The European Landscape for Regenerative Medicine

Margarida Menezes Ferreira

Senior Assessor at INFARMED

PT expert at BWP/CHMP - EMA

member of the CAT - EMA

(margarida.menezes@infarmed.pt)

“I attend this conference as an individual expert and do not represent the CAT. The views

expressed here are my personal views, and may not be understood or quoted as being made on

behalf of the CAT or reflecting the position of the CAT”

Tokyo, December 8-9, 2014

ARIGATO - OBRIGADO Thank you for your hospitality since we first met in 1543!

Nanbam screens . Museu Nacional d Arte Antiga, Lisboa

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Businessweek July 1998

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National

authorisations

DE, IT, FR • Somatic cell therapy

• Gene therapy

TEP not defined

ADVANCED THERAPY MEDICINAL

PRODUCTS - ATMP

Tissue engineered

Centralised marketing

authorisations (MA)

from 1/2009 = CAT

TEP / regenerative medicine

Combined products

Non-substantial manipulation

Long term efficacy follow up

Hospital exemption

...

• NEW DEFINITIONS

for GeneTherapy and

Somatic Cell Therapy

ATMP specific

Dossier requirements

for MA

Directive 2001/83/EC revised

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"The Long and Winding Road"

Margarida Menezes Ferreira

(Directive 2009/120/EC – revised Annex I of Directive 2001/83/CE )

Advanced Therapy Medicinal Products – ATMP definitions

Gene therapy medicinal product

• recombinant nucleic acid for regulating, repairing, replacing, adding or deleting a genetic sequence;

• its effect relates directly to the recombinant nucleic acid sequence it contains, or to the product of genetic

expression of this sequence.

• NOT vaccines against infectious diseases.

Somatic cell therapy medicinal product

• cells or tissues subject to substantial manipulation

• cells or tissues not for the same essential function(s) in the recipient and the donor

• for treating, preventing or diagnosing a disease through the pharmacological, immunological or metabolic action of

its cells or tissues.

Tissue engineered product

• engineered cells or tissues = subject to substantial manipulation

• cells or tissues not for the same essential function(s) in the recipient and the donor

• used to regenerating, repairing or replacing a human tissue, / primary function combined with devices

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ADVANCED THERAPY MEDICINAL PRODUCTS - ATMP

• Definitions suporting regenerative medicine TEP / Combined - medical devices

• Clarfying fronteers - Non-substantial manipulation to separate from transplantation

• Centralised MA from Jan 2009 / new Committee CAT

• national system for hospital exemption for named patient and non routine within one MS

• Traceability – flow between cell donation vigilance - pharmacoviglance

• Specific GMP requirements

• Long term safety and efficacy follow up

• hESC - national prohibitions apply

• Incentives for SME

• Revise Annex 1 of Directive 2001/83/EC to establish new dossier requirements

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"The Long and Winding Road"

Directive 2009/120/EC – specific requirements for ATMP

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Directive 2001/83/EC revised by 2009/120/EC - requirements for ATMP

Directive 2009/120/EC – specific requirements for ATMP

Human cells collected and donor tested according to Directives 2004/23/CE, 2006/17/CE and 2006/86/CE

Traceability of all raw, starting materials and active substance

TSE minimization and viral safety of active substance considering all raw and starting materials

• Scaffolds, cells, vectors, bank to produce vector = starting materials

• bioactive molecules and cell medium not part of AS = raw materials

Characterisation include identity, purity, viability, potency, kariology, tumourigenicity, genetic stability

Genetically modified cells = gene therapy + cell therapy requirements

Biocompatibility of matrix, scafold, cells, excipients, substances in final product

Risk based approach to construct the dossier

Risk management plan include long term follow-up of safety and efficacy

Use favourable legal tools specific for ATMP

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Long term safety and efficacy

follow up

RISK BASED APPROACH

Article 14º

RISK BASED APPROACH FOR ATMP’S

The risk analysis, when applied, shall be included and described in Module 2. ”

“ Due to the specific nature of advanced therapy medicinal products, a risk-based approach may be applied to determine the extent of quality, non-clinical and clinical data to be included in the marketing authorisation application, ….

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• Guideline is intended to support the Applicant to identify the risks and associated risk factors and to establish a risk profile for their ATMP under development

• With the use of the identified risk profile the Applicant will be able to justify the extent of data to be included in the MAA dossier

RISK BASED APPROACH GUIDELINE – published feb 2013

Risk: an unfavorable effect that can be attributed to the ATMP and is of concern to the patient and/or to third parties.

Risk factor: a qualitative or quantitative characteristic that contributes to a specific risk following administration of an ATMP.

Risk profiling: a methodological approach to systematically integrate all available information on risks and risk factors in order to obtain a profile of each individual risk associated with a specific ATMP.

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Risk profiling: Plot Map

Consequences for the dossier

The Risk-based approach for ATMP 11

Risk based approach not mandatory

Strategy for each risk and discussion on conclusions and justifications

supporting the extent of data – to be included in the MAA CTD Mod 2.2 .

Result of the risk-based approach can be used as one starting point for

the safety specifications as part of the Risk Management Plan.

RISK BASED APPROACH

Examples of Risks regarding ATMPs

• Transmission of disease (viral, bacterial, fungal)

• Unwanted immune reaction

• Unwanted ectotopic engraftment/biodistribution

• Tumor formation

• Unintented alteration of cell homeostasis

• Toxicity of compounds and/or final product

• Shedding and transmission

• ...

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RISK BASED APPROACH

Examples of potential risk factors for CBMP

• Origin of cells (autologous vs allogeneic)

• Ability to proliferate and differentiate

• Ability to initiate an immune response (as target or effector)

• Level of cell manipulation ( in vitro / ex vivo expansion/activation, genetic manipulation)

• manufacturing process including biologically active reagents

• Mode of administration (ex vivo perfusion, local, systemic)

• Duration of exposure (short to permanent)

• ...

The Risk-based approach for ATMP 13

RISK BASED APPROACH

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Cell Based Medicinal Products

(Directive 2009/120/EC + Regulation 1394/2007)

Somatic cell therapy medicinal product

Tissue engineered Products - TEP

Include cells or tissues subject to substantial manipulation

“cells or tissues subject to substantial manipulation so that biological characteristics,

physiological functions or structural properties relevant for the intended clinical

use have been altered “

Or just indicated for heterologous use

“not intended to be used for the same essential function(s)”

• used to treating, preventing or diagnosing a disease through the

pharmacological, immunological or metabolic action of its cells or tissues. =

somatic cell therapy

• used with a view to, regenerating, repairing or replacing a human tissue =

TEP

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NOT substantial = NOT medicinal product :

Regulation 1394/2007/EC

“heterologous use” = medicinal product

• – cutting;

• – grinding;

• – shaping;

• – centrifugation;

• – soaking in antibiotic or antimicrobial solutions;

• – sterilization;

• – irradiation;

• – cell separation, concentration or purification;

• – filtering;

• – lyophilization;

• – freezing;

• – cryopreservation;

• – vitrification;

• …

1

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TO BE A MEDICINAL PRODUCT not a TRANSPLANT

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• CERTIFIED GMP UNDER MUTUAL RECOGNITION WITHIN EU AND WITH OTHER AGREED NON EU MEMBERS

• SUPPLIER QUALIFICATION FOR ALL RAW MATERIALS AND TRACEABILITY

• VALIDATION OF ASSEPTIC MANUFACTURING PROCESS – GMP ANN1

• EQUIPMENT QUALIFICATION – GMP ANN15

• BATCH RELEASE BASED ON PRODUCT TESTING BY QP

• PRE-ASSESSMENT FOR PRODUCT QUALITY, SAFETY EFFICACY AND FOLLOW-UP

• MODE OF ADMINISTRATION UNDER MANUFACTURER SUVERVISION

• PHARMACOVIGILANCE FOR LIFE

• LIABILITY ON ALL PARTS OF THE PROCUREMENT / PROCESS / PRODUCT / USE

Cell – product definition - diversity

• Autologous or allogeneic

• Toti – pluri – adult starting material

• Separated – enriched - clonal

• Single population – multifactorial complex combination

• Cultured – cell divisions – genetic stability

• Cell bank or cell stock -

• Differentiation to be concluded prior or post administration

• Cell suspension – matrix - combined

• …

CAT CLASSIFICATION PROCEDURE

Margarida Menezes Ferreira

AUTOLOGOUS NO SUBSTANTIAL MANIPULATION Adipose stromal fraction cells separated by Collagenase Cells obtained and administered in the same surgical procedure

CLASIFICATION NON BINDING – lack of harmonisation within EU and elsewhere DEFINITIONS REQUIRED – cell, tissue, organism, vaccine, industrialprocess, heterologous use …

DIFFERENT ESSENTIAL FUNCTION (NON-HOMOLOGOUS USE) bone marrow mesenchymal stromal cells in bone …… 163 pages of comments from 60 stakeholders many from organisations

Li MD et al Regen. Med. (2014) 9(1), 27–39

• Autologous / obtained in hospital or academic setting

- MSC’s for cardiac repair / bone reconstruction

- Adypocytes for reconstruction

- Chondrocyte

- Dendritic cells for cancer

- …

CELL BASED MP IN EUROPEAN MEMBER STATES UNDER HOSPITAL EXEMPTION OR SPECIAL AUTHORISATION PROVISIONS

EU CENTRALISED AUTHORISATION

- 2 Chondrocyte – CHONDROCELECT

MACI

- 1 Dendritic cells - PROVENGE

Sources of variability in cell therapy

MATERIALS

• Donor

• Collection

• Dynamic starting cell

material

• Biological raw materials

MANUFACTURE

• Same process different

dynamics

• Length of process

• different differentiation

stages

• Complex process – multiple

stages

ADMINISTRATION

• Complex system often

surgical procedures

• Patient response

CONTROL

• Bioanalytical methods

• No standardised

reference materials

Margarida Menezes Ferreira

hierarchy of guidelines !

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Directive 2009/120/EC – SPECIFICATIONS required for CB-ATMP

TARGET PROFILE

identity,

purity,

viability,

potency,

kariology, tumourigenicity, genetic stability

Genetically modified cells = gene therapy + cell therapy requirements

EXTENSIVE CHARACTERISATION

Based on previous knowledge + development

relevant for

CONSISTENCY - PROCESS VALIDATION - CQA

COMPARABILITY

Margarida Menezes Ferreira

CHARACTERISATION – physico-chemical

= Phenotype + Quantify / viable total (flow cytometry) - Relevant cells

- Inert cells

- Deleterious cells

- Apoptotic cells

- Viable cells

- Cell debris

- Exosomes

= Genotype – (sequencing – PCR – STR)

- separated / purified populations

- clonal cells

- differentiation stage

- genetically modified vs non GM

PURITY = phenotypic and genotypic profile

Margarida Menezes Ferreira

Potency has to be quantitative and related to relevant biological properties =

drawn from characterisation (and preclinical studies)

Potency may evolve during development – define reference preparations

Potency assay required for consistency, comparability, stability – validated for

MA

Potency of active substance if final product not possible

Functional assay might not be quantitative but can serve to cross validate

potency measurement of surrogate markers – mixed approaches possible

and often necessary

Quantification of mRNA should be complemented with the expressed protein

cells and induced differentiation / engraftment / ex vivo use might need kinetic

studies to validate relevant biological activity(ies)

potency assay – considerations

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Confounding aspects to potency testing of CBMP

• insufficent knowledge on the active component(s)

• limited sample size / shelf life (autologous, primary cells)

• unknown mode of action / lack of appropriate biological atribute

• Structural complexity / Multifactorial actions - poor specificity

• Interfering substances / poor parallelism - poor accuracy

• inappropriate tools – acceptance criteria / specifications too wide

• non linearity – characterisation under dynamic conditions

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MANUFACTURING PROCESS

• Commercial devices

• Not substantial manipulation

Generally not CPP Microbiol safety RSpecs

• Developpment studies to define critical raw materials critical steps and cQA

• Upscale - comparability

CPP - AS CQA or RSpecs Microbiol safety

• Developpment studies to define critical raw materials critical steps and cQA

CPP - AS CQA Microbiol safety

• Combination - biocompatibility CPP for TEP Microbiol safety

• Criopreservation

• Bedside preparation

RSpecs Process validation Microbiol safety

CELL SOURCING • Standardise collection acceptance criteria

administration

SEPARATION

EXPANSION

MODIFICATION

FINAL PRODUCT

FORMULATION

?

• Standardise practice Margarida Menezes Ferreira

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http://ec.europa.eu/health/files/eudralex/vol-4/vol4-an2__2012-06_en.pdf

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authorisation of tissues and cells procurement + donor testing by transplantation authority authorisation of collection and testing and tissue establishments (TE) for banking

Export / Import activities in the EU by authorised TE TE ensures that imported cells from 3rd countries allows traceability to donor and collection and testing under equivalent standards as Directive

Cells exported from EU comply with this Directive

Human cells = starting materials

Raw materials : reagents general text in the Eur Phar in preparation for 2014-15

• serum/medium

• cytokines / growth factors

• enzymes (such as trypsin)

• antibodies

• individual proteins

• buffers

• plasmids/ viral vectors

Identity Purity Biological Activity / Functionality Specific Activity Total Protein content Impurities, Product-related Impurities, Process-related Viral Safety / TSE compliance Microbial Contamination Stability / Storage conditions

-GUIDELINE the use of bovine serum in the manufacture of human biological medicinal products (EMA/CHMP/BWP/457920/2012 rev.1) UNDER NEW REVISION

- GUIDELINE the use of porcine trypsin used in the manufacture of human biological medicinal products (EMA/CHMP/BWP/814397/2011) DRAFT

ALL MEDICINAL PRODUCTS USING STEM CELLS AS STARTING MATERIAL Adult stem cells - Hematopoietic stem cells (HSC); Mesenchymal/stromal stem cells (MSCs);

Tissue specific stem cells Embryonic stem cells (hESCs) • maintained in in vitro culture conditions as cell lines • pluripotent - can differentiate to every cell type. in vitro differentiation generates cell populations with

heterogeneity of cell surface markers as well as marker genes for pluripotency • transplanted form teratoma (benign tumours) • can be differentiated in vitro using either external factors in the culture medium, or by genetic modification

Induced pluripotent stem cells (iPS) • artificially generated stem cells reprogrammed from somatic adult cells • self-renewing capacity • pluripotent • form teratoma • differentiation capacity seems to be dependent on the cell type and age of the cells from which the iPS cells

were reprogrammed.

GENERAL

identifying potential risks related to pluripotency, differentiation and lineage commitment

Embryonic stem cells and iPS cells should be lineage-committed before administration to patients

Raw materials used in manufacturing require proper qualification (ie clinical grade) according to their use and persistance in the final product – cells / viral vectors / factors / cytokines / antibodies / hormones / conditioned media always viral safety and TSE’s - traceability

iPS if genetically modified = gene + cell therapy guidelines + GL on cell bank ICH Q5D

QUALITY …

Li MD et al Regen. Med. (2014) 9(1), 27–39

• analysis of the impact on EU approvals

• Hospital exemption

• Classification status (EU vs national)

• EU requirements (eg GMP)

• Marketing authorisation procedure

• Certification

• Scientific advice

• Incentives (fee reductions for pre and post MA other than SME’s)

REVISION OF ATMP REGULATION 1394/2007 TO START SOON

THANK YOU FOR YOUR ATTENTION !