Regulatory challenges for combination-ATMP productsGert BosBSI Healthcare

Drug device Combination ProductsInforma, Prague, CZ17 November 2009

This presentation

ATMP defined Regulation and implementation CAT Evaluation procedure Certification State of play today Scientific recommendation Dossier Requirements NoBo involvement

SME

Regulation

• Regulation 1394/2007 Published on Dec 10 2007, applicable from Dec 30 2008

• Definition Advanced Therapy MP• Definition Tissue Engineered product (MP)• Principles of medicines legislation to apply• Mandatory centralised procedure• Gene therapy and somatic cell therapy MP to be brought under annex I of 2001/83

• Committee for Advanced Therapies (CAT)

http://ec.europa.eu/enterprise/pharmaceuticals/advtherapies/index.htm

‘Advanced therapy medicinal product’

• any of the following MPs for human use: a gene therapy MP as defined in 2001/83/EC, a somatic cell therapy MP as defined in 2001/83/EC, a tissue engineered product.

• ‘Tissue engineered product’ means a product that: contains or consists of engineered cells or tissues, and is presented as having properties for, or is used in or

administered to human beings with a view to regenerating, repairing or replacing a human tissue.

Tissue engineered products

• cells or tissues of human or animal origin, or both. • cells or tissues viable or non-viable• additional substances, such as cellular products & bio-molecules, Biomaterials & chemical substances, scaffolds or matrices.

• non-viable human or animal cells and/or tissues in products that do not act principally by pharmacological, immunological or metabolic action, excluded.

‘engineered’ cells & combination-ATMP

Engineered cells:• Cells/tissues subject to substantial manipulation, non-

substantial manipulations listed, and/or• cells or tissues not intended to be used for same

essential function(s) in recipient as in donor.

Combination-ATMP:• MDD or AIMD, and• cellular or tissue part contain viable cells or tissues, or• Non-viable cellular/tissue part acting pharmaceutically

Examples of combination-ATMPs

• Artificial skin embedded in wound care product

• Chondrocytes in cartilage scaffold with cell sorting and seeding device

• bone void fillers with human bone morphogenic proteins

• Wound dressings with human growth hormones

Highlights regulation

• Pre-market: Combination ATMPs: ERs of MDD Specific GMP and GCP guidelines Specific rules for labeling and packaging

• Post-market: Follow-up efficacy and adverse reactions Risk management traceability

Implementing legislation

• Procedure for evaluation and certification• Dossier req. module 3, 4• Site visits• Guide on minimum quality and non-clinical data

Implementing legislation

• Amending 2001/83, annex I, part IV New definitions GTMP and somatic CTMP Risk based approach Updated req. modules 3, 4, 5

3 SANCO directives on tissues and cells

• 2004/23/EC: standards of quality & safety for donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells

• 2006/17/EC: technical requirements for donation, procurement and testing of human tissues and cells

• 2006/86/EC: traceability requirement, notification serious adverse events, requirements for coding, processing, preservation, storage and distribution of human tissues and cells

Committee for Advanced Therapies (CAT)

CK Schneider, PEI

Evaluation procedure

• PRE authorisation: Product compliance to ERs Guidelines to GMP (2003/94/EC) and GCP Rules for packaging and labelling

• POST authorisation: Follow up efficacy and adverse reactions, and risk

management Traceability

CAT

Lucia D’Apota, EMEA

Rapporteur &

Co-rapporteur

+

CHMP co-ordinator

+

ATMP experts

Tasks Committee for Advanced Therapies

• Initial evaluation, re-examination, PMS=> draft opinion to CHMP

• Classification: product = ATMP?=> scientific recommendation from CAT

• Certification=> CAT opinion => EMEA certification

• Scientific advices for ATMP=> CAT involved

• Other=> consultation by CHMP, advice to Commission

ATMP evaluationTwo phase review

MH Pinheiro, EMEA

ATMP evaluation – combination products

• Agency must recognise results of any assessment by a notified body MDD / AIMD

• May request NoBo further information on assessment

• If not included Agency to seek scientific opinion from NoBo CAT may decide no NoBo involvement needed

ATMP evaluation – re-examination

• 15 days and 60 days without clock stop• Same concept, new reviewers• CAT must be consulted by CHMP• CAT to provide draft opinion

• Withdrawals publicly accessible

State of play 2009

• First meetings CAT• CAT looking for interested parties• Discussion CAT/EMEA with NBOG – NBmed• Templates and SOPs• Guideline on traceability• Guideline GMP for ATMPs• Integration work GTWP and CPWP into CAT

Scientific advise

MH Pinheiro, EMEA

Certification quality and non-clinical data

• Only for SMEs• Quality data, or Quality and non-clinical• For scientific evaluation and certification• Evaluated by CAT• 90 days with clock stops• Possibility for site visit• STAND ALONE evaluation procedure• Not directly binding for clinical trial / market approval• Certificate does not replace data for later submission• No benefit/risk, no guarantees

Certification quality and non-clinical data

EMEA

One slide on risk management

J Petracek, EMEA

CAT monthly report

• http://www.emea.europa.eu/pressoffice/presshome.htm

CAT monthly report

Borderlines

• TEP may contain viable and non-viable cells• No viable cells & no principal metabolic action

=> no ATMP• Cell/device not by default engineered: substantial

manipulation to be considered• ATMP with autologous and allogenic cells

=> allegenic use• TEP and sCT => TEP• GT and TEP or sCt, then GT > TEP > sCT• Hospital exemptions under national laws

ATMP containing devices

• Devices as referred to in art. 7 of ATMP Not a med.dev. (scaffolds, biomaterials, matrices) Description physical characteristics, performance Description interaction genes, cells, tissues

• Combined ATMP: Cellular / tissue part as above Info on choice / intended function MDD/AIMD Evidence conformity to Essential Requirements Evidence compliance with BSE/TSE requirements If available: results NoBo assessment

Further NoBo involvement

• Several Notified Bodies volunteer knowledge to CAT

• Discussion EMEA / NB-med / NBOG on cooperation planned in 2 weeks

• NoBo to chair ISO/CD 13022 on standard for Risk-Management of cell-based products

• NoBo participates in RGM/1 in UK, Gert Bos participates as member elect

ISO/TC194/SC1 – Tissue product safety

• CEN TC 316 • Secretariat: DIN• Chair: Sabine Kloth• Work on ISO/CD 13022 standard for Risk-Management

of cell-based products• Input into this from EMEA / CAT

Example: equipment used for the manufacture of ATMPs

RGM/1

• Technical Committee to mirror the work of ISO/TC 150/SC7 "Tissue-engineered medical products"

• Work on standardization to support regulation in regenerative medicine

• Chair: Ben Sheridan – BSi

• NB proposed seat: Gert Bos

Additional items and further reading……..

• 2001/20/EC – clinical trials• 2002/98/EC – blood derivatives• Regulation 1234/2008 – new variations• EMEA/CHMP/96268/2005 – EMEA guideline on risk management

systems for medicinal products for human use• EMEA/149995/2008 – guideline of safety and efficacy follow up – risk

management on ATMPs

• #@! Obtaining re-imbursement !

• www.emea.europa.eu/htms/human/advanced_therapies/intro.htm• ec.europa.eu/enterprise/pharmaceuticals/pharmacos/new_en.htm• www.emea.europa.eu/htms/human/advanced_therapies/interested_parties.htm

32Contact Us

Name: Gert BosTitle: Head of Regulatory and Clinical Affairs

Address: BSIKitemark House, Maylands AvenueHemel Hempstead, HP2 4SQ, UK

Telephone: +44 (0)1442 278664Fax: +44 (0)8450 765601

Email: Gert.Bos@bsigroup.comLinks: www.bsigroup.com/healthcare