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)

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Other CAT procedures (July 2015)

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: AdvancedTherapies@ema.europa.eu, Paula.Salmikangas@fimea.fi

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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)