ATIMPs GCP 2009 content Donation, Procurement & Testing Tissue/Blood Establishments & Animal Facilities Manufacturing & Importation Overarching Principles Traceability Safety Reporting & Long Term Follow-up National CA Ethics Committee Investigator Sponsor Protocol Investigator Brochure Essential Documents Annex-Traceability Records

5. Madrid, 28- Marzo-2012 L.Briones, PhD, MBA. BIO ROI Consulting SL. 5 ATIMPs GCP 2009: regulations Donation, Procurement and Testing of ATIMPs Clinical Trials with ATIMP Sponsor Investigator Manufacturer/Importer + Tissue/Blood establishment Procurement organisations Animal facilities Donors

6. Madrid, 28- Marzo-2012 L.Briones, PhD, MBA. BIO ROI Consulting SL. 6 ATIMPs GCP 2009: regulations Donation, Procurement and Testing of ATIMPs EU Directive 2004/23/EC, Q&S. ( H. cells & tissues) – EU Directive 2006/17/EC – EU Directive 2006/86/EC EU Directive 2002/98/EC, Q&S (H.blood & comp.) – EU Directive 2004/33/EC – EU Directive 2005/61/EC – EU Directive 2005/62/EC Donors – EU Directive 2004/23/EC (H. Cells & tissues) – EU Directive 2002/98/EC ((H. Blood & comp.) – Annex 2 GMP/Vol. 4 (animal origin) – CPWP/83508/2009 (xenogenic cells)

7. Madrid, 28- Marzo-2012 L.Briones, PhD, MBA. BIO ROI Consulting SL. 7 ATIMPs GCP 2009: regulations Tissue or Blood Establishments and Animal Facilities Regulations sect. 3 Manufacturing and Importation of ATIMPs Art. 13, Directive 2001/20/EC

8. Madrid, 28- Marzo-2012 L.Briones, PhD, MBA. BIO ROI Consulting SL. 8 ATIMPs GCP 2009 Overarching Principles Traceability Chain of custody bidirectional links Follow-up : during & after trial end – long-term follow-up Specifics, ie. Embrionic stem cells; viral vectors, etc Specifics: tissues/cells of animal origin Medical care & decisions-> qualified Physician/Dentist – Experienced /expert sponsor representative role

9. Madrid, 28- Marzo-2012 L.Briones, PhD, MBA. BIO ROI Consulting SL. 9 ‘… to locate and identify each individual unit of tissue/cell during any step from procurement, through processing, testing and storage, to distribution to the recipient or disposal and vice versa. … to identify the donor and the tissue establishment or the manufacturing facility receiving, processing or storing the tissue/cells, … to identify the recipient(s) at the medical facility/facilities applying the tissue/cells to the recipient(s) … to locate and identify all relevant data relating to products and materials coming into contact with those tissues/cells ATIMPs GCP 2009 Traceability: the ability to …

10. Madrid, 28- Marzo-2012 L.Briones, PhD, MBA. BIO ROI Consulting SL. 10 General requirements Traceability system in place => bidirectional links Accountability Records: if bankrupct of sponsor ….->-> National CA Personal data protection vs subject traceability Donors code ~ full indentity by tissue/blood establishm. Subject code ~ full indentity by investigator/ institution ATIMPs GCP 2009 Traceability donor animal source donationproductsubject Tissue establishment Animal facility Manufacturing site Investigator / Institution

11. Madrid, 28- Marzo-2012 L.Briones, PhD, MBA. BIO ROI Consulting SL. 11 Responsibilities Sponsor: system in place, contractual agreements,… Tissue /blood establishment, procurements Manufacturer of the ATIMP Investigator/Institution – Investigator / Pharmacist / others – Traceability system al clinical site Archiving All parties > 30 years ~ through contractual agreements ATIMPs GCP 2009 Traceability

12. Madrid, 28- Marzo-2012 L.Briones, PhD, MBA. BIO ROI Consulting SL. 12 Clinical Trials-> E2a ICH (1994) Clinical Safety Data Management, Def. and Standards for Expedited Reporting Guideline + Notification of Adverse Events and Reactions + SAEs associated with trials procedures + Significant hazards to the subject + Sponsor: information/training to the investigator AE related to product application process Infections Re. to product failure (including lack of efficacy) Unexpected reactions: ie. Inmunologicals Re. to Mandatory concomitant medications Re. to Medical devices (combined ATMIP) + Causality assesment, protocol, AE Reporting Plan ATIMPs GCP 2009 Safety Reporting & Long-Term Follow-up

13. Madrid, 28- Marzo-2012 L.Briones, PhD, MBA. BIO ROI Consulting SL. 13 Follow-up ~ sponsor Need, duration and nature Risk annalysis strategy Risks for close contacts and offspring Follow-up for – protection of the subject – specific data collection Subject Alert Cards, during & after the End End of Trial definition ~ protocol Follow-up, part or not of the clinical trial Subjects withdrawal, follow-up subject to consent ATIMPs GCP 2009 Safety Reporting & Long-Term Follow-up

14. Madrid, 28- Marzo-2012 L.Briones, PhD, MBA. BIO ROI Consulting SL. 14 National CA evaluation + strategy for traceability, Follow-up, End of Trial definition and risk-assesment Ethics Committee evaluation Traceability vs personal data protection Close contacts and offspring follow-up Written Informed Consent Representative of the sponsor in some processes Irreversible nature of certain ATIMPs Protection, donor from sibling/parent pressure ATIMPs GCP 2009 National CA - Ethics Committee

15. Madrid, 28- Marzo-2012 L.Briones, PhD, MBA. BIO ROI Consulting SL. 15 Traceability at clinical site Keep records of traceability Specific AE & AR Knowledge of risk annalysis ATIMP accountability ATIMP conditions of use, application, … Requirements and training of other professionals Inform the subject /legal representative – Special ATIMP risks and precautions – Guidance on how to communicate risks to close contacts.. – ….. ATIMPs GCP 2009 Investigator

16. Madrid, 28- Marzo-2012 L.Briones, PhD, MBA. BIO ROI Consulting SL. 16 Traceability system Keep their part of records Implement AE-AR reporting process Ongoing risk analysis Combined products, risks Identify clinical, safety or efficacy follow-up Requirement for standardisation of surgical procedures Train the investigator: – ATIMP handling, storage,… – Concomitant therapy, surgical procedures, … ATIMPs GCP 2009 Sponsor

17. Madrid, 28- Marzo-2012 L.Briones, PhD, MBA. BIO ROI Consulting SL. 17 Protocol. Section # 6 ICH GCP + ……. Flexibility: variability in nature of ATIMPs, diseases Donor type, material suitability Medical device, if combined therapy Blinding issues, preparation vs administration Traceability system // Safety reporting End of Trial definition // Follow-up strategy Subject withdrawal Specifics, concomitant therapies, surgery, Representative of the sponsor Gene therapy ATIMPs GCP 2009 Protocol – Investigator Brochure

18. Madrid, 28- Marzo-2012 L.Briones, PhD, MBA. BIO ROI Consulting SL. 18 ATIMPs GCP 2009 Essential Documents Traceability records: > 30 years Each party, information for bidirectional traceability – Before the Clinical Phase of the Trial – During the Clinical Conduct – After Completion or Termination of the Trial Investigator/Institution E6 ICH GCP. #8. 3. 21.SUBJECT IDENTIFICATION CODE LIST ATIMP + records linking Traceable ATIMP patient code patient identification medical file

19. Madrid, 28- Marzo-2012 L.Briones, PhD, MBA. BIO ROI Consulting SL. 19 ATIMPs GCP 2009 Annex- Traceability records ………. Subject Medical Records product name/code trial reference code trial subject code administration dates and dose

20. Madrid, 28- Marzo-2012 L.Briones, PhD, MBA. BIO ROI Consulting SL. 20 THANKS BIO ROI Consulting Strategy & Education lbriones@bioroi.com T. + 34 639 83 31 61 ATIMPs GCP 2009