regulatory challenges of combined advanced therapy products · 2018. 4. 2. · cmc strategy forum...

Lääkealan turvallisuus- ja kehittämiskeskus 2.8.2014 Paula Salmikangas 1

Regulatory Challenges of Combined Advanced Therapy Products

CMC Strategy Forum Europe

Prague 8.5.2013

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GTMPs

sCTMPs

TEPs


´medical device´

any instrument, apparatus, appliance, software, material or other article intended for

— diagnosis, prevention, monitoring, treatment or

alleviation of disease or handicap,

— investigation, replacement or modification of

the anatomy or of a physiological process,

— control of conception,

and which does not achieve its principal intended action in or on the human body by pharmacological, immunological or metabolic means, but which may be assisted in its function by such means;”

Principal MoA for medical devices should be physical

New, more precise definitions coming for pharmacological, immunological and metabolic action (in revision of Dir. 93/42/EC)

Definition of a Medical Device (Art. 1, 93/42/EEC)

http://www.google.fi/url?sa=i&rct=j&q=medical+device&source=images&cd=&cad=rja&docid=hfRonAUoCtfjlM&tbnid=81I9jt15Y3Fx1M:&ved=0CAUQjRw&url=http%3A%2F%2Fwww.mntap.umn.edu%2Fmeddevices%2F&ei=kq1eUbuwOISetAaElYD4DA&bvm=bv.44770516,d.Yms&psig=AFQjCNGhRFz0U9MaEk4fX8XsxMSsoBaXNw&ust=1365245647102478


´active implantable medical device´ any device intended to be totally or partially introduced, surgically or medically, into the human body or by medical intervention into a natural orifice, and which is intended to remain after the procedure;”

Definition of an Active Implantable Device (Art. 1 90/385/EEC)

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Combined ATMP means a product that fulfils the following conditions: - must incorporate, as an integral part of the product one or more medical devices (93/42/EEC) or active implantable medical devices (90/385/EEC) its´ cellular or tissue part must contain viable cells or tissues or the non-viable cellular/tissue part must have action that is primary to that of the device(s)

Regulation 1394/2007/EC


Blood 2002/98/EC

Clinical Trials 2001/20/EC

Paediatrics 1901/2006/EC

‘Annex I’ 2003/63/EC 2009/120/EC

Tissues / Cells 2004/23/EC

PhVig legislation Dir. 2010/84/EU Reg. 1235/2010/EC

Other starting materials

Medical Devices 93/42/EC, 90/385/EC

GMP 2003/94/EC

Orphans 141/2000/EC

Variations 1084(5)/2003/EC 1234/2008/EC

Advanced Therapy 1394/2007/EC

Falsified Med. Dir. 2011/62/EC

Medicinal

Products Community Code

Dir. 2001/83/EC

Medicinal

Products Centralised procedure

Reg. 726/2004/EC

The EU legal / regulatory framework


Conformity assessment by Notified Bodies

Notified Bodies assess medium and high risk devices for conformity (mainly class II & III devices and all active implantable devices)

Currently 77 Notified Bodies for medical devices in Europe, all designated and monitored by their national authority (http://ec.europa.eu/enterprise/newapproach/nando/).

The type of medical devices assessed by each Notified Body varies; currently 48/77 assessed MDs intended for wound care, 37/77 MDs incorporating medicinal substances, 26/77 MDs utilising tissues of animal origin, 16/77 MDs incorporating derivatives of human blood

The assessment includes evaluation of design and construction, lifetime performance, clinical and safety data, chemical, physiological and biological properties, biocompatibility, device/MP compatibility, microbiological safety, preclinical testing, etc. = design dossier CE certificate and report

http://ec.europa.eu/enterprise/newapproach/nando/


Evaluation procedure for combined ATMPs

Art.9, 1394/2007/EC

Where a combined advanced therapy medicinal product is concerned, the whole product shall be subject to final evaluation by the Agency

The application for a MA for a combined advanced therapy medicinal product shall include evidence of conformity with the essential requirements (device legislation)

The application for a MA for a combined ATMP shall include, where available, the results of the assessment by a notified body in accordance with Directive 93/42/EEC or Directive 90/385/EEC

The Agency shall recognise the results of that assessment in its evaluation of the medicinal product concerned

The Agency may request the relevant notified body to transmit any information related to the results of its assessment (1 mo)

If the application does not include the results of the assessment, the Agency shall seek an opinion on the conformity of the device part …from a notified body identified in conjunction with the applicant, unless the Committee for Advanced Therapies advised by its experts for medical devices decides that involvement of a notified body is not required.


IMPs 2005 2006 2007 2008 2009 2010 2011 2012 * GTMP 9 23 35 59 75 99 119 147 sCTMP 8 47 84 123 162 239 288 353 TEP 5 12 28 48 74 80 90 109

Multinational CTs 2012: GTMP 7/28 , TEPs 10/19 , SCTMPs 5/65

Main indications: - Cancer immunotherapy (sCTMP and GTMP) - cardio-vascular - TEPs for repair of skin/eye/liver/bone/cartilage - vaccines (GTMPs for HIV, HPV, HCV etc.) * Cumulative number of new applications (report is suggestive and should not be considered exhaustive). This report has been

generated from the information in EudraCT Data Warehouse..

Number of ATMP clinical trials / EU


2009 2010 2011 2012 Total

Gene therapy 3 7 1 4 15

Gene therapy, combined ATMP 0 0 0 1 1

Cell therapy 6 7 3 2 18

Cell therapy, combined ATMP 0 1 0 0 1

TEP 1 8 5 4 18

TEP, combined ATMP 0 2 1 1 4

ATMP (not subclassified) 0 1 0 0 1

not ATMP 2 1 2 4 9

Total 12 27 12 16 67

Classifications 2009-2012


1) Devices having the main function

2)Devices as structural/delivery parts 3) Cells with device

Devices in combination products

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Synthetic biomaterials

Biodegradable polymers: poly(α-hydroxy)esters (PGA, PLA, PLGA); Polycaprolactones, polycarbonates, etc.; Ceramics/glasses: HA, ß-TCP, bioactive glasses

Advantages: biodegradable, easy processing, good pore architecture and mechanical properties; Disadvantages: inflammation, variable degradation rates, loss of cell function

Natural biomaterials

Proteins (collagen, fibrin, elastin), Polysaccharides (alginate, chitosan)

Advantages: good cell attachment, natural function, remodelling, less

inflammation; Disadvantages: poor mechanical properties, stability and processing

Composites

Collagen-ceramics, Collagen-HA, Collagen-TCP; combine advantages of both materials

Device materials in combined ATMPs


Combination products

Cells with matrix/scaffold

Gene activated matrices

According to 2009/120 the active substance in combination products are the cells/genes AND the device part

therefore all critical studies (Q, NC, C) should be performed with

the combination

cells scaffolds

signalling molecules

Blood/ nutrient supply

Tissue regeneration

Integrity of

organels

Viability

Gene

expression

Signalling

Proliferation

Differentation

Quality of

proteins

Motility

Apoptosis

Respiration

Energy

Morphology Functionality

Metabolic

activity


Critical aspects of a combination?

- Signalling cell - cell, device – cells - Proliferation vs. differentiation in vitro/in vivo - Structural integrity and functionality of the cells/genes and the device(s) - Biocompatibility, toxicity, biodistribution, stability vs. turnover etc. - Analytical tools available to analyse cells in combination with devices?

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Collagen membrane Calsium phosphate- coated titanium

Hyaluronic acid-based matrix

The impact of the decive / scaffold / membrane on the cells? Passive vs. active? Bioactive vs. biotolerable?

Cells in a combination product seldomly responsible of the activity/potency of the product alone!

Biomaterials, when part of normal tissue ECM act as signalling molecules to cells (collagen, hyaluronic acid, calsium phosphate..) impacting cell growth and differentation

Cell-matrix/scaffold interactions


GUIDELINE ON HUMAN CELL-BASED MEDICINAL PRODUCTS EMEA/CHMP/410869/2006

autologous vs allogeneic / cell like or tissue like / immunoactive / proliferative vs. differentiated

Identity – markers, morphology, cell interactions, metabolism, matrix / scaffold

Cell purity – relevant cells, ratio of viable to non viable

Impurities - product / process – unwanted cells, degradation products,

metabolites / adventitious agents (cells and biomatrices), bioactive reagents

Potency – according to intended function

– required for comparability, consistency and stability

Tumourigenicity , Karyology / Genetic Stability, Biocompatibility

How to evaluate these from combination products? We need innovative analytical approaches!


S. Neuss et al. / Biomaterials 29 (2008) 302–313


Guideline on cell-based medicinal products (EMEA/CHMP/410869/2006) • Any matrices, fibers, beads, or other materials that are used in

addition to or in combination with the cells should be described and their function underpinned by means of chemical, biological, physical (e.g. structure and degradation) and mechanical properties.

• The characterisation of a CBMP should encompass all the components

present in the finished product. Characterisation may prove particularly challenging for products containing cells together with matrices, scaffolds and innovative devices. Characterisation data are likely to be necessary for single components as well as for the combined final product. Characterisation data could encompass data obtained throughout the development and/or manufacturing process. It should be noted that in a combined product the characteristics of both the cellular and the non-cellular components may be altered by the process of integration.


Impurities and degradation product that originate from the structural component (matrix, scaffold, device) shall be described and specifications for the relevant impurities should be set.

Interaction of the cellular component and any additional non-cellular components with the device should be evaluated and the development and characteristics of the combined product as a whole should be presented.

Tissue differentiation and functionality are highly dependent on the local environment and thus on the choice of biomaterials and cell signalling biomolecules (e.g. growth factors). Therefore, studies should be carried out to verify critical aspects of the character and performance of biomaterials and other non-cellular components used in the CBMP, for example biocompatibility and mechanical strength.

Additional studies (e.g. cell adhesion studies, growth studies) may

be necessary to demonstrate aspects of biocompatibility specific to cell-based applications.


Topics for further guidance on combination products

• different types and materials of devices, their roles in the combination, passive vs. active; inertbioactivebiodegradable=risk-based?)

• structural/functional characteristics of different materials and different cells, look-back of treatment failures?

• biocompatibility of different device materials with cells and the patient, toxicity, erosion, cell biodistribution, etc.?

• problems of biodegradable materials (e.g.difficulties in sterilisation, water absorption, low mechanical strength, immune responses etc.)

• different roles of cells in the combination products (main functional role vs. supportive role) level of information

needed (risk-based approach)?

• when a device and cells form a persistent combination (new tissue, ECM, integration) vs. normal tissue turn over? Follow-up?

• analytical tools to assess the combination in vitro and in vivo? markers to follow e.g degradation?

• Characterisation, potency, comparability,…..


In conclusion

A lot of new products in the pipeline; most still in phase II and developed by academia / hospitals /SMEs

first combination products: TEPs for cartilage/eye/skin/bone repair

Regulation 1394/2007/EC and device legislation have clarified authorisation and use of novel combined products in Europe; problems with ”grey zone” products

CAT/EMA assistance available: classification, certification of Q/NC data, informal ITF meetings, scientific advice, guidance Critical aspects of the combinations to be identified; biocompatibility

between cells and device materials is varying certain materials inhibit cell proliferation, others may act as signalling molecules for the cells!

New analytical tools are needed for charaterisation and IPC/batch release/stability testing of the combined products


Thank you for your attention!

regulatory challenges of combined advanced therapy products · 2018. 4. 2. · cmc strategy forum...

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