The presentation discussed the regulatory challenges for combination advanced therapy medicinal products under the European Union's Regulation 1394/2007, including the definition and evaluation process for these products, the role of the Committee for Advanced Therapies and Notified Bodies, as well as current state of implementation and recommendations.

1. Regulatory challenges for
combination-ATMP products
Gert Bos
BSI Healthcare
Drug device Combination Products
Informa, Prague, CZ
17 November 2009

2. This presentation
 ATMP defined
 Regulation and implementation
 CAT
 Evaluation procedure
 Certification
 State of play today
 Scientific recommendation
 Dossier Requirements
 NoBo involvement
SME

3. Regulation
• Regulation 1394/2007
 Published on Dec 10 2007, applicable from Dec 30 2008
• Definition Advanced Therapy MP
• Definition Tissue Engineered product (MP)
• Principles of medicines legislation to apply
• Mandatory centralised procedure
• Gene therapy and somatic cell therapy MP
 to be brought under annex I of 2001/83
• Committee for Advanced Therapies (CAT)
http://ec.europa.eu/enterprise/pharmaceuticals/advtherapies/index.htm

4. ‘Advanced therapy medicinal product’
• any of the following MPs for human use:
 a gene therapy MP as defined in 2001/83/EC,
 a somatic cell therapy MP as defined in 2001/83/EC,
 a tissue engineered product.
• ‘Tissue engineered product’ means a product that:
 contains or consists of engineered cells or tissues, and
 is presented as having properties for, or is used in or
administered to human beings with a view to regenerating,
repairing or replacing a human tissue.

5. Tissue engineered products
• cells or tissues of human or animal origin, or both.
• cells or tissues viable or non-viable
• additional substances, such as
 cellular products & bio-molecules,
 Biomaterials & chemical substances,
 scaffolds or matrices.
• non-viable human or animal cells and/or tissues in
products that do not act principally by
pharmacological, immunological or metabolic
action, excluded.

6. ‘engineered’ cells & combination-ATMP
Engineered cells:
• Cells/tissues subject to substantial manipulation, non-
substantial manipulations listed, and/or
• cells or tissues not intended to be used for same
essential function(s) in recipient as in donor.
Combination-ATMP:
• MDD or AIMD, and
• cellular or tissue part contain viable cells or tissues, or
• Non-viable cellular/tissue part acting pharmaceutically

7. Examples of combination-ATMPs
• Artificial skin embedded in wound care product
• Chondrocytes in cartilage scaffold with cell sorting
and seeding device
• bone void fillers with human bone morphogenic
proteins
• Wound dressings with human growth hormones

8. Highlights regulation
• Pre-market:
 Combination ATMPs: ERs of MDD
 Specific GMP and GCP guidelines
 Specific rules for labeling and packaging
• Post-market:
 Follow-up efficacy and adverse reactions
 Risk management
 traceability

9. Implementing legislation
• Procedure for evaluation and certification
• Dossier req. module 3, 4
• Site visits
• Guide on minimum quality and non-clinical data

10. Implementing legislation
• Amending 2001/83, annex I, part IV
 New definitions GTMP and somatic CTMP
 Risk based approach
 Updated req. modules 3, 4, 5

11. 3 SANCO directives on tissues and cells
• 2004/23/EC: standards of quality & safety for
donation, procurement, testing, processing,
preservation, storage and distribution of human
tissues and cells
• 2006/17/EC: technical requirements for donation,
procurement and testing of human tissues and cells
• 2006/86/EC: traceability requirement, notification
serious adverse events, requirements for coding,
processing, preservation, storage and distribution of
human tissues and cells

12. Committee for Advanced Therapies (CAT)
CK Schneider, PEI

13. Evaluation procedure
• PRE authorisation:
 Product compliance to ERs
 Guidelines to GMP (2003/94/EC) and GCP
 Rules for packaging and labelling
• POST authorisation:
 Follow up efficacy and adverse reactions, and risk
management
 Traceability

14. CAT
Rapporteur &
Co-rapporteur
+
CHMP co-
ordinator
+
ATMP experts
Lucia D’Apota, EMEA

15. Tasks Committee for Advanced Therapies
• Initial evaluation, re-examination, PMS
=> draft opinion to CHMP
• Classification: product = ATMP?
=> scientific recommendation from CAT
• Certification
=> CAT opinion => EMEA certification
• Scientific advices for ATMP
=> CAT involved
• Other
=> consultation by CHMP, advice to Commission

16. ATMP evaluation
Two phase review
MH Pinheiro, EMEA

17. ATMP evaluation – combination products
• Agency must recognise results of any assessment
by a notified body MDD / AIMD
• May request NoBo further information on
assessment
• If not included
 Agency to seek scientific opinion from NoBo
 CAT may decide no NoBo involvement needed

18. ATMP evaluation – re-examination
• 15 days and 60 days without clock stop
• Same concept, new reviewers
• CAT must be consulted by CHMP
• CAT to provide draft opinion
• Withdrawals publicly accessible

19. State of play 2009
• First meetings CAT
• CAT looking for interested parties
• Discussion CAT/EMEA with NBOG – NBmed
• Templates and SOPs
• Guideline on traceability
• Guideline GMP for ATMPs
• Integration work GTWP and CPWP into CAT

20. Scientific advise
MH Pinheiro, EMEA

21. Certification quality and non-clinical data
• Only for SMEs
• Quality data, or Quality and non-clinical
• For scientific evaluation and certification
• Evaluated by CAT
• 90 days with clock stops
• Possibility for site visit
• STAND ALONE evaluation procedure
• Not directly binding for clinical trial / market approval
• Certificate does not replace data for later submission
• No benefit/risk, no guarantees

22. Certification quality and non-clinical data
EMEA

23. One slide on risk management
J Petracek, EMEA

24. CAT monthly report
• http://www.emea.europa.eu/pressoffice/presshome.htm

25. CAT monthly report

26. Borderlines
• TEP may contain viable and non-viable cells
• No viable cells & no principal metabolic action
=> no ATMP
• Cell/device not by default engineered: substantial
manipulation to be considered
• ATMP with autologous and allogenic cells
=> allegenic use
• TEP and sCT => TEP
• GT and TEP or sCt, then GT > TEP > sCT
• Hospital exemptions under national laws

27. ATMP containing devices
• Devices as referred to in art. 7 of ATMP
 Not a med.dev. (scaffolds, biomaterials, matrices)
 Description physical characteristics, performance
 Description interaction genes, cells, tissues
• Combined ATMP:
 Cellular / tissue part as above
 Info on choice / intended function MDD/AIMD
 Evidence conformity to Essential Requirements
 Evidence compliance with BSE/TSE requirements
 If available: results NoBo assessment

28. Further NoBo involvement
• Several Notified Bodies volunteer knowledge to CAT
• Discussion EMEA / NB-med / NBOG on cooperation
planned in 2 weeks
• NoBo to chair ISO/CD 13022 on standard for Risk-
Management of cell-based products
• NoBo participates in RGM/1 in UK, Gert Bos
participates as member elect

29. ISO/TC194/SC1 – Tissue product safety
• CEN TC 316
• Secretariat: DIN
• Chair: Sabine Kloth
• Work on ISO/CD 13022 standard for Risk-Management
of cell-based products
• Input into this from EMEA / CAT
Example: equipment used for the manufacture of ATMPs

30. RGM/1
• Technical Committee to mirror the work of ISO/TC
150/SC7 "Tissue-engineered medical products"
• Work on standardization to support regulation in
regenerative medicine
• Chair: Ben Sheridan – BSi
• NB proposed seat: Gert Bos

31. Additional items and further reading……..
• 2001/20/EC – clinical trials
• 2002/98/EC – blood derivatives
• Regulation 1234/2008 – new variations
• EMEA/CHMP/96268/2005 – EMEA guideline on risk management
systems for medicinal products for human use
• EMEA/149995/2008 – guideline of safety and efficacy follow up – risk
management on ATMPs
• #@! Obtaining re-imbursement !
• www.emea.europa.eu/htms/human/advanced_therapies/intro.htm
• ec.europa.eu/enterprise/pharmaceuticals/pharmacos/new_en.htm
• www.emea.europa.eu/htms/human/advanced_therapies/interested_parties.htm

32. 32
Contact Us
Name: Gert Bos
Title: Head of Regulatory and Clinical Affairs
Address: BSI
Kitemark House, Maylands Avenue
Hemel Hempstead, HP2 4SQ, UK
Telephone: +44 (0)1442 278664
Fax: +44 (0)8450 765601
Email: Gert.Bos@bsigroup.com
Links: www.bsigroup.com/healthcare