Scope of this note

This note provides an analysis of the current EU regulatory framework that applies to the use of human stem cells, including for the development and manufacture of medicinal products containing or consisting of human stem cells.

The note discusses, in particular, the Advanced Therapy Medicinal Product Regulation (1394/2007) (ATMP Regulation) and the application of the Clinical Trials Regulation (536/2014). The relevant guidelines on clinical trials concerning medicinal products containing or consisting of stem cells are also considered. The provisions of the Tissue and Cells Directive (2004/23/EC) will be also discussed.

This note focuses on EU-level provisions that apply to stem cell use. Specific legislative provisions of each EU member state concerning stem cell use and research will not be discussed.

This note does not apply to the position in the UK from 1 January 2021.

What are stem cells?

Human stem cells are undifferentiated cells that have the ability to divide and produce new undifferentiated stem cells (self-renewal capacity, that is, ability to replicate themselves in an undifferentiated form), or differentiate into cells with specialised functions such as blood cells, skin cells, liver cells and bone cells (potency or differentiation capacity). All specialised cell types are generated from stem cells. Stem cells are the only cells in the human body that can generate new cell types (see also Sections 1.1 and 1.2 of EMA: Reflection paper on stem cell-based medicinal products (EMA/CAT/571134/2009)).

There are two main types of stem cells:

• Embryonic stem cells (ESCs): these are stem cells derived from the inner cell mass of preimplantation embryos (blastocysts) that are three to five days old. These stem cells are "pluripotent": pluripotent stem cells (PSCs), meaning that they can divide into unaltered daughter stem cells that maintain the same properties of the progenitor cells, or differentiate into virtually all specialised cell types of the human body.

• Adult stem cells or somatic stem cells: these are cells found in small numbers in most adult tissues of the human body, such as the bone marrow, epidermis of the skin and the lining of the small intestine. Adult stem cells serve to replace cells that are lost through normal wear and tear, injury, or disease of human tissues. When compared with embryonic stem cells, they have a lower potency, that is, they are able to differentiate into a more limited range of specialised cell types. Subtypes of adult stem cells include:

  • hematopoietic stem cells (HSCs): contained in the red bone marrow, they generate all red and white blood cells and platelets and are also found in lower numbers in peripheral blood. Hematopoietic stem cells are also present in the placental and umbilical cord blood at birth (in concentrations similar to levels found in the adult bone marrow); and

  • mesenchymal/stromal stem cells (MSCs): they are mostly derived from bone marrow stroma or adipose tissue (although they have been isolated from other tissues, for example, liver, gastric epithelium, placenta, umbilical cord and blood).

In addition to these two categories, there is an additional type of PSCs: induced pluripotent stem cells (iPSCs). These are reprogrammed adult/somatic stem cells (that is, artificially generated stem cells), obtained by inducing dedifferentiation of adult/somatic stem cells through in vitro cell reprogramming. Specific genes that induce pluripotency are introduced into the nuclei of adult/somatic stem cells, giving them embryonic stem-cell-like properties. Induced pluripotent stem cells can also be stimulated to differentiate into specialised types of cells.

Possible uses of stem cells

Given the unique regenerative properties of stem cells, they offer great promise for biomedical research and for therapeutic applications in various diseases. Stem cells are a useful tool for researchers to study the cellular changes associated with disease occurrence and progression (that is, to better understand how diseases arise and develop), as well as the body's mechanisms to regenerate and create new tissue. In the process of drug development, stem cells can also be used to test medicinal products under development before they are used in humans (pharmacology studies and toxicology testing). See also section 1.10 of European Commission, European Group on Ethics in Science and New Technologies, Adoption of an opinion on ethical aspects of human stem cell research and use, Publications Office, 2006.

Stems cells have also been used for transplantation. Bone marrow transplants, for example, are a type of stem cell therapy that is in common use in patients with cancer and certain blood-related diseases, such as leukaemia, lymphoma, neuroblastoma and multiple myeloma (see Tissue and Cells Directive for the details of the regulation of stem cells transplants).

Stem cells can also be used as starting material for medicinal products (the final medicinal products may consist of terminally differentiated cells derived from stem cells, undifferentiated stem cells or a combination of stem cells with differentiated profiles; see EMA: Reflection paper on stem cell-based medicinal products (EMA/CAT/571134/2009)). When stem cells undergo substantial manipulation or when they are used for a different essential function in the recipient and donor, the resulting products are no longer seen as traditional stem cells transplants, but rather as medicinal products classified as advanced therapy medicinal products (ATMPs), a type of biological medicinal product (Section 3.2.1.1(b), Module 3, Part I, Annex I, Directive 2001/83/EC on the Community code relating to medicinal products for human use).

There is some ongoing concern about individuals, companies and hospitals promoting the use of unproven or unregulated cell-based therapies (not limited to stem cell-based therapies). In response, the EMA has issued a warning on 28 April 2020 highlighting the potential serious risks of such therapies to patients for little or no clinical benefit (see EMA warns against using unproven cell-based therapies (EMA/CAT/94295/2020)).

Advanced therapy medicinal products

Stem cells can be used to produce stem-cell based ATMPs. There are three types of ATMPs:

• Gene therapy medicinal products (as defined in Part IV of Annex I to Directive 2001/83/EC).

• Somatic cell therapy medicinal products (as defined in Part IV of Annex I to Directive 2001/83/EC).

• Tissue engineered products (as defined in Article 2.1(b) of the ATMP Regulation).

(Article 2.1(a), ATMP Regulation.)

A brief description of each type of ATMP is provided below. Depending on their specific characteristics, stem-cell based ATMPs can be classified as somatic cell therapy medicinal products or tissue engineered products.

A. First stem-cell based ATMP authorised in EU

In December 2014, the European Medicines Agency (EMA) adopted its first positive opinion for a marketing authorisation in relation to an ATMP containing stem cells (see EMA: First stem-cell therapy recommended for approval in EU, 19 December 2014). This ATMP is Holocar, a tissue engineered product used in the eye to replace damaged cells on the surface (epithelium) of the cornea. Its active substance are ex-vivo expanded autologous human corneal epithelial cells containing stem cells (see EMA: Holoclar, ex vivo expanded autologous human corneal epithelial cells containing stem cells, 2 March 2015).

B. Gene therapy medicinal products

A gene therapy medicinal product is a biological medicinal product which fulfils the following two characteristics:

• Contains an active substance which contains or consists of a recombinant nucleic acid used in or administered to human beings with a view to regulating, repairing, replacing, adding or deleting a genetic sequence.

• Its therapeutic, prophylactic or diagnostic effect relates directly to the recombinant nucleic acid sequence it contains, or to the product of genetic expression of this sequence.

(Section 2.1, Part IV, Annex I, Directive 2001/83/EC.)

Gene therapy medicinal products generally consist of a vector or delivery formulation/system that contains a genetic construct engineered to express a specific transgene for the regulation, repair, replacement, addition or deletion of a genetic sequence. The active substance is the nucleic acid sequence(s), or genetically modified microorganism(s), virus(es) or cells (or a combination of multiple elements). By using such gene therapy constructs, in vivo genetic regulation or genetic modification of somatic cells can be achieved (see Section 1 of EMA: Guideline on the quality, non-clinical and clinical aspects of gene therapy medicinal products (EMA/CAT/80183/2014)).

A product which may fall within the definition of somatic cell therapy medicinal product or tissue engineered product, and gene therapy medicinal product, shall be considered as a gene therapy medicinal product (Article 2.5, ATMP Regulation).

C. Somatic cell therapy medicinal products

A somatic cell therapy medicinal product is a biological medicinal product which has the following two characteristics:

• Contains or consists of cells or tissues that have been subject to substantial manipulation so that biological characteristics, physiological functions or structural properties relevant for the intended clinical use have been altered, or cells or tissues that are not intended to be used for the same essential functions in the recipient and the donor.

• It is presented as having properties for, or is used in or administered to human beings with a view to treating, preventing or diagnosing a disease through the pharmacological, immunological or metabolic action of its cells or tissues.

(Section 2.1, Part IV, Annex I, Directive 2001/83/EC.)

For the qualification as somatic cell therapy medicinal product, the following manipulations are not in particular considered as substantial manipulations: cutting, grinding, shaping, centrifugation, soaking in antibiotic or antimicrobial solutions, sterilisation, irradiation, cell separation, concentration or purification, filtering, lyophilisation, freezing, cryopreservation and vitrification (see Annex I, ATMP Regulation).

Substantial manipulations can include cell expansion (culture, ex-vivo), differentiation and/or activation with growth factors and ex-vivo modification of cells (viral vector transduction, genome editing).

D. Tissue engineered product

Article 2.1(b) of the ATMP Regulation defines a tissue engineered product as a product that fulfils the two following conditions:

• Contains or consists of engineered cells or tissues. Cells or tissues shall be considered "engineered" if they fulfil at least one of the following conditions:
  • they have been subject to substantial manipulation, other than the manipulations listed in Annex I to the ATMP Regulation, so that biological characteristics, physiological functions or structural properties relevant for the intended regeneration, repair or replacement are achieved; or
  • they are not intended to be used for the same essential function or functions in the recipient as in the donor.

(Article 2.1(c), ATMP Regulation.)

• 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.

A tissue engineered product may contain cells or tissues of human origin, of animal origin, or of both. The cells or tissues may be viable or non-viable. Products containing or consisting exclusively of non-viable human or animal cells and/or tissues, which do not contain any viable cells or tissues and which do not act principally by pharmacological, immunological or metabolic action, are excluded from the definition of tissue engineered products. The product may also contain additional substances, such as cellular products, bio-molecules, bio-materials, chemical substances, scaffolds or matrices.

A product which may fall within the definition of a tissue engineered product and within the definition of a somatic cell therapy medicinal product shall be considered as a tissue engineered product (Article 2.4, ATMP Regulation).

E. Specific rules provided by ATMP Regulation

The ATMP Regulation provides specific rules concerning the marketing authorisation, supervision and pharmacovigilance of ATMPs. All ATMPs, including stem-cell based ATMPs, must be authorised by the European Commission via the centralised marketing authorisation procedure (see Practice note, EU marketing authorisation procedures: Advanced therapy medicinal products) with prior scientific assessment by the EMA. The centralised authorisation procedure is mandatory, meaning that this type of medicinal product cannot be authorised at a national level (see Article 3.1 and Annex I, Section 1a, Regulation 726/2004).

There is a special committee established within the EMA, the Committee for Advanced Therapies (CAT), that is responsible for, among other tasks, preparing a draft opinion on the quality, safety, and efficacy of ATMPs as part of the scientific assessment of the medicinal product. This draft opinion is then submitted for final approval to the Committee for Medicinal Products for Human Use (CHMP). The CHMP will make a recommendation to the European Commission on whether or not the product should be granted a marketing authorisation and, if so, under which conditions of use. The European Commission then takes a decision on whether or not to grant the ATMP a marketing authorisation, taking into consideration the CHMP's recommendation (the European Commission is the authorising body for all centrally authorised products). A marketing authorisation which has been granted in accordance with the centralised procedure is valid throughout the EU.

Certain quality aspects (starting materials, manufacturing process, characterisation and quality control and so on), non-clinical aspects (animal models, tumorigenicity, differentiation in vivo and so on) and clinical considerations (pharmacodynamics, dose finding studies, clinical safety and efficacy and so on) were addressed in a reflection paper on stem cell-based medicinal products published by EMA on February 2011 (Reflection Paper) (see EMA: Reflection paper on stem cell-based medicinal products (14 January 2011) (EMA/CAT/571134/2009)). This Reflection Paper should be read in conjunction with the CHMP's guideline on human cell-based medicinal products, which addresses general aspects of the development, manufacturing, quality control, clinical and non-clinical development of cell-based medicinal products (see EMA: Guideline on human cell-based medicinal products (21 May 2008) (EMEA/CHMP/410869/2006)). The European Commission has also adopted guidelines on good manufacturing practice (GMP) specific to ATMPs (see European Commission: Guidelines on Good Manufacturing Practice specific to Advanced Therapy Medicinal Products).

E(i). Combined ATMPs

Combined ATMPs are ATMPs that fulfil the following conditions:

• Incorporate, as an integral part of the product, one or more medical devices or active implantable medical devices (as defined in the medical device legislation).

• Their cellular or tissue part contains viable cells or tissues or their cellular or tissue part containing non-viable cells or tissues is liable to act on the human body with action that can be considered as primary to that of the devices referred to.

(Article 2.1(d), ATMP Regulation.)

• The regulatory framework applicable to combination products (meaning medicinal products, including ATMPs, that are placed on the EU market together with medical devices in different combination types) varies (see Practice note, Borderline considerations: medicinal products, medical devices, cosmetics and software: Combined advanced therapy medicinal products).

• The entire product can either be regulated under the pharmaceutical or the medical devices legislation, depending on which component (the medicinal product or the medical device) has the principal function (that is, depending on the product's principal mode of action). A product is regulated either by the medical device legislation or by the pharmaceutical legislation, but not both (the procedures of both regulatory regimes do not apply cumulatively, even if there are some cross-references between both legislations).

• Where an ATMP contains viable cells or tissues, the pharmacological, immunological or metabolic action of those cells or tissues shall be considered as the principal mode of action of the product (that is, irrespective of the role of the medical device component, these ATMPs are always regulated and authorised under the ATMP Regulation as combined ATMPs). For ATMPs containing non-viable cells or tissues, the analysis of which component has the principal function shall be conducted. This is also referred to in recital 4 to the ATMP Regulation, which states:

"According to Directive 2001/83/EC and the Medical Device Directives, the basis for determining which regulatory regime is applicable to combinations of medicinal products and medical devices is the principal mode of action of the combination product. However, the complexity of combined advanced therapy medicinal products containing viable cells or tissues requires a specific approach. For these products, whatever the role of the medical device, the pharmacological, immunological or metabolic action of these cells or tissues should be considered to be the principal mode of action of the combination product. Such combination products should always be regulated under this Regulation [the ATMP Regulation]." (Emphasis added.)

ATMPs containing stem cells and incorporating one or more medical device(s) fall within the definition of combined ATMPs, provided that they meet the above mentioned requirements. The EMA's CAT provides scientific recommendations on the classification of ATMPs and has in the past classified some products containing stem cells and a device component as combined ATMPs. As examples:

• Adipose-derived stem cells seeded into a non-absorbable polypropylene tubular scaffold mimicking the extracellular environment of the urinary tract, for urinary diversion in patients requiring radical cystectomy for the treatment of bladder cancer.

• Allogenic adipose-derived stem cells (ADSC) differentiated in vitro towards the cardiovascular lineage and combined with carrier and implanting device.

• Autologous adipose-derived stem cells obtained from a stromal vascular fraction seeded on a collagen matrix scaffold.

(For other cases, see EMA: Summaries of scientific recommendations on classification of advanced therapy medicinal products.)

Combined ATMPs are qualified as medicinal products as a whole and are authorised under the pharmaceutical legislation (that is, they are subject to scientific evaluation by EMA and authorisation by the European Commission). However, the application for a marketing authorisation for a combined ATMP must include, for the medical device part, evidence of conformity with the general safety and performance requirements of Annex I to the Medical Device Regulation (MDR) or, for legacy devices, with the Essential Requirements of Annex I to Directive 93/42/EEC or Directive 90/385/EEC (see Articles 6 and 9, ATMP Regulation).

The application for a marketing authorisation for a combined ATMP must include, where available, the results of the assessment by a notified body (CE Certificate of Conformity) of the medical device part or active implantable medical device part under the MDR (or under the previous Directive 93/42/EEC or Directive 90/385/EEC, for legacy devices). If the application does not include the results of the assessment, the EMA will seek an opinion on the conformity of the device part with said requirements from a notified body identified in conjunction with the applicant (unless CAT decides that involvement of a notified body is not required; see EMA: Procedural advice on the evaluation of combined advanced therapy medicinal products and the consultation of Notified Bodies in accordance with Article 9 of Regulation (EC) No. 1394/2007 (EMA/354785/2010)).

In addition, the application must include a description of the physical characteristics and performance of the product and a description of the product design methods, in accordance with Annex I to Directive 2001/83/EC (Article 7, ATMP Regulation).

Clinical trials with stem-cells based ATMPs

At the EU level, there is no specific legislation governing the conduct of clinical trials with stem-cells based ATMPs. The general requirements laid down in the Clinical Trials Regulation and other provisions adopted at a national level by the EU member states are therefore applicable when conducting clinical trials with stem cells-based ATMPs. Nevertheless, specific guidance documents concerning clinical trials with stem cells-based ATMPs have been adopted.

F. General provisions governing clinical trials

The Clinical Trials Regulation applies to all clinical studies conducted in the EU with medicinal products (under the new Clinical Trials Regulation, clinical trials are a type of the wider category of clinical studies). It does not apply to non-interventional studies (also known as observational trials). Clinical studies are defined as any investigation in relation to humans, with the objective of ascertaining the safety and/or efficacy of medicinal products, and intended:

• To discover or verify the clinical, pharmacological or other pharmacodynamic effects of one or more medicinal products.

• To identify any adverse reactions to one or more medicinal products.

• To study the absorption, distribution, metabolism and excretion of one or more medicinal products.

(Article 2.2(1), Clinical Trials Regulation.)

The Clinical Trials Regulation provides, among others, requirements concerning the authorisation and conduct of clinical trials, safety reporting, and manufacturing, import and labelling of investigational medicinal products. The Clinical Trials Regulation entered into application on 31 January 2022. There was a transition period until 30 January 2023, during which clinical trial sponsors could choose whether to apply to start a clinical trial via the Clinical Trials Information System (CTIS) or under the previous Clinical Trials Directive. From 31 January 2023, all initial clinical trial applications must be submitted via CTIS.

Under the Clinical Trials Regulation, sponsors can apply for authorisations in up to 30 EU/EEA member states at the same time (one single online application) and with the same documentation (there is no more need to submit clinical trial applications separately to national competent authorities and ethics committees in each country, as was the case under the Clinical Trials Directive). The evaluation, authorisation and supervision of clinical trials continue to be responsibilities of each EU or EEA member state.

Under the Clinical Trials Regulation, investigational medicinal products that are ATMPs are defined as "Advanced therapy investigational medicinal products" (Article 2.2(7)). Except for an extension to the assessment periods of clinical trial applications for clinical trials involving investigational ATMPs, the Clinical Trials Regulation does not include specific provisions concerning clinical trials on ATMPs. Consequently, as a general rule, clinical trials with investigational stem-cells based ATMPs will be subject to the same requirements applicable to clinical trials concerning other categories of medicinal products.

Article 90 of the Clinical Trials Regulation provides that the Regulation shall not affect the application of national laws concerning the restriction or prohibition of the use of specific types of human or animal cells, or the sale, supply and use of medicinal products that contain or consist of or derived from such cells.

G. Guidelines governing clinical trials of stem cells-based ATMPs

Although there are no specific EU level provisions governing the conduct of clinical trials with stem cells-based ATMPs, some relevant guidance documents have been published by the EMA. These guidelines must be taken into account when designing clinical trials concerning ATMPs containing or consisting of stem cells.

Relevant guidance documents adopted by EMA include:

• Guidelines on Good Manufacturing Practice specific to Advanced Therapy Medicinal Products (C(2017) 7694 final) (22 November 2017), which include some considerations relating to investigational ATMPs.

• Guidelines on Good Clinical Practice specific to Advanced Therapy Medicinal Products (C(2019) 7140 final) (10 October 2019).

• Reflection paper on stem cell-based medicinal products (EMA/CAT/571134/2009) (14 January 2011).

• Guideline on human cell-based medicinal products (21 May 2008) (EMEA/CHMP/410869/2006), which includes a set of recommendations from the EMA concerning pre-clinical and clinical testing on stem cell-based medicinal products.

• Guideline on the quality, preclinical and clinical aspects of medicinal products containing genetically modified cells (17 December 2020) (EMA/CAT/GTWP/671639/2008 Rev 1 Corr), which should be followed in case of medicinal products containing genetically modified cells.

• Guideline on safety and efficacy follow-up and risk management of advanced therapy medicinal products (20 November 2008) (EMEA/149995/2008).

• Guideline on strategies to identify and mitigate risks for first-in-human and early clinical trials with investigational medicinal products (20 July 2017) (EMEA/CHMP/SWP/28367/07 Rev 1).

• Guideline on the risk-based approach according to annex I, part IV of Directive 2001/83/EC applied to Advanced therapy medicinal products (11 February 2013) (EMA/CAT/CPWP/686637/2011).

• (See also EMA: Guidelines relevant for advanced therapy medicinal products.)

• Stem-cells based investigational ATMPs should also comply with the quality and safety standards provided in the Tissue and Cells Directive (recital 11 to the Directive specifies that "Those cells and tissues that in clinical trials are applied to the human body should comply with the quality and safety standards laid down in this Directive"). See Tissues and Cells Directive for further details.

Tissue and Cells Directive

The Tissue and Cells Directive governs the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells intended for human applications and of manufactured products derived from human tissues and cells intended for human applications.

"Cells" are defined in this Directive as "individual human cells or a collection of human cells when not bound by any form of connective tissue" and "tissue" as "all constituent parts of the human body formed by cells" (Article 3(a) and (b)). This covers both embryonic stem cells and adult/somatic stem cells. Recital 7 to the Tissue and Cells Directive states:

"This Directive should apply to tissues and cells including haematopoietic peripheral blood, umbilical-cord (blood) and bone-marrow stem cells, reproductive cells (eggs, sperm), foetal tissues and cells and adult and embryonic stem cells."

The donation, procurement, testing, processing, preservation, storage and distribution in the EU of stem cells intended for human applications (and of manufactured products thereof) is therefore subject to the rules provided in the Tissue and Cells Directive and to those of the implementing national legislation of each individual EU member states in which these activities are undertaken. Moreover, the Tissue and Cells Directive is also applicable to the donation, procurement and testing of human cells or tissues contained in ATMPs (Article 3, ATMP Regulation).

The Tissue and Cells Directive is without prejudice of specific national legislation of EU member concerning the use or non-use of any specific type of human cells, including germ cells and embryonic stem cells.

Research using stem cells (for example, in vitro research or animal models) is not covered by the scope of the Tissue and Cells Directive, as this Directive does not cover purposes other than application to the human body.

Some of the main requirements provided in the Tissue and Cells Directive include:

• The authorisation of tissue establishments and cell preparation processes.

• Requirements relating to traceability and import and export.

• The obligation to notify serious adverse events and reactions.

• Certain quality and safety requirements of tissues and cells

H. Authorisation of tissue establishments and cell preparation processes

Article 6 of the Tissue and Cells Directive requires that establishments undertaking activities of testing, processing, preservation, storage or distribution of human tissues and cells intended for human applications ("tissue establishments"; see the definition in Article 3(o) of the Directive) are accredited, designated, authorised or licensed by a competent authority of an EU member state for the purpose of those activities.

For this purpose, human tissue establishments must comply with several requirements concerning:

• Organisation and management.

• Personnel.

• Equipment and materials.

• Facilities and premises.

• Documentation and records.

• Quality review.

These requirements are detailed in Annex I to Commission Directive 2006/86/EC implementing Directive 2004/23/EC as regards traceability requirements, notification of serious adverse reactions and events and certain technical requirements for the coding, processing, preservation, storage and distribution of human tissues and cells, an implementing directive of the Tissue and Cells Directive (see Implementing Directives).

Article 6 of the Tissue and Cells Directive requires that written approval from the competent authority of the relevant EU member state is obtained before any substantial changes being made to the activities of the tissue establishment. The competent authority may suspend or revoke the accreditation, designation, authorisation or licensing of a tissue establishment or of a tissue and cell preparation process, if such establishment or process is not compliant with the requirements laid down in the Tissue and Cells Directive.

H(i). Traceability and import and export requirements

The obligations related to the traceability of tissues and cells from the donor to the recipient (and vice versa), and to import and export are set out in Articles 8 and 9 of the Tissue and Cells Directive respectively.

H(ii). Traceability requirements

Article 8 of the Tissue and Cells Directive imposes certain obligations related to the traceability of tissues and cells from the donor to the recipient and vice versa:

• All tissues and cells procured, processed, stored or distributed in the EU must be able to be traced from the donor to the recipient and vice versa. This traceability requirement also applies to all relevant data relating to products and materials coming into contact with these tissues and cells.

• Under a donor identification system, a unique code is assigned to each donation and to each of the products associated with it. This system consists of the "Single European Code", which includes a donation identification sequence and a product identification sequence, as further specified in Annex VII to Commission Directive 2006/86/EC (see Implementing Directives). The Single European Code is provided in an eye-readable format and is preceded by the acronym "SEC". The Single European Code is applicable to all tissues and cells distributed for human application (with some exceptions such as tissues and cells distributed directly for immediate transplantation to the recipient).

• Tissue establishments are required to keep the data necessary to ensure traceability at all stages and for a minimum period of 30 years after clinical use.

H(iii). Import and export of tissue and cells

Article 9 of the Tissue and Cells Directive requires all imports of tissues and cells from third countries, and exports of such products to third countries, to be undertaken by tissue establishments accredited, designated, authorised or licensed for the purpose of those activities. The imported tissues and cells must be able to be traced from the donor to the recipient and vice versa as required by Article 8. Imported tissues and cells need to meet standards of quality and safety equivalent as to the ones set out in the Tissue and Cells Directive.

Article 9(3) provides the exceptional cases in which the competent authority can directly authorise the import or export of specific tissues or cells:

• Tissues and cells distributed directly for immediate transplantation to the recipient.

• Tissues and cells imported into the EU in case of emergency.

Recital 2 to Directive 2015/566/EU, another implementing Directive of the Tissue and Cells Directive (see Implementing Directives), states that a common example of situations where these exceptions are used and competent authorities directly authorise the import of specific tissues and cells is the "import of haematopoietic stem cells from bone marrow, peripheral blood or cord blood which is used in the treatment of a number of life-threatening conditions".

J. Notification of serious adverse events and reactions

Article 11 of the Tissue and Cells Directive requires EU member states to have a system in place to report, investigate, register and transmit information about serious adverse events and reactions (as defined in Article 3(m) and (n) of the Directive) which may influence the quality and safety of tissues and cells and which may be attributed to the procurement, testing, processing, storage and distribution of tissues and cells, as well as any serious adverse reaction observed during or after clinical application which may be linked to the quality and safety of tissues and cells.

The responsible person designated by each tissue establishment is responsible for reporting any serious adverse events and reactions to the competent authorities. This reporting system is currently established at a national level by the competent authorities of each EU member state.

K. Implementing Directives

The following directives have been adopted at EU level to implement specific provisions of the Tissue and Cells Directive:

• Commission Directive 2006/17/EC implementing Directive 2004/23/EC as regards certain technical requirements for the donation, procurement and testing of human tissues and cells, which provides, among other things, the requirements for the procurement of human tissues and cells, selection criteria for donors of tissues and cells and the laboratory tests that are required for donors.

• Commission Directive 2006/86/EC implementing Directive 2004/23/EC as regards traceability requirements, notification of serious adverse reactions and events and certain technical requirements for the coding, processing, preservation, storage and distribution of human tissues and cells, which provides, among others, the requirements for authorisation of tissue establishments and of tissue and cell preparation processes at tissue establishments, the details in relation to the notification of serious adverse events and reactions and the structure and requirements of the Single European Code.

• Commission Directive (EU) 2015/566 implementing Directive 2004/23/EC as regards the procedures for verifying the equivalent standards of quality and safety of imported tissues and cells, which provides detailed provisions concerning the import of tissues and cells.

New SoHO Regulation

On 14 July 2022, the European Commission published a Proposal for a Regulation on standards of quality and safety for substances of human origin intended for human application (SoHO Regulation). Once adopted, the SoHO Regulation will repeal and replace the Tissue and Cells Directive (as well as the Blood Directive (2002/98/EC)). A general two-year transition period is provided in the draft (three years for some provisions), to allow a smooth transition from the Tissue and Cells Directive regime to the new SoHO Regulation. There are other transitional provisions included in the proposed regulation, including a transitional regime for establishments that were already authorised as tissue establishments. The proposed regulation is currently under discussion in parallel by the Council and the European Parliament (see Legislation Tracker, Quality and safety of substances of human origin intended for human application).

Stem cells are explicitly mentioned in recital 6 to the SoHO Regulation.

Ethical considerations

The research and use of human embryonic stem cells is controversial and raises ethical concerns, as this type of stem cell is obtained from early-stage embryos (blastocysts) that are destroyed in the process of extracting the stem cells. These early-stage embryos can be produced through in vitro fertilisation or by transfer of an adult nucleus to an enucleated egg cell or oocyte (somatic cell nuclear transfer (SCNT)). The embryos can potentially be either "spare embryos" (supernumerary embryos) created in the context of infertility treatments to enhance the success rate of IVF, but no longer needed for this purpose, or research embryos, which would be created or the sole purpose of research.

The Convention on Human Rights and Biomedicine (Oviedo Convention) provides in Article 18 (Research on embryos in vitro) that it is up to national law to allow or not research on embryos in vitro, although when such research is allowed, national law shall ensure adequate protection of the embryo. However, in Article 18(2) it clearly provides that "The creation of human embryos for research purposes is prohibited".

There is no harmonisation concerning embryonic stem cells research and use at the EU level and the approaches of EU member states diverge, with the use of human embryonic stem cells being allowed in some countries, with varying requirements, and prohibited in others. As observed by the European Commission in Section 2.2.2 of the Communication on the European Citizens' Initiative "One of us":

"Human embryonic stem cell research in Europe is subject to national laws and regulations which vary from country to country. These range from countries which permit the establishment of human embryonic stem cell lines to those which do not permit this step but allow the importation of embryonic stem cell lines, those which prohibit any form of research on human embryonic stem cells, and those that have no specific legislation on the matter. Currently, human embryonic stem cell research is permitted, subject to controls and conditions in 18 Member States, whilst 3 prohibit it and the rest have no specific legislation."

(See European Commission: Communication from the Commission on the European Citizens' Initiative "One of Us" (28 May 2014).)

The European Group on Ethics in Science and New Technologies (EGE) to the European Commission has issued in November 2000 Opinion no 15 on the "Ethical Aspects of Human Stem Cell Research and Use", which elaborates on the ethical issues of embryonic stem cell research and use (European Commission: European Group on Ethics in Science and New Technologies: Adoption of an opinion on ethical aspects of human stem cell research and use (17 January 2006)).

Regulation (EU) 2021/695 establishing Horizon Europe (the main EU funding programme for research and innovation) provides that "activities intended to create human embryos solely for the purpose of research or for the purpose of stem cell procurement, including by means of somatic cell nuclear transfer" will not be financed (Article 18.1(c)). Moreover, it shows the different approaches of EU member states in this regard by providing that "Research on human stem cells, both adult and embryonic, may be financed depending both on the contents of the scientific proposal and the legal framework of the member states involved. No funding shall be provided within or outside the Union for research activities that are prohibited in all member states. No funding shall be provided in a member state for a research activity which is forbidden in that member state" (Article 18.2). Further details are provided in the Joint Declarations of the European Parliament, Council and European Commission of 12 May 2021 (see OJ 2021 C 185/1)).

In these circumstances, the relevant national provisions and limits must be taken into account when conducting stem cell research in the EU.

Due to the ethical issues surrounding the use of embryonic stem cells, researchers have investigated for ways to reprogramme adult stem cells to give them embryonic stem-cell-like properties. Also adult stem cells themselves, although having lower potency than embryonic stem cells, do not raise the ethical questions associated with the research and use of embryonic stem cells.

Checklist of applicable regulatory framework

The requirements concerning stem cells use in the EU may vary between individual member states as highlighted above. However, there are many provisions adopted at the EU level that must be taken into account. Accordingly, when advising a client using stem cells in the EU, the broad areas that should be considered are the:

• ATMP Regulation. Medicinal products containing or consisting of stem cells fall within the definition of ATMPs when the cells undergo substantial manipulation or when they are used for a different essential function in the recipient and donor. In such cases, the requirements of the ATMP Regulation need to be considered.

• Tissue and Cells Directive. The provisions of the Tissue and Cells Directive and the related national implementing provisions must be followed in what concerns stem cells transplantation, as well as for the donation, procurement and testing of human cells or tissues contained in ATMPs. Monitoring of the adoption procedure of the SoHO Regulation is also advised, as this draft Regulation is expected to replace the Tissue and Cells Directive in the future.

• Clinical Trials Regulation. Provisions concerning clinical trials for medicinal products and the specific guidelines adopted in relation to the studies involving stem cell-based medicinal products must be complied with.

This article was originally published by Practical Law.

Authored by Fabien Roy and Cláudia Mendes Pinto.