INTERNATIONAL INTERNATIONAL REGULATIONSREGULATIONS

FOR TISSUES & CELLSFOR TISSUES & CELLS

Carolina StylianouCarolina StylianouMinistry of HealthMinistry of Health

CyprusCyprus

14th Training Course BLOOD AND MARROW TRANSPLANTATION

Targu Mures, Romania

Fact: Tissue and Cell therapy is a field in which an intensive worldwide exchange takes place.

Need: Safeguard public health

Goal: worldwide standards

Bone Grafts Distributed/Exported by USABone Grafts Distributed/Exported by USA

0

200,000

400,000

600,000

800,000

1,000,000

1,200,000

1,400,000

1994 2000 2007

Tissue grafts/devices are exported to 45 countries

HHaematopoietic Stem Cellsaematopoietic Stem Cells EUROCET EUROCET data for 2008 data for 2008

Import by EU Member StatesImport by EU Member States - 1122 units of HSC - 1122 units of HSC (Belgium, Bulgaria, Denmark, Germany, Estonia, Ireland, (Belgium, Bulgaria, Denmark, Germany, Estonia, Ireland,

Greece, Spain, France, Italy, Lithuania, the Netherlands, Greece, Spain, France, Italy, Lithuania, the Netherlands, Portugal, Romania, Slovenia, and the United Kingdom). Portugal, Romania, Slovenia, and the United Kingdom).

Export by EU Member StatesExport by EU Member States - 269 units of HSC (Belgium, - 269 units of HSC (Belgium, Bulgaria, Czech Republic, Denmark, Germany, Ireland, Bulgaria, Czech Republic, Denmark, Germany, Ireland, Spain, France, Italy, Cyprus, the Netherlands, Portugal, Spain, France, Italy, Cyprus, the Netherlands, Portugal, Romania and the United Kingdom).Romania and the United Kingdom).

EUROCET (European Registry for Organs, Tissues and Cells, EUROCET (European Registry for Organs, Tissues and Cells,

http://http://www.eurocet.orgwww.eurocet.org//

In many cases data concerning volumes of exports is not In many cases data concerning volumes of exports is not available.available.

To Safeguard Public HealthTo Safeguard Public Health

Common quality standardsCommon quality standards Common glossaries.Common glossaries.

(Harmonisation and comparable (Harmonisation and comparable datadatato disseminate reliable information)to disseminate reliable information)

International RegulationsInternational Regulations

Tissues? Cells?Tissues? Cells?

Bone marrowBone marrow Peripheral Blood Stem cellsPeripheral Blood Stem cells Cord bloodCord blood SkeletalSkeletal SkinSkin VascularVascular OcularOcular Amniotic membraneAmniotic membrane Reproductive cellsReproductive cells

EU directives on Tissues and EU directives on Tissues and CellsCells

2004/23 2004/23 of the European Parliament and of the of the European Parliament and of the Council on setting standards of quality and safety for Council on setting standards of quality and safety for the donation, procurement, testing, processing, the donation, procurement, testing, processing, preservation, storage and distribution of human preservation, storage and distribution of human tissues and cellstissues and cells

2006/172006/17 implementing Directive 2004/23/EC of the implementing Directive 2004/23/EC of the European Parliament and of the Council as regards European Parliament and of the Council as regards certain technical requirements for the donation, certain technical requirements for the donation, procurement and testing of human tissues and cellsprocurement and testing of human tissues and cells

2006/862006/86 implementing Directive 2004/23/EC of the implementing Directive 2004/23/EC of the European Parliament and of the Council as regards European Parliament and of the Council as regards traceability requirements, notification of serious traceability requirements, notification of serious adverse reactions and events and certain technical adverse reactions and events and certain technical requirements for the coding, processing, requirements for the coding, processing, preservation, storage and distribution of preservation, storage and distribution of human human tissues and cellstissues and cells

Stem cells ?Stem cells ?

AdultAdult EmbryonicEmbryonic AllogeneicAllogeneic AutologousAutologous HaematopoieticHaematopoietic SomaticSomatic

Same provisions in regulations

Apply toApply to ProcurementProcurement TestingTesting ProcessingProcessing StorageStorage DistributionDistribution Export/Import Export/Import Clinical use of Clinical use of

tissues & cellstissues & cells

Do not apply toDo not apply to In vitro researchIn vitro research Tissues & cells used Tissues & cells used

as autologous graft as autologous graft within the same within the same surgical proceduresurgical procedure

Hospital exemption Hospital exemption productsproducts

Blood and blood Blood and blood products products (2002/98/EC)(2002/98/EC)

Organs or parts of Organs or parts of organs organs

•AdvancedAdvanced therapy medicinal productstherapy medicinal products

Directive 2004/23 EUDirective 2004/23 EU

• Applies to tissues and cells including Applies to tissues and cells including haematopoietic peripheral blood, haematopoietic peripheral blood, umbilical –cord blood and bone marrow umbilical –cord blood and bone marrow stem cells. stem cells.

• Lays down the standards of quality and Lays down the standards of quality and safety for human tissues and cells safety for human tissues and cells intended for human applications, in intended for human applications, in order to ensure a high level of protection order to ensure a high level of protection of human health.of human health.

The Competent Authorities The Competent Authorities ResponsibilitiesResponsibilities

Supervision of tissue and cell procurement Supervision of tissue and cell procurement and testingand testing

Accreditation, designation, authorisation/Accreditation, designation, authorisation/ licensing of tissue establishmentslicensing of tissue establishments Inspections and control measures to Inspections and control measures to

ensure complianceensure compliance Vigilance and Surveillance of activitiesVigilance and Surveillance of activities Report to the EU Commission on activities Report to the EU Commission on activities

undertaken in relation to the provisions of undertaken in relation to the provisions of the Directivesthe Directives

Report to the EU Commission on Report to the EU Commission on SAEs/SARs and SAEs/SARs and notify other competent notify other competent authorities for tissues/cells that are authorities for tissues/cells that are distributed distributed

Tissue establishment Tissue establishment ResponsibilitiesResponsibilities

Voluntary unpaid donation (donors Voluntary unpaid donation (donors may receive compensation strictly may receive compensation strictly limited to expenses and limited to expenses and inconveniences)inconveniences)

ConsentConsent No unauthorised disclosure of donor No unauthorised disclosure of donor

or patient personal data or patient personal data Donor evaluation and selection is Donor evaluation and selection is

carried out under specified carried out under specified conditionsconditions

But also…But also… Quality system based on the principles of Quality system based on the principles of

good practicegood practice1. Standard operating procedures2. Guidelines3. Training and reference manuals4. Reporting forms5. Donor records6. Information on the final destination of

tissues and cells7. Ensure traceability from donor to recipient8. Validation of processes9. Processing of tissues/cells while exposed to

environment must be in grade A air quality with a background air of at least quality D

As well as…As well as…

Designated responsible personDesignated responsible person Appropriately trained personnelAppropriately trained personnel Written agreements with third parties in Written agreements with third parties in

order to ensure that the quality of order to ensure that the quality of tissues/cells is not compromisedtissues/cells is not compromised

Ensure the quality of tissues/cells during Ensure the quality of tissues/cells during distributiondistribution

Report and/or investigate serious adverse Report and/or investigate serious adverse events to the competent authorityevents to the competent authority

Criteria for SARs reporting to Criteria for SARs reporting to the Competent authoritiesthe Competent authorities

Any unintended response, including a communicable disease, in the donor or recipient associated with the procurement or human application of tissues and cells that is fatal, life threatening, disabling, incapacitating or which results in, or prolongs, hospitalisation or morbidity.

(infection, hypersensitivity, malignancy, toxicity, mismatch, genetic abnormality or other transmission)

Criteria for SAEs reporting to Criteria for SAEs reporting to Competent AuthoritiesCompetent Authorities

Deviations should not be reported as SAEs to CAs Deviations should not be reported as SAEs to CAs unless:unless:

Inappropriate tissues or cells have been released Inappropriate tissues or cells have been released for clinical use, even if not usedfor clinical use, even if not used

The event could have implications for other The event could have implications for other patients or donors because of shared practices, patients or donors because of shared practices, services, supplies or donorsservices, supplies or donors

The event resulted in the loss of any irreplaceable The event resulted in the loss of any irreplaceable autologous tissues or cells or any highly matched autologous tissues or cells or any highly matched (i.e. recipient specific) allogeneic tissues or cells(i.e. recipient specific) allogeneic tissues or cells

The event resulted in the loss of a significant The event resulted in the loss of a significant quantity of unmatched allogeneic tissues or cells.quantity of unmatched allogeneic tissues or cells.

MovementMovement of tissues and cellsof tissues and cells Transport Transport between tissue establishments between tissue establishments

DistributionDistribution between a tissue establishment and a site of between a tissue establishment and a site of human applicationhuman application

Import/ExportImport/Export EU Member State and a Third country. The CA EU Member State and a Third country. The CA can introduce prohibition of or restriction on the importation can introduce prohibition of or restriction on the importation of human tissues and cells to ensure a high level of health of human tissues and cells to ensure a high level of health protection. protection.

Tissue establishments that receive such imports/send such Tissue establishments that receive such imports/send such exports shall ensure that these meet standards of quality and exports shall ensure that these meet standards of quality and safety equivalent to the ones described in this Directive.safety equivalent to the ones described in this Directive. MMovement of tissues and cells between countries within ovement of tissues and cells between countries within European Economic Area actually falls within the definition of European Economic Area actually falls within the definition of transport and distribution and not import and export. If a transport and distribution and not import and export. If a tissue establishment imports tissues and cells and supplies tissue establishment imports tissues and cells and supplies other tissue establishments, the responsibility resides with other tissue establishments, the responsibility resides with this first establishment as the original place of entry.this first establishment as the original place of entry.

Competent Authority

Competent Authority

Tissue Establishment Tissue Establishment

Distribution

QUICK ALERTSAE/SAR

Report

Investigation

Inform

Investigation

COMMISSION

CIRCA

Dissemination of data between TEs and CAs after a SAE/SAR

Advanced Therapy Medicinal Products Advanced Therapy Medicinal Products for human usefor human use

Gene therapy medicinal productGene therapy medicinal product Somatic cell therapy medicinal product Somatic cell therapy medicinal product Tissue engineered medicinal productTissue engineered medicinal product

Cells or tissues have been subjected to substantial Cells or tissues have been subjected to substantial manipulation, so that biological characteristics, physiological manipulation, so that biological characteristics, physiological functions or structural properties relevant for the intended functions or structural properties relevant for the intended regeneration, repair or placement are achieved.regeneration, repair or placement are achieved.

AND/ORAND/OR Cells or tissues that are not intended to be used for the same Cells or tissues that are not intended to be used for the same

essential function /functions in the recipient as in the donor.essential function /functions in the recipient as in the donor.

Substantial manipulation is Substantial manipulation is notnot considered cutting, grinding, considered cutting, grinding, shaping, centrifugation, soaking in antibiotic or antimicrobial shaping, centrifugation, soaking in antibiotic or antimicrobial solutions, sterilisation, irradiation, cell separation, filtering, solutions, sterilisation, irradiation, cell separation, filtering, lyophilisation, freezing, cryopreservation, vitrification.lyophilisation, freezing, cryopreservation, vitrification.

EU Regulation and Directive on EU Regulation and Directive on Advanced Therapy Medicinal productsAdvanced Therapy Medicinal products

Regulation No 1394/2007 of the of European Parliament and of the Council on advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004

(Where an advanced therapy medicinal product contains human cells or tissues, the donation, procurement and testing of those cells or tissues shall be made in accordance with Directive 2004/23/EC)

2009/120 amending Directive 2001/83/EC of the European Parliament and of the Council on the Community code relating to medicinal products for human use as regards advanced therapy medicinal products

(The traceability system shall be complementary to, and compatible with, the requirements established in Directive 2004/23/EC of the European Parliament and of the Council , as regards human cells and tissues other than blood cells, and Directive 2002/98/EC, as regards human blood cells)

Committee for Advanced TherapiesCommittee for Advanced Therapies

The Committee for Advanced Therapies (CAT) was The Committee for Advanced Therapies (CAT) was established in accordance with Regulation (EC) No established in accordance with Regulation (EC) No 1394/2007 for ATMPs. It is a multidisciplinary 1394/2007 for ATMPs. It is a multidisciplinary committee, gathering together some of the best committee, gathering together some of the best available experts in Europe to assess the quality, available experts in Europe to assess the quality, safety and efficacy of ATMPs, and to follow scientific safety and efficacy of ATMPs, and to follow scientific developments in the field.developments in the field.

The main responsibility of the CAT is to prepare a The main responsibility of the CAT is to prepare a draft opinion on each ATMP application submitted to draft opinion on each ATMP application submitted to the European Medicines Agency, before the the European Medicines Agency, before the Committee for Medicinal Products for Human Use Committee for Medicinal Products for Human Use (CHMP) adopts a final opinion on the granting, (CHMP) adopts a final opinion on the granting, variation, suspension or revocation of a marketing variation, suspension or revocation of a marketing authorisation for the medicine concerned. At the authorisation for the medicine concerned. At the request of the Agency's Executive Director or of the request of the Agency's Executive Director or of the European Commission, an opinion is also drawn up European Commission, an opinion is also drawn up on any scientific matter relating to ATMPs.on any scientific matter relating to ATMPs.

Hospital Exemption Hospital Exemption ProductsProducts

This is a custom-made cell-containing This is a custom-made cell-containing product that is prepared on a non-routine product that is prepared on a non-routine basis according to specific quality standards. basis according to specific quality standards. It is made available to an individual patient It is made available to an individual patient in a European hospital under the exclusive in a European hospital under the exclusive responsibility of a doctor. responsibility of a doctor.

It is authorised for use by the regulatory It is authorised for use by the regulatory authority of the Member State where the authority of the Member State where the product is made.product is made.

In the USA…..In the USA…..

The Centre for Biologics Evaluation and Research The Centre for Biologics Evaluation and Research ((CBERCBER) at the FDA, regulates HCT/Ps under 21 ) at the FDA, regulates HCT/Ps under 21 CFR, parts 1270 and 1271. CFR, parts 1270 and 1271.

The FDA’s revised regulations are contained in The FDA’s revised regulations are contained in Part 1271 and apply to tissues recovered after Part 1271 and apply to tissues recovered after 2005, which are the current tissue rules. 2005, which are the current tissue rules. Examples of tissues regulated are Examples of tissues regulated are musculoskeletal tissue, skin, corneas, heart musculoskeletal tissue, skin, corneas, heart valves, valves, haematopoietic stem cellshaematopoietic stem cells and and reproductive cells.reproductive cells.

The 3 FDA rules……The 3 FDA rules…… Registration and listing - Requires tissue establishments to

register and list their HCT/Ps with the FDA. This includes the types and uses of the products that will be regulated by these rules. Also, all foreign establishments importing HCT/Ps into the US must register and list such HCT/Ps.

The donor eligibility rule - Requires HCT/P establishments to screen and test tissue and cell donors for relevant communicable disease agents or diseases.

Current good tissue practices - The requirements that govern the methods used in, and the facilities and controls used for, the manufacture of HCT/Ps, including all steps in recovery, donor screening and testing, processing, labelling, packaging and distribution. Also included are the requirements for process validation, labelling, tracking, complaint files and adverse reaction reporting. In general CGTP ensures that HCT/Ps do not contain communicable disease agents, are not contaminated and that they do not become contaminated during manufacturing.

In Australia…….In Australia……. Therapeutic Goods Act 1989 - therapeutic goods

which are imported into Australia, supplied for use in Australia or exported from Australia, conform with a standard applicable to the goods. The Act includes non-cord blood HPCs.

Therapeutic Goods Order 75 - Haematopoietic progenitor cells derived from cord blood must meet the requirements of the document entitled "International Standards for Cord Blood Collection, Processing, Testing, Banking, Selection, and Release" Third edition, dated December 2006, published by the Foundation for the Accreditation of Cellular Therapy and NetCord.

The future…..The future…..

Implementation of European/Global Surveillance and Implementation of European/Global Surveillance and Vigilance systemVigilance system

Role of Regulators, engagement of Clinicians, role of Professional Societies, clarity in reporting requirements, openness, transparency and non-punitive culture, effective communication, patient focus, system standardisation, education of stakeholders

Implementation of a European Coding System

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