0. Kehittyneen terapian lääkevalmisteiden (ATMP) myyntilupaprosessi ja CAT Fimea GLP-keskustelupäivä
Paula Salmikangas
CAT Chair

1. medical device + ATMP  combined ATMP
Gene Therapy
Medicinal Products
Somatic Cell Therapy
Medicinal Products
Tissue Engineering
Products
Genetically modified cells
medical device + ATMP  combined ATMP

2. Committee for Advanced Therapies (CAT) and CAT Activities
Dedicated Scientific Committee for ATMPs at the European Medicines Agency
Expertises specific to ATMPs (defined in legislation)
1 Member + 1 alternate per member state
5 Member nominated by CHMP (joint members)
2 Members + 2 alternates representing Patient Organisiation
2 Members + 2 alternates representing Doctors
Set up by Regulation (EC) No. 1394/2007
Operational since January 2009 (monthly meetings)

3. EMA Committees for ATMPs
CAT
Chair: P.Salmikangas
CHMP
Chair: Dr. T.Salmonsson
5 „double members“
18 quality experts
12 non-clinical experts
21 clinical experts
(including 4 members
representing physicians)
- 1 inspector
4 patient representatives
8 other (scientists, heads
of departments etc.)
Total 68 (5 nominations
pending)

4. Tasks of the CAT Tasks of the Committee for Advanced Therapies (CAT)
Scientific Advice
Support to PDCO
Support to CHMP / COMP
Interaction with stakeholders
Publications, Guidelines
Tasks of the CAT
Tasks of the Committee for Advanced Therapies (CAT)
EVALUATION
CERTIFICATION
CLASSIFICATION

5. ATMP Evaluation procedure
ATMPs will follow the Centralised procedure (mandatory scope)  single MA (marketing authorisation) for entire EU:
210 Day procedure
Evaluation by two independent (Rapp/CoRapp) teams from CAT, includes
CHMP-co-ordinators to ensure transparency between the two Committees
All scientific discussion and adoption of key documents at CAT, followed by CHMP discussion
CAT/CHMP opinion goes to the European Commission, which grants or refuses the MA

6. CHMP CAT RAPPORTEUR TEAM CO-RAPPORTEUR TEAM
CHMP Co-ordinator (at CHMP level) +
CAT Rapporteur
(at CAT level)
incl.
Q/S/E Experts
CHMP Co-ordinator (at CHMP level) +
CAT Co-Rapporteur (at CAT level)
incl.
Q/S/E Experts
CHMP
CAT (Co)Rapp coordinate procedure & discussions at CAT
+ prepare draft opinions and assessment reports
Peer review by 1 CHMP member 1 (or more) CAT member(s)
CAT
CHMP Co-ordinator responsible for flow of information between CAT & CHMP + discussion/adoption of opinion at CHMP

7. Marketing authorization applications / CAT 2009-2015 (July)
Total
Approved
Submitted
GTMP
SCTMP
TEP
Variations 1 14 6 7 15 5   3
Approved: ChondroCelect for cartilage repair, 2009
MACI for cartilage repair, 2012 (closure of EU manufacturing site 09/2014)
Glybera for treatment of LPL deficiency, 2013
Provenge for treatment of advanced prostate cancer, 2013 (withdrawn 05/2015)
Holoclar for treatment of limbal stem cell deficiency, 2015
5 ATMPs under evaluation, 3 GTMP, 1 CTMP, 1 TEP

8. Other CAT procedures (July 2015)

9. Certification procedure
Only for SMEs
Scientific evaluation by CAT of
(early) quality / development data (Module 3)
(early) non-clinical data (Module 4)
90 day procedure
Evaluation to the scientific standards of a marketing autorisation application
The SME applicant will always received the evaluation report (and List of issue for future consideration)
If positive evaluation: Certificate by EMA
6 Certification procedures finalised (July 2015)
Bone marrow derived progenitor cells for cardiac repair
Presentation C Schneider (13 February 2012)

10. Classification procedure for ATMPs
Incentive
Open to all applicants
Scientific Recommendation from CAT on the Regulatory Classification of their ATMP
60-day procedure (often shorter)
Publication of summary information on classification
134 procedures finalised
(July 2015)

11. Classification request by an Applicant
Regulation 1394/2007: CAT is responsible for classification of ATMPs
Putative ATMP
Classification request by an Applicant
ATMP
Not ATMP
Medicinal
product
Tissue/cell
preparation
Blood Product
DIR 2001/83
1394/2007
If a product is not considered an ATMP, it is not in CAT’s remit to classify this product

12. Introduced changes during the revision EMA/CAT/600280/2010
Substantial manipulation
Enzymatic digestion
Same essental function(s) in the recipient and the donor
Homologous vs non-homologous use
Additional changes to clarify the existing concepts
e.g. the boundary between vaccines against infectious diseases and gene therapy medicinal products and criteria for combined ATMPs

13. Tissue dissociation by enzymatic digestion
22 April 2017
Tissue dissociation by enzymatic digestion
Aim: Dissociate cells-cell contacts, i.e. epithelium
Involve several steps including:
Collagenase treatment
to digest extracellular matrix and
Protease (e.g. trypsin)
to disperse tightly associated cells.
Result: Disruption of stable cell-cell interactions (i.e. gap junctions, tight junctions, adherens junctions) which play a crucial role for the biological activity or structural characteristics of the cells and tissues
Considered: Substantial manipulation

14. Tissue dissociation by enzymatic digestion
22 April 2017
Tissue dissociation by enzymatic digestion
Aim: Dissociate cells and extracellular matrix, Ex: Islet preparation from pancreas
Result: Only conjunctive tissue is digested and cell-cell contact is maintained.
Considered: Non substantial manipulation

15. Same essential function in the recipient and the donor
Legislation: Cells or tissues that are not intended to be used for the same essential function(s) in the recipient and the donor
The CAT classification is based on two different criteria:
Location
Function
For stem cells (HSC and MSC), the function is not dependent on the histological location

16. Hematopoietic stem cells (HSC) transplantation
Same essential function in the recipient and the donor
Hematopoietic stem cells (HSC) transplantation
Apheresis
Cell therapy unit
Non substantial
manipulations
Thawing and washing
Administration

17. Not same essential function(s) in the recipient and the donor
Bone marrow-derived autologous CD34 cells
Intended for improvement of heart function in patients with refractory angina and chronic myocardial ischemia
Majority of BM cells hematopoietic
progenitors, role in hematopoiesis
Considered: Not same essential function
Classified: Tissue-engineered product
Difficult to demonstrate efficacy; large
clinical trials ongoing (BAMI, 3000 pts)

18. Degree of Manipulation Degree of Oversight* (1,2,3)
International Regulatory Perspectives: Degree of Regulatory Oversight for Eight Categories of Cell Therapy Products
Category of Product
Source
Degree of Manipulation
Intended Use
Degree of Oversight* (1,2,3)
Investigational
Market Use
Category A
Autologous
Minimal
Homologous
Category B
Substantial
Non-homologous
Category C
Category D
Category E
Allogeneic
Category F
Category G
Category H

19. Changes in the EU legal regulatory framework impacting ATMPs
PhVig legislation
Dir. 2010/84/EU
Reg. 1235/2010
Tissues/Cells
2004/23/EC
Other starting
materials
Blood
2002/98/EC
Medical Devices
93/42/EC, 90/385/EC
Clinical Trials
2001/20/EC
Medicinal
Products
Community Code
Dir. 2001/83/EC
Medicinal
Products
Centralised procedure
Reg. 726/2004
GMP
2003/94/EC
Paediatrics
1901/2006
Orphans
141/2000
‘Annex I’
2003/63/EC
2009/120/EC
Variations
1084(5)/2003
1234/2008
Advanced Therapy
1394/2007
Falsified Med.
Dir. 2011/62/EU
EC report from open consultation 4/2014

20. Changes in the regulatory framework impacting ATMPs
Clinical trial regulation 536/2014
 need guidance for ATIMPs
 Specific GMP requirements for ATIPMs
Revision of the Device legislation
 Combined ATMPs and borderline MP/ device cases?
New T&C legislation on importation
 CAT identified several problems for small ATMP developers and especially
concerning cell-based products (short shelf-lives), e.g. concerning the request
to import also ATMP starting materials through licensed tissue banks
Revision of the ATMP Regulation 1394/2007 and correction all problematic points have been
much awaited by the developers, but perhaps not amongst the ones to be opened soon…?
 Commission has started to work on those points, that can be changed/improved
without the need to change the legislation; CAT input required

21. Revision of the GMP framework for CT
GMP requirements
GMP mandatory for all products entering clinical trials
GMP or equivalent quality system for Hospital Exemption (Jacie standard for transplantation)
Many trials from academic / hospital investigators
Other quality systems in use in tissue banks
Current requirements heavily critized during consultation
Revision of the GMP framework for CT
Special GMP guidance for all ATMPs (both CT and MA)  under public consultation Q3/2015

22. Guideline(s) on investigational ATMPs
EC has given the CAT the mandate to draft guideline(s) for
investigational ATMPs (01/2015)
No available IMP guideline for cell-based ATMPs, old GL on
gene therapy IMPs
 two separate documents will be drafted, maybe fused later
on, if feasible
 main focus on first in man studies, but will provide guidance
also for later phases
- IP meeting Q4/2015 – Q1/2016 on the IMP GLs

23. Several challenges in ATMP development
manufacturing constraints
- GMP requirements for production
- starting and raw materials; material supply
- production technologies, comparability
- variability and process validation
characterisation, potency testing
(related to clinical outcome)
non-clinical challenges
- availability of relevant animal models
- proof of concept, safety aspects (species specificities)
clinical aspects
- possibilities for blinding, availability of compators, efficacy!
- dose finding and biodistribution studies in humans, concomitantmedication/surgical procedures,
economic constraints (funding, HTA negotiations), value of ATMPs in various indications not yet established, high production and testing costs per batch, differences on national level (classification, clinical trial requirements, hospital exemption…)

24. Risk-based approach
Propectively planned strategy to justify the need for data in the MAA, not a traditional risk analysis
Does not provide a rigid classification system of different risks of
a product as whole (e.g. high-risk product vs. low-risk product)
Is intended to provide flexibility to regulation of ATMPs
Additional help or burden for developers?
How to do the risk/risk factor profiling?
 GL on risk-based approach (EMA/CAT/CPWP/686637/2011)
 Q/A document on RBA under preparation
 scientific advice

25. Adaptive pathways
Prospectively planned approach for MA with conditions
Based on existing procedures (conditional MA, MA with
exceptional circumstances, joint EMA/HTA SA…)
Pilot phase with 3 ATMPs ongoing
Important to understand the impact of conditional MA
 post-marketing obligations
 impact on reimbursement negotiations

26. CAT participates to joint cross-committee objectives
- adaptive pathways (3 ATMPs in the pilot)
- benefit/risk project
- patient registries, ….
CAT specific objectives
- finalise the RP on classification and GL on GTMPs
- draft a guideline for investigational ATMPs (EC task); - CAT/IP meeting
Q3/4, in relation to the GL on investigational ATMPs
- support EC in developing GMP guideline for ATMPs
- provide training for assessor´s (2015, webinars) and developers (CAT workshop
with learned societies with ISCT in Sevilla)
- new survey of clinical trials and developers ( )

27. Where to find information
Further information from the CAT and it’s monthly reports
 Committees  CAT
Summaries of scientific recommendations on classification of ATMP
Go to: Advanced therapies
ATMP classification
Summaries
For general queries:

28. Thank you for your attention!
Colton And Abbygail Ainslie,
Siblings With SCID, Among First Cured Of 'Bubble Boy Disease'
(Photo: Facebook/Jessica Ainslie)
B.Mellor, Nature 2008
Thank you for your attention!
Special thanks to Margarida Menezes Ferreira (CAT)
Patrick Celis (CAT)
Rocio Salvador Roldan (EC)
Marit Hystad (CAT)
Nicolas Ferry (CAT)
Egbert Flory (CAT)