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An agency of the European Union
Kehittyneen terapian lääkevalmisteiden (ATMP) myyntilupaprosessi ja CAT
Fimea GLP-keskustelupäivä 2.9.2015
Paula SalmikangasCAT Chair
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Gene Therapy Medicinal Products
Somatic Cell Therapy Medicinal Products
Tissue EngineeringProducts
Genetically modified cells
medical device + ATMP combined ATMP
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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)
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CATCATChair: P.Salmikangas
5 „double members“5 „double members“
EMA Committees for ATMPs
CHMPCHMPChair: Dr. T.Salmonsson
- 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)
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CLASSIFICATION
EVALUATION
CERTIFICATION
Tasks of the CATTasks of the Committee for Advanced Therapies (CAT)
Scientific Advice
Support to PDCO
Support to CHMP / COMP
Interaction with stakeholders
Publications, Guidelines
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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
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RAPPORTEUR TEAM
CO-RAPPORTEUR TEAM
CHMP Co-ordinator responsible for flow of information between CAT & CHMP + discussion/adoption of opinion at CHMP
CHMP Co-ordinatorCHMP Co-ordinator(at CHMP level)(at CHMP level)++CAT RapporteurCAT Rapporteur (at CAT level)(at CAT level)incl.incl.Q/S/E Q/S/E ExpertsExperts
CHMP Co-ordinatorCHMP Co-ordinator (at CHMP level)(at CHMP level)++CAT Co-RapporteurCAT Co-Rapporteur (at CAT level)(at CAT level)incl.incl.Q/S/E Q/S/E ExpertsExperts
CAT (Co)Rapp coordinate procedure & discussions at CAT + prepare draft opinions and assessment reports
CATCAT
CHMPCHMPPeer review by 1 CHMP Peer review by 1 CHMP member 1 (or more) CAT member 1 (or more) CAT member(s)member(s)
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2009 2010 2011 2012 2013 2014 2015 Total
Approved
Submitted GTMP SCTMP TEP
Variations
3 1 2 3 2 2 1 2 1 2 1 1 1 2 2 1 1
0 0 1 1 9 4
14 6 1 7
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5 1 1 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
Marketing authorization applications / CAT 2009-2015 (July)
Presentation C Schneider (13 February 2012)10
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
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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)
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Putative ATMPClassification request by an Applicant
DIR 2001/83
Tissue/cellpreparation
Blood Product
Not ATMP
1394/2007
Medicinal product
ATMP
Regulation 1394/2007: CAT is responsible for classification of ATMPs
If a product is not considered an ATMP, it is not in CAT’s remit to classify this product
Substantial manipulation
Enzymatic digestion
Same essental function(s) in the recipient and the donorHomologous 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
Introduced changes during the revision EMA/CAT/600280/2010
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
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
Tissue dissociation by enzymatic digestion
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
Same essential function in the recipient and the donor
Hematopoietic stem cells (HSC) transplantation
Apheresis Cell therapy unit Non substantial manipulations
Thawing and washingAdministration
Same essential function 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
Not same essential function(s) in the recipient and the donor
www.trialx.com
Difficult to demonstrate efficacy; large
clinical trials ongoing (BAMI, 3000 pts)
International Regulatory Perspectives: Degree of Regulatory
Oversight for Eight Categories of Cell Therapy Products
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Category of Product
SourceDegree of Manipulati
onIntended Use
Degree of Oversight* (1,2,3)
Investigational
Market Use
Category A Autologous Minimal Homologous
Category B Autologous Substantial Non-homologous
Category C Autologous Minimal Non-homologous
Category D Autologous Substantial Homologous
Category E Allogeneic Minimal Homologous
Category F Allogeneic Substantial Homologous
Category G Allogeneic Minimal Non-homologous
Category H Allogeneic Substantial Non-homologous
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Blood2002/98/EC
Clinical Trials2001/20/EC
Paediatrics1901/2006
‘Annex I’2003/63/EC
2009/120/EC
Tissues/Cells2004/23/EC
PhVig legislationDir. 2010/84/EU
Reg. 1235/2010
Other starting
materials
Medical Devices93/42/EC, 90/385/EC
GMP2003/94/EC
Orphans141/2000
Variations1084(5)/2003
1234/2008Advanced Therapy1394/2007
Falsified Med.Dir. 2011/62/EU
Medicinal
ProductsCommunity Code
Dir. 2001/83/EC
Medicinal
ProductsCentralised procedure
Reg. 726/2004
Changes in the EU legal regulatory framework impacting ATMPs
EC report from open consultation 4/2014
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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
- 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
GMP requirements
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
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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…)
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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
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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
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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 - 2015 with ISCT in Sevilla)- new survey of clinical trials and developers (2010-2014)
Where to find information
Further information from the CAT and it’s monthly reports
http://www.ema.europa.eu Committees CAT
Summaries of scientific recommendations on classification of ATMP
Go to: Advanced therapies
ATMP classification
Summaries
For general queries: [email protected], [email protected]
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Thank you for your attention!
B.Mellor, Nature 2008
Colton And Abbygail Ainslie, Siblings With SCID, Among First Cured Of 'Bubble Boy Disease'
(Photo: Facebook/Jessica Ainslie)
Special thanks to Margarida Menezes Ferreira (CAT) Patrick Celis (CAT) Rocio Salvador Roldan (EC)
Marit Hystad (CAT) Nicolas Ferry (CAT) Egbert Flory (CAT)