Lääkealan turvallisuus- ja kehittämiskeskus 17.9.2014 Paula Salmikangas 1

Certification of quality and/or non-clinical data for ATMPs

GLP Seminar, Helsinki 16.9.2014

Lääkealan turvallisuus- ja kehittämiskeskus 17.9.2014 Paula Salmikangas 2

Gene TherapyMedicinal Products

Somatic Cell Therapy Medicinal Products

Tissue EngineeringProducts

Genetically modified cells

medical device + ATMP  combined ATMP

Advanced Therapy Medicinal Products

Lääkealan turvallisuus- ja kehittämiskeskus 15.5.2013 Paula Salmikangas 3

Blood2002/98/EC

Clinical Trials2001/20/EC

Paediatrics1901/2006

‘Annex I’2003/63/EC2009/120/EC

Tissues/Cells2004/23/EC

PhVig legislationDir. 2010/84/EUReg. 1235/2010

Other startingmaterials

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

MedicinalProducts

Community CodeDir. 2001/83/EC

MedicinalProducts

Centralised procedureReg. 726/2004

The EU legal / regulatory  framework

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somatic cell therapy products, gene therapy products and tissue engineered products classified as medicinal products (ATMPs)

cells either manipulated or intended for non‐homologous use

a centralised marketing authorisation route for all ATMPs

establishment of Committee for Advanced Therapies, CAT, for‐ classification‐ certification‐ evaluation of ATMPs‐ scientific advice and guidelines

when marketing authorization granted, it is valid in whole EU

possible to have post‐authorization efficacy and safety studies

Regulation 1394/2007/EC

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CATChair: P.Salmikangas

5 „double members“

EMA Committees for ATMPs

CHMPChair: Dr. T.Salmonsson

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2009       2010        2011         2012     2013     2014   Total Approved

Submitted

GTMP

SCTMP

TEP

Variations

3               1              2               3              2            1

2               1                                                              1

1

1  2                2 1

0              0 1                 1 9            2    

12

3

1

6

13

4

1

1

2

Approved:     ChondroCelect for cartilage repairMACI for cartilage repairGlybera for treatment of LPL deficiencyProvenge for treatment of advanced prostate cancer

Currently

4 ATMPs under evaluation , 2 new starting Q3‐4/2014

Marketing authorization applications / CAT  2009‐2014 (May) 

Lääkealan turvallisuus- ja kehittämiskeskus

Special issues for ATMP assessment ATMPs are complex pharmaceuticals‐ gene therapy: transgene, type of vector, genetically modified cells‐ cell therapy: autologous, allogeneic, complex process, combination products‐ assessment requires expertise from several areas e.g. tissue engineering, genetherapy, cell therapy, biotechnology, surgery, pharmacovigilance, riskmanagement, medical devices and ethics

Specific administration of certain ATMPs (catheters, surgery etc.) Specific safety issues (e.g. integrational mutagenesis of GTMPs, 

biodistribution/ectopic tissue formation of cell‐based MPs) Mode of action: treatment of disease to repair/regeneration Special challenges concerning manufacturing/quality, safety and efficacy

studies

Lääkealan turvallisuus- ja kehittämiskeskus8

PRODUCT DEFINITION – qualified cell population (s) in the appropriate vehicle for the intended action

PRODUCT CHARACTERISATION - to ensure:•Consistency of the active substance / finished product•Validation of the manufacturing process•Comparability when manufacturing changes are

introduced•Stability throughout shelf life•Release specifications selected from characterisation

studies

cell based medicinal product DEFINITIONS AND QUALITY

SPECIFIC REQUIREMENTS FOR CBMP : Directive 2009/120/EC + GL CBMP

Identity – phenotypic profile - cell markers Purity and Viability – relevant population / populations in mixture / viable cell %Impurities – unwanted cells, reagents, adventitious agents, sterility, endo, mycoplasmaPotency – quantitative measure of the biological activity – related to the intended actionkaryology, tumourigenicity, genetic stability – specially relevant for dividing differentiating cell populations

Lääkealan turvallisuus- ja kehittämiskeskus

Lääkealan turvallisuus- ja kehittämiskeskus 17.9.2014 Paula Salmikangas 10

Lääkealan turvallisuus- ja kehittämiskeskus 17.9.2014 Paula Salmikangas11

infections (microbial contamination of starting materialsor during processing)

tumourigenicity (cell transformation, integration to genome)

dedifferentation / loss of function of the cells

immunogenicity, rejection

ectopic engraftment of cells to non-target tissues

shedding (genet. modif. CBMPs; germ line, environment)

small sample sizes, short shelf-lives, availability of properanimal models, applicability of analytical methods etc.

Risks vs. limitations of ATMPs

Risk-based approach for all ATMPshttp://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/03/WC500139748.pdf

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Maciulaitis, R. et al. (2012)Molecular Therapy 20: 479-482

ATMP clinical trials in EU (EudraCT Database)

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Lääkealan turvallisuus- ja kehittämiskeskus 17.9.2014 Paula Salmikangas 14

ATMP certification

Only for SMEs

Scientific evaluation by CAT of- quality data (module 3)- non-clinical data (module 4)

90 day procedure

CAT evaluation report and EMA certificate

5 certifications finalised:- Bone marrow derived progenitor cells for cardiac repair

(quality: May 2010)- Autologous expanded smooth muscle derived cells for

treatment of stress urinary incontinence (quality: Oct 2012 ;non-clinical: Sept 2013)

- Autologous oral mucosal cells (quality + non-clinical: April 2014)- Autologous bone marrow derived MSC (quality: April 2014)

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Lääkealan turvallisuus- ja kehittämiskeskus 17.9.2014 Paula Salmikangas 16

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Lääkealan turvallisuus- ja kehittämiskeskus 17.9.2014 Paula Salmikangas 18

As part of the certification, a site visit can berequested by the assessors and/or CAT

GMP-related visit for quality and manufacturingGLP-related visit for non-clinical studies

- no standards yet for the site visits- no site visits conducted thus far

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Lääkealan turvallisuus- ja kehittämiskeskus 17.9.2014 Paula Salmikangas 20

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Lääkealan turvallisuus- ja kehittämiskeskus 23.4.2010Paula Salmikangas

Thank you for your attention!